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The Migraine-Melatonin Connection
June 23, 2013 by Dr Matthew D. Long
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The Migraine-Melatonin Connection
June 23, 2013 by Dr Matthew D. Long
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The Migraine-Melatonin Connection
June 23, 2013 by Dr Matthew D. Long
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Migraine has always been a problem of chemistry. Although chiropractors have a justifiable interest in the role that the spine might play in stimulating migraine attacks, underneath it all lies a brain with some real chemical challenges. In previous posts we have looked at the instability that characterises migraine illness - a sensitivity that leads us to the concept of 'triggers'. Interestingly, one of the most commonly cited triggering agents happens to be changes in sleep habits. Insufficient sleep, greater than normal sleep, disturbed sleep or alterations to daily bedtime or waking all have been strongly correlated with initiating migraine attacks. Furthermore, symptoms such as daytime sleepiness, poor quality sleep and general fatigue are also common burdens of the disease (1,2).
So how does sleep relate to migraine?
Recent research suggests that some migraineurs might be deficient in melatonin production (3,4). Melatonin (a derivative of serotonin) is manufactured in the pineal gland in response to light and it functions to regulate the sleep-wake cycle. Furthermore, it has been implicated in migraine pathophysiology due to its anti-inflammatory effects, ability to scavenge free-radicals, inhibition of dopamine and release of nitric oxide synthase (5). Melatonin also has a role in membrane stabilisation. With sleep-related factors featuring so prominently in migraineur's lives, it makes sense that we examine the relationship between poor sleep hygiene, melatonin synthesis and the tendency to migraine.
Interestingly, it has been shown that those with impaired sleep showed greater sensitivity in the caudal trigeminal nucleus, leading to superficial allodynia (6). Given the central role of the trigeminal system in headache pain this possibly suggests a mechanism by which upper cervical irritation might further aggravate the situation. Indeed, the upper three cervical levels are innervated by sensory fibres that ultimately terminate in the spinal tract of the trigeminal system, suggesting that this pathway would be more easily brought to threshold in migraineurs suffering from impaired sleep. However, treating upper cervical dysfunction is only one potential avenue of management. It is also apparent that we should seek to reduce background sensitivity in the pain pathways by ensuring adequate melatonin levels are present. Indeed, a study in The Journal of Headache and Pain showed that melatonin treatment decreases trigeminal neuron sensitivity in an animal model of headache (7), which supports a possible role for melatonin in preventing migraine.
But what do human trials tell us?
A study in 2004 showed promising results in migraine prevention when 3 mg of melatonin was taken 1 hour prior to bedtime (8). More recently sleep researchers from the São Paulo Headache Center presented results at the 65th Annual Meeting of the American Academy of Neurology, demonstrating that 3 mg of melatonin was more effective than 25 mg of amitriptyline at reducing monthly migraine frequency (9).
Interestingly, melatonin has also been studied as a treatment for other migraine co-morbidities, such as irritable-bowel syndrome. A paper published in 2005 showed that 88% of subjects reported mild-to-excellent improvement in IBS symptoms (10) when taking supplemental melatonin. This makes sense, given the strong correlation between migraine, abdominal migraine, infantile colic and irritable bowel syndrome (11). Indeed, it has been proposed that colic may well represent a disorder on the migraine spectrum, and it too is characterised by abnormal melatonin regulation. A paper in the European Journal of Pediatrics showed that breast milk, which contains substantial levels of melatonin (unlike formula), might have a role in reducing colic symptoms in babies. The authors wrote that "Exclusively breast-fed infants had a significantly lower incidence of colic attacks, lower severity of irritability attacks and a trend for longer nocturnal sleep duration."
As chiropractors it is important to look at the migraine patient from twin perspectives.
The first is to seek to reduce irritation within the somatosensory system that might act as a trigger. Most commonly this is seen in the upper cervical region, but it can certainly be argued that any source of somatic discomfort can bring the migraineur closer to threshold.
Secondly, we should look at the symptom profile of our patients and try to identify those with a clear relationship between sleep and their headaches. For these individuals it just might be worthwhile doing a 3 month trial of melatonin supplementation in an effort to reduce instability in the trigeminal system.
Something to think about...
Dr Matthew D. Long
BSc (Syd) M.Chiro (Macq)
So how does sleep relate to migraine?
Recent research suggests that some migraineurs might be deficient in melatonin production (3,4). Melatonin (a derivative of serotonin) is manufactured in the pineal gland in response to light and it functions to regulate the sleep-wake cycle. Furthermore, it has been implicated in migraine pathophysiology due to its anti-inflammatory effects, ability to scavenge free-radicals, inhibition of dopamine and release of nitric oxide synthase (5). Melatonin also has a role in membrane stabilisation. With sleep-related factors featuring so prominently in migraineur's lives, it makes sense that we examine the relationship between poor sleep hygiene, melatonin synthesis and the tendency to migraine.
Interestingly, it has been shown that those with impaired sleep showed greater sensitivity in the caudal trigeminal nucleus, leading to superficial allodynia (6). Given the central role of the trigeminal system in headache pain this possibly suggests a mechanism by which upper cervical irritation might further aggravate the situation. Indeed, the upper three cervical levels are innervated by sensory fibres that ultimately terminate in the spinal tract of the trigeminal system, suggesting that this pathway would be more easily brought to threshold in migraineurs suffering from impaired sleep. However, treating upper cervical dysfunction is only one potential avenue of management. It is also apparent that we should seek to reduce background sensitivity in the pain pathways by ensuring adequate melatonin levels are present. Indeed, a study in The Journal of Headache and Pain showed that melatonin treatment decreases trigeminal neuron sensitivity in an animal model of headache (7), which supports a possible role for melatonin in preventing migraine.
But what do human trials tell us?
A study in 2004 showed promising results in migraine prevention when 3 mg of melatonin was taken 1 hour prior to bedtime (8). More recently sleep researchers from the São Paulo Headache Center presented results at the 65th Annual Meeting of the American Academy of Neurology, demonstrating that 3 mg of melatonin was more effective than 25 mg of amitriptyline at reducing monthly migraine frequency (9).
Interestingly, melatonin has also been studied as a treatment for other migraine co-morbidities, such as irritable-bowel syndrome. A paper published in 2005 showed that 88% of subjects reported mild-to-excellent improvement in IBS symptoms (10) when taking supplemental melatonin. This makes sense, given the strong correlation between migraine, abdominal migraine, infantile colic and irritable bowel syndrome (11). Indeed, it has been proposed that colic may well represent a disorder on the migraine spectrum, and it too is characterised by abnormal melatonin regulation. A paper in the European Journal of Pediatrics showed that breast milk, which contains substantial levels of melatonin (unlike formula), might have a role in reducing colic symptoms in babies. The authors wrote that "Exclusively breast-fed infants had a significantly lower incidence of colic attacks, lower severity of irritability attacks and a trend for longer nocturnal sleep duration."
As chiropractors it is important to look at the migraine patient from twin perspectives.
The first is to seek to reduce irritation within the somatosensory system that might act as a trigger. Most commonly this is seen in the upper cervical region, but it can certainly be argued that any source of somatic discomfort can bring the migraineur closer to threshold.
Secondly, we should look at the symptom profile of our patients and try to identify those with a clear relationship between sleep and their headaches. For these individuals it just might be worthwhile doing a 3 month trial of melatonin supplementation in an effort to reduce instability in the trigeminal system.
Something to think about...
Dr Matthew D. Long
BSc (Syd) M.Chiro (Macq)
References:
1. Stronks, D. L., Tulen, J. H. M., Bussmann, J. B. J., Mulder, L. J. M. M., & Passchier, J. (2004). Interictal daily functioning in migraine. Cephalalgia, 24(4), 271–279. doi:10.1111/j.1468-2982.2004.00661.x
2. Seidel, S., Hartl, T., Weber, M., Matterey, S., Paul, A., Riederer, F., et al. (2009). Quality of sleep, fatigue and daytime sleepiness in migraine - a controlled study. Cephalalgia, 29(6), 662–669. doi:10.1111/j.1468-2982.2008.01784.x
3. Masruha, M. R., Lin, J., de Souza Vieira, D. S., Minett, T. S. C., Cipolla-Neto, J., Zukerman, E., et al. (2010). Urinary 6-sulphatoxymelatonin levels are depressed in chronic migraine and several comorbidities. Headache, 50(3), 413–419. doi:10.1111/j.1526-4610.2009.01547.x
4. Bruera, O., Sances, G., Leston, J., Levin, G., Cristina, S., Medina, C., et al. (2008). Plasma melatonin pattern in chronic and episodic headaches. Evaluation during sleep and waking. Functional neurology, 23(2), 77–81.
5. Peres, M. F., Masruha, M. R., Zukerman, E., Moreira-Filho, C. A., & Cavalheiro, E. A. (2006). Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opinion on Investigational Drugs, 15(4), 367–375. doi:10.1517/13543784.15.4.367
6. Lovati, C., D'Amico, D., Bertora, P., Raimondi, E., Rosa, S., Zardoni, M., et al. (2010). Correlation between presence of allodynia and sleep quality in migraineurs. Neurological sciences, 31 Suppl 1, S155–8. doi:10.1007/s10072-010-0317-2
7. Tanuri, F. C., Lima, E., Peres, M. F. P., Cabral, F. R., Graça Naffah-Mazzacoratti, M., Cavalheiro, E. A., et al. (2009). Melatonin treatment decreases c-fos expression in a headache model induced by capsaicin. The journal of headache and pain, 10(2), 105–110. doi:10.1007/s10194-009-0097-3
8. Peres, M. F. P., Zukerman, E., da Cunha Tanuri, F., Moreira, F. R., & Cipolla-Neto, J. (2004). Melatonin, 3 mg, is effective for migraine prevention. Neurology, 63(4), 757.
9. Peres M, Gonçalves AL. Double-blind, placebo controlled, randomized clinical trial comparing melatonin 3 mg, amitriptyline 25 mg, and placebo for migraine prevention. Program and abstracts of the American Academy of Neurology 65th Annual Meeting, March 16-23, 2013; San Diego, California. Abstract S40.005.
10. Lu, WZ, Gwee, KA, Moochhalla, S, Ho, KY (2005). Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Alimentary Pharmacology and Therapeutics, 22(10), 927–934. doi:10.1111/j.1365-2036.2005.02673.x
11. Romanello, S., Spiri, D., Marcuzzi, E., Zanin, A., Boizeau, P., Riviere, S., et al. (2013). Association between childhood migraine and history of infantile colic. JAMA, 309(15), 1607–1612. doi:10.1001/jama.2013.747
12. Cohen Engler, A., Hadash, A., Shehadeh, N., & Pillar, G. (2011). Breastfeeding may improve nocturnal sleep and reduce infantile colic: Potential role of breast milk melatonin. European journal of pediatrics, 171(4), 729–732. doi:10.1007/s00431-011-1659-3
1. Stronks, D. L., Tulen, J. H. M., Bussmann, J. B. J., Mulder, L. J. M. M., & Passchier, J. (2004). Interictal daily functioning in migraine. Cephalalgia, 24(4), 271–279. doi:10.1111/j.1468-2982.2004.00661.x
2. Seidel, S., Hartl, T., Weber, M., Matterey, S., Paul, A., Riederer, F., et al. (2009). Quality of sleep, fatigue and daytime sleepiness in migraine - a controlled study. Cephalalgia, 29(6), 662–669. doi:10.1111/j.1468-2982.2008.01784.x
3. Masruha, M. R., Lin, J., de Souza Vieira, D. S., Minett, T. S. C., Cipolla-Neto, J., Zukerman, E., et al. (2010). Urinary 6-sulphatoxymelatonin levels are depressed in chronic migraine and several comorbidities. Headache, 50(3), 413–419. doi:10.1111/j.1526-4610.2009.01547.x
4. Bruera, O., Sances, G., Leston, J., Levin, G., Cristina, S., Medina, C., et al. (2008). Plasma melatonin pattern in chronic and episodic headaches. Evaluation during sleep and waking. Functional neurology, 23(2), 77–81.
5. Peres, M. F., Masruha, M. R., Zukerman, E., Moreira-Filho, C. A., & Cavalheiro, E. A. (2006). Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opinion on Investigational Drugs, 15(4), 367–375. doi:10.1517/13543784.15.4.367
6. Lovati, C., D'Amico, D., Bertora, P., Raimondi, E., Rosa, S., Zardoni, M., et al. (2010). Correlation between presence of allodynia and sleep quality in migraineurs. Neurological sciences, 31 Suppl 1, S155–8. doi:10.1007/s10072-010-0317-2
7. Tanuri, F. C., Lima, E., Peres, M. F. P., Cabral, F. R., Graça Naffah-Mazzacoratti, M., Cavalheiro, E. A., et al. (2009). Melatonin treatment decreases c-fos expression in a headache model induced by capsaicin. The journal of headache and pain, 10(2), 105–110. doi:10.1007/s10194-009-0097-3
8. Peres, M. F. P., Zukerman, E., da Cunha Tanuri, F., Moreira, F. R., & Cipolla-Neto, J. (2004). Melatonin, 3 mg, is effective for migraine prevention. Neurology, 63(4), 757.
9. Peres M, Gonçalves AL. Double-blind, placebo controlled, randomized clinical trial comparing melatonin 3 mg, amitriptyline 25 mg, and placebo for migraine prevention. Program and abstracts of the American Academy of Neurology 65th Annual Meeting, March 16-23, 2013; San Diego, California. Abstract S40.005.
10. Lu, WZ, Gwee, KA, Moochhalla, S, Ho, KY (2005). Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Alimentary Pharmacology and Therapeutics, 22(10), 927–934. doi:10.1111/j.1365-2036.2005.02673.x
11. Romanello, S., Spiri, D., Marcuzzi, E., Zanin, A., Boizeau, P., Riviere, S., et al. (2013). Association between childhood migraine and history of infantile colic. JAMA, 309(15), 1607–1612. doi:10.1001/jama.2013.747
12. Cohen Engler, A., Hadash, A., Shehadeh, N., & Pillar, G. (2011). Breastfeeding may improve nocturnal sleep and reduce infantile colic: Potential role of breast milk melatonin. European journal of pediatrics, 171(4), 729–732. doi:10.1007/s00431-011-1659-3