ISSN 0017-8748 doi: 10.1111/head.12217 Published by Wiley Periodicals, Inc.
Headache © 2014 American Headache Society
Comment Observation and Rebuttals Headache and Sleep: Also Assess Circadian Rhythm Sleep Disorders
enous melatonin rhythm is a rhythm driven by the central circadian pacemaker, and the timing of the onset of melatonin secretion in the evening (dim light melatonin onset [DLMO]) is strongly associated with the timing of sleep in normal individuals,5-7 making evaluation of DLMO a useful marker of the timing of the circadian system8 and thus a useful diagnostic tool for diagnosing CRSD. DLMO is used to determine whether abnormal sleep timing is associated with abnormal circadian rhythm timing (and thus DLMO can confirm the presence of a CRSD). For example, in ASPD, sleep timing is advanced to an earlier than desired time, and DLMO would be expected to also be advanced, while in DSPS, sleep timing is delayed to a later than desired time. DLMO is also a potentially valuable tool in the differential diagnosis of sleep disorders that are typically thought to have a noncircadian origin, eg, psychophysiological insomnia,3,9-12 because clinical symptoms can sometimes mimic CRSD symptoms. The headache centre of the Gelderse Vallei Hospital works closely together with the sleep center of that hospital and is the Dutch national referral center for headache patients with insomnia. As part of routine examination, DLMO in these patients is measured from saliva samples collected by the patients in their home, as described elsewhere.13 Headache patients with late DLMO are typically treated with melatonin, 1-5 mg, administered 5 hours before DLMO, but not earlier than 19:00 hours. Patients complete an internet questionnaire just before their
In their excellent review on headache and sleep, Freedom and Evans1 clearly demonstrate the importance of evaluating sleep in headache patients. They stress the importance of taking a good sleep history, and, if necessary, to use sleep questionnaires and (ambulatory) polysomnography to diagnose frequently occurring and easily treatable sleep disorders, such as sleep apnea syndrome and restless legs. However, they did not mention including evaluation and treatment of circadian rhythm sleep disorders (CRSD). Evaluation of headache patients for CRSD is especially warranted given the link between mutations in CK1δ (a component of the molecular circadian clock) and migraine.2 CRSD are a group of frequently occurring sleepwake disorders in which patients have problems with the timing of sleep because of a misalignment between the timing of the internal biological clock and the external 24-hour clock.3 When diagnosed adequately, CRSD can be treated relatively easily, but when untreated, the patient is unable to sleep when sleep is expected or needed. Currently, 7 distinct CRSD are recognized in the International Classification of Sleep Disorders.4 These are (1) time zone change (jet lag) syndrome, (2) shift work sleep disorder, (3) irregular sleep-wake pattern, (4) delayed sleep-phase disorder (DSPS), (5) advanced sleepphase disorder (ASPD), (6) non-24-hour sleep-wake disorder, and (7) CRSD not otherwise stated (NOS). Several types of assessments are typically recommended to diagnose CRSD, ie, sleep logs and diaries, questionnaires, actigraphy, polysomnography, and circadian phase (timing) markers. The 24-hour endog-
Conflict of Interest: The authors report no conflict of interest.
175
176
January 2014 Table.—Headache Symptoms in Patients Treated With Melatonin
n
%
Headache before melatonin treatment No headache during melatonin treatment Considerable decrease of headache during melatonin treatment Total
328 109 149
33.2% 45.4%
258
78.6%
No headache before melatonin treatment Headache during melatonin treatment
676 93
13.8%
Boldface emphasizes the results.
first visit to the headache clinic and again 6 weeks after starting the melatonin treatment. This questionnaire evaluates headache symptoms and other potential side effects from the melatonin. The same questionnaire is also completed by patients presenting to our sleep clinic with insomnia symptoms (but without headache) who are treated with melatonin. We found that headache disappeared or considerably diminished during melatonin treatment in 78.6% of 328 patients with headache and CRSD. However, headache occurred during melatonin treatment in 13.8% of 676 patients with CRSD without prior headache (see the Table). The high percentage of patients with decreases of their headache during melatonin treatment supports a hypothesized causative relationship with melatonin treatment.14 Several potential mechanisms have been suggested to explain how melatonin reduces headache, including anti-inflammatory effects, toxic free radical scavenging, reduction of proinflammatory cytokine upregulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilization, gamma-aminobutyric acid GABA and opioid analgesia potentiation, glutamate neurotoxicity protection, neurovascular regulation, 5-hydroxytryptamine modulation, and the similarity in chemical structure to indometacin.15 An alternative explanation is that melatonin synchronizes the patients’ biological clock to their lifestyle, resulting in better sleep and less psychological stress, which in turn decrease headache.14
Because of these findings, we suggest that in addition to evaluating sleep in headache patients as advocated by Freedom and Evans,1 such patients should also be evaluated for potential CRSD using salivary DLMO. Jörgen Rovers, MD; Marcel Smits, MD, PhD; Jeanne F. Duffy, MBA, PhD From the Headache Clinic, Gelderse Vallei Hospital, Ede, The Netherlands (J. Rovers, M. Smits); Centre for Sleep-Wake Disturbances and Chronobiology, Gelderse Vallei Hospital, Ede, The Netherlands (M. Smits); Division of Sleep Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA (J.F. Duffy).
REFERENCES 1. Freedom T, Evans RW. Headache and sleep. Headache. 2013; Jul 12. doi: 10.1111/head.12178. [Epub ahead of print]. 2. Brennan KC, Bates EA, Shapiro RE, et al. Casein kinase iδ mutations in familial migraine and advanced sleep phase. Sci Transl Med. 2013;5: 183ra56,1-183ra56,11. 3. Dagan Y. Circadian rhythm sleep disorders (CRSD). Sleep Med Rev. 2002;6:45-55. 4. International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. Chicago, IL: American Academy of Sleep Medicine; 2001. 5. Lewy A. Clinical implications of the melatonin phase response curve. J Clin Endocrinol Metab. 2010;95:3158-3160. 6. Sack RL, Auckley D, Auger RR, et al. Circadian rhythm sleep disorders: Part I, basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review. Sleep. 2007;30: 1460-1483. 7. Sack RL, Auckley D, Auger RR, et al. Circadian rhythm sleep disorders: Part II, advanced sleep phase disorder, delayed sleep phase disorder, freerunning disorder, and irregular sleep-wake rhythm. An American Academy of Sleep Medicine review. Sleep. 2007;30:1484-1501. 8. Lewy AJ, Cutler NL, Sack RL. The endogenous melatonin profile as a marker for circadian phase position. J Biol Rhythms. 1999;14:227-236. 9. Papaioannou I, Twigg GL, Kemp M, et al. Melatonin concentration as a marker of the circadian phase in
Headache patients with obstructive sleep apnoea. Sleep Med. 2012;13:167-171. 10. Morgenthaler TI, Lee-Chiong T, Alessi C, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007;30:1445-1459. 11. Srinivasan V, Smits M, Spence W, et al. Melatonin in mood disorders. World J Biol Psychiatry. 2006;7:138151. 12. van den Heuvel CJ, Lushington K. Chronobiology and insomnia: Pathophysiology and treatment of circadian rhythm sleep disorders. Expert Rev Neurother. 2002;2:249-260.
177 13. Keijzer H, Smits MG, Peeters T, Looman CW, Endenburg SC, Gunnewiek JM. Evaluation of salivary melatonin measurements for dim light melatonin onset calculations in patients with possible sleep-wake rhythm disorders. Clin Chim Acta. 2011;412:1616-1620. 14. Nagtegaal JE, Smits MG, Swart AC, Kerkhof GA, van der Meer YG. Melatonin-responsive headache in delayed sleep phase syndrome: Preliminary observations. Headache. 1998;38:303-307. 15. Peres MF, Masruha MR, Zukerman E, MoreiraFilho CA, Cavalheiro EA. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opin Investig Drugs. 2006;15:367-375.
Headache © 2014 American Headache Society
Comment Observation and Rebuttals Headache and Sleep: Also Assess Circadian Rhythm Sleep Disorders
enous melatonin rhythm is a rhythm driven by the central circadian pacemaker, and the timing of the onset of melatonin secretion in the evening (dim light melatonin onset [DLMO]) is strongly associated with the timing of sleep in normal individuals,5-7 making evaluation of DLMO a useful marker of the timing of the circadian system8 and thus a useful diagnostic tool for diagnosing CRSD. DLMO is used to determine whether abnormal sleep timing is associated with abnormal circadian rhythm timing (and thus DLMO can confirm the presence of a CRSD). For example, in ASPD, sleep timing is advanced to an earlier than desired time, and DLMO would be expected to also be advanced, while in DSPS, sleep timing is delayed to a later than desired time. DLMO is also a potentially valuable tool in the differential diagnosis of sleep disorders that are typically thought to have a noncircadian origin, eg, psychophysiological insomnia,3,9-12 because clinical symptoms can sometimes mimic CRSD symptoms. The headache centre of the Gelderse Vallei Hospital works closely together with the sleep center of that hospital and is the Dutch national referral center for headache patients with insomnia. As part of routine examination, DLMO in these patients is measured from saliva samples collected by the patients in their home, as described elsewhere.13 Headache patients with late DLMO are typically treated with melatonin, 1-5 mg, administered 5 hours before DLMO, but not earlier than 19:00 hours. Patients complete an internet questionnaire just before their
In their excellent review on headache and sleep, Freedom and Evans1 clearly demonstrate the importance of evaluating sleep in headache patients. They stress the importance of taking a good sleep history, and, if necessary, to use sleep questionnaires and (ambulatory) polysomnography to diagnose frequently occurring and easily treatable sleep disorders, such as sleep apnea syndrome and restless legs. However, they did not mention including evaluation and treatment of circadian rhythm sleep disorders (CRSD). Evaluation of headache patients for CRSD is especially warranted given the link between mutations in CK1δ (a component of the molecular circadian clock) and migraine.2 CRSD are a group of frequently occurring sleepwake disorders in which patients have problems with the timing of sleep because of a misalignment between the timing of the internal biological clock and the external 24-hour clock.3 When diagnosed adequately, CRSD can be treated relatively easily, but when untreated, the patient is unable to sleep when sleep is expected or needed. Currently, 7 distinct CRSD are recognized in the International Classification of Sleep Disorders.4 These are (1) time zone change (jet lag) syndrome, (2) shift work sleep disorder, (3) irregular sleep-wake pattern, (4) delayed sleep-phase disorder (DSPS), (5) advanced sleepphase disorder (ASPD), (6) non-24-hour sleep-wake disorder, and (7) CRSD not otherwise stated (NOS). Several types of assessments are typically recommended to diagnose CRSD, ie, sleep logs and diaries, questionnaires, actigraphy, polysomnography, and circadian phase (timing) markers. The 24-hour endog-
Conflict of Interest: The authors report no conflict of interest.
175
176
January 2014 Table.—Headache Symptoms in Patients Treated With Melatonin
n
%
Headache before melatonin treatment No headache during melatonin treatment Considerable decrease of headache during melatonin treatment Total
328 109 149
33.2% 45.4%
258
78.6%
No headache before melatonin treatment Headache during melatonin treatment
676 93
13.8%
Boldface emphasizes the results.
first visit to the headache clinic and again 6 weeks after starting the melatonin treatment. This questionnaire evaluates headache symptoms and other potential side effects from the melatonin. The same questionnaire is also completed by patients presenting to our sleep clinic with insomnia symptoms (but without headache) who are treated with melatonin. We found that headache disappeared or considerably diminished during melatonin treatment in 78.6% of 328 patients with headache and CRSD. However, headache occurred during melatonin treatment in 13.8% of 676 patients with CRSD without prior headache (see the Table). The high percentage of patients with decreases of their headache during melatonin treatment supports a hypothesized causative relationship with melatonin treatment.14 Several potential mechanisms have been suggested to explain how melatonin reduces headache, including anti-inflammatory effects, toxic free radical scavenging, reduction of proinflammatory cytokine upregulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilization, gamma-aminobutyric acid GABA and opioid analgesia potentiation, glutamate neurotoxicity protection, neurovascular regulation, 5-hydroxytryptamine modulation, and the similarity in chemical structure to indometacin.15 An alternative explanation is that melatonin synchronizes the patients’ biological clock to their lifestyle, resulting in better sleep and less psychological stress, which in turn decrease headache.14
Because of these findings, we suggest that in addition to evaluating sleep in headache patients as advocated by Freedom and Evans,1 such patients should also be evaluated for potential CRSD using salivary DLMO. Jörgen Rovers, MD; Marcel Smits, MD, PhD; Jeanne F. Duffy, MBA, PhD From the Headache Clinic, Gelderse Vallei Hospital, Ede, The Netherlands (J. Rovers, M. Smits); Centre for Sleep-Wake Disturbances and Chronobiology, Gelderse Vallei Hospital, Ede, The Netherlands (M. Smits); Division of Sleep Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA (J.F. Duffy).
REFERENCES 1. Freedom T, Evans RW. Headache and sleep. Headache. 2013; Jul 12. doi: 10.1111/head.12178. [Epub ahead of print]. 2. Brennan KC, Bates EA, Shapiro RE, et al. Casein kinase iδ mutations in familial migraine and advanced sleep phase. Sci Transl Med. 2013;5: 183ra56,1-183ra56,11. 3. Dagan Y. Circadian rhythm sleep disorders (CRSD). Sleep Med Rev. 2002;6:45-55. 4. International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. Chicago, IL: American Academy of Sleep Medicine; 2001. 5. Lewy A. Clinical implications of the melatonin phase response curve. J Clin Endocrinol Metab. 2010;95:3158-3160. 6. Sack RL, Auckley D, Auger RR, et al. Circadian rhythm sleep disorders: Part I, basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review. Sleep. 2007;30: 1460-1483. 7. Sack RL, Auckley D, Auger RR, et al. Circadian rhythm sleep disorders: Part II, advanced sleep phase disorder, delayed sleep phase disorder, freerunning disorder, and irregular sleep-wake rhythm. An American Academy of Sleep Medicine review. Sleep. 2007;30:1484-1501. 8. Lewy AJ, Cutler NL, Sack RL. The endogenous melatonin profile as a marker for circadian phase position. J Biol Rhythms. 1999;14:227-236. 9. Papaioannou I, Twigg GL, Kemp M, et al. Melatonin concentration as a marker of the circadian phase in
Headache patients with obstructive sleep apnoea. Sleep Med. 2012;13:167-171. 10. Morgenthaler TI, Lee-Chiong T, Alessi C, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007;30:1445-1459. 11. Srinivasan V, Smits M, Spence W, et al. Melatonin in mood disorders. World J Biol Psychiatry. 2006;7:138151. 12. van den Heuvel CJ, Lushington K. Chronobiology and insomnia: Pathophysiology and treatment of circadian rhythm sleep disorders. Expert Rev Neurother. 2002;2:249-260.
177 13. Keijzer H, Smits MG, Peeters T, Looman CW, Endenburg SC, Gunnewiek JM. Evaluation of salivary melatonin measurements for dim light melatonin onset calculations in patients with possible sleep-wake rhythm disorders. Clin Chim Acta. 2011;412:1616-1620. 14. Nagtegaal JE, Smits MG, Swart AC, Kerkhof GA, van der Meer YG. Melatonin-responsive headache in delayed sleep phase syndrome: Preliminary observations. Headache. 1998;38:303-307. 15. Peres MF, Masruha MR, Zukerman E, MoreiraFilho CA, Cavalheiro EA. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opin Investig Drugs. 2006;15:367-375.
