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nous opiate dynorphin. Dynorphin fibers were also found in most
brain regions containing orexin fibers, suggesting a close interaction between the orexin and opiate systems.3 Indeed, a recent
study showed that another behavioral effect of orexins, increase in
food intake, is opioid-mediated and can be attenuated by naloxone, an opiate antagonist.7
In addition to the opioidergic mechanism, the monoaminergic
action of tramadol has to be considered in its anticataplectic activity. Drugs that either activate cholinergic tone or decrease monoaminergic activity promote cataplexy, whereas anticholinergic and
monoaminergic enhancers reduce the symptoms.6 Moreover, an
interaction between the opioid and monoaminergic mechanisms is
possible, because monoaminergic nuclei— e.g., the locus coeruleus— contain endogenous opiates.3
It should be noted that in the cases presented withdrawal from
tranylcypromine, an anticataplectic drug, might be a confounding
factor. Furthermore, tolerance development and addiction are possible risks of tramadol treatment, which led us to switch both
patients to reboxetine despite the good response to tramadol.
Further systematic studies investigating the effects of opiates
and the pathophysiologic role of opioidergic neurotransmission in
narcolepsy are warranted. This might result in new therapeutic
options for this disabling disorder.
From the Max Planck Institute of Psychiatry, Munich, Germany.
Received February 18, 2003. Accepted in final form May 12, 2003.
Address correspondence and reprint requests to Dr. Adam Wichniak, Institute of Psychiatry and Neurology, Third Department of Psychiatry, 9
Sobieskiego, 02-957 Warsaw, Poland; e-mail: email@example.com
Copyright © 2003 by AAN Enterprises, Inc.
1. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset
narcolepsy and a generalized absence of hypocretin peptides in human
narcoleptic brains. Nat Med 2000;6:991–997.
2. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000;27:469 – 474.
3. Chou TC, Lee CE, Lu J, et al. Orexin (hypocretin) neurons contain
dynorphin. J Neurosci 2001;21:RC168.
4. Raffa RB, Friderichs E, Reimann W, et al. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol,
an “atypical” opioid analgesic. J Pharmacol Exp Ther 1992;260:275–285.
5. Fry JM, Pressman MR, DiPhillipo MA, Forst-Paulus M. Treatment of
narcolepsy with codeine. Sleep 1986;9:269 –274.
6. Nishino S, Mignot E. Pharmacological aspects of human and canine
narcolepsy. Prog Neurobiol 1997;52:27–78.
7. Clegg DJ, Air EL, Woods SC, Seeley RJ. Eating elicited by orexin-a, but
not melanin-concentrating hormone, is opioid mediated. Endocrinology
Melatonin as treatment for idiopathic
Todd D. Rozen, MD
Idiopathic stabbing headache, also termed ice pick or jab and jolts
headache, consists of short-lasting stabs of sudden, severe pain
lasting typically for less than 1 second. The pain can occur anywhere on the head but normally involves the orbit, temple, or
parietal region.1 Spikes of pain may occur once a day or up to 50
times per day at irregular or regular intervals. Attacks may occur
daily or just once in a year. The individual stab of pain is so severe
and so sudden in onset that a sufferer will immediately stop any
activity and grimace. With chronic daily idiopathic stabbing headache there can develop a fear of pending attacks. Idiopathic stabbing headache is associated with migraine, cluster, and
hemicrania continua.2 Each spike of pain cannot be treated individually because of its short duration but if the pain spikes are
occurring multiple times per day a preventive medication is required. Ice pick headaches are considered one of the
indomethacin-responsive headache syndromes along with hemicrania continua and chronic paroxysmal hemicrania. These are
unique headache conditions defined by their complete responsiveness to indomethacin and relative refractoriness to any other therapy. Why indomethacin is effective is unknown, but it must exert
its effects differently than other nonsteroidal anti-inflammatory
drugs. Unique properties of indomethacin include its ability to
lower cerebral blood flow and decrease CSF pressure.3 Many individuals cannot tolerate long-term indomethacin therapy (gastrointestinal or renal side effects) or have contraindications to using
indomethacin such as being on anticoagulation. In these individuals there are few if any effective alternative treatments.
Melatonin is a pineal hormone and marker of circadian function. Its chemical structure is very similar to that of indomethacin4 (figure). Melatonin has recently been shown to have
antinociceptive and anti-inflammatory properties in animal studies and enhances the anti-inflammatory effects of indomethacin in
these same animal models.5 Because of the structural similarities
to indomethacin and possible pain relieving properties, melatonin
was given to three patients with idiopathic stabbing headache to
Patient 1. A 38-year-old woman had a 1-year history of multiple daily repetitive short-lasting head pains that would occur in
her temples and top of her head. Each spike of pain lasted 1 to 2
seconds. There were no associated autonomic symptoms. She averaged 10 to 18 pain spikes per day. She had a history of episodic
migraine. Indomethacin was started but the patient could not
tolerate doses above 125 mg per day. Indomethacin reduced attack
frequency by 25%. Melatonin was initiated as sole therapy and at
Figure. Chemical structures of indomethacin and melatonin. A methoxy indole nucleus is present in both. Reprinted with permission from Blackwell Publishing (Peres
MP, Stiles MA, Oshinsky M, Rozen TD. Remitting form of
hemicrania continua with seasonal pattern. Headache
a dose of 12 mg at bedtime she became pain free and remained so
through a 2-month follow-up.
Patient 2. A 23-year-old woman had a 2-year history of shortlasting very intense spikes of pain, each lasting several seconds
September (2 of 2) 2003
and occurring at least two times per day, mostly in the temples.
She was taking warfarin for a deep vein thrombosis so indomethacin could not be initiated. Melatonin 6 mg was started and
within several hours the stabbing pains ceased with only transient breakthroughs. She remained on melatonin for 6 days and it
was then discontinued. The stabs returned at a frequency of one to
two spikes per day, increasing to five to six per day around menses. Melatonin 9 mg was initiated as an evening dose and her
stabs of pain were alleviated within 24 hours. She remains painfree through a 4-month follow-up.
Patient 3. A 52-year-old woman had a history of ice pick
headaches occurring multiple times per day for many years. The
short-lasting pains would involve the left temporal region. On
indomethacin SR 75 mg two times per day she was pain-free. The
stabbing headaches would always return if the indomethacin was
stopped. She was switched to melatonin 3 mg alone at bedtime
and has remained pain free with no recurrence through a 2-month
Discussion. Idiopathic stabbing headache is one of the
indomethacin-responsive headache syndromes. For individuals
who have a contraindication to indomethacin, very few alternatives are available. Recently, celecoxib has shown efficacy in three
patients, but the COX-2 inhibitors have many of the same patient
contraindications as indomethacin.2 Melatonin appears to be an
effective alternative treatment for idiopathic stabbing headache.
Melatonin clearly has a more favorable side effect profile than
indomethacin. A recommended dosing strategy is starting with a
bedtime dose of 3 mg and increasing by 3 mg every 3 to 4 nights
until pain relief, with 24 mg as an upper dose limit. The largest
and safest dose of melatonin allowed in humans is unknown.
Melatonin has shown efficacy in other headache conditions such
as cluster6 and headache in delayed sleep phase syndrome.7
Pilot tolerability and effectiveness study of
levetiracetam for postherpetic neuralgia
sodium channel blockers were discontinued 2 weeks earlier, but
stable use at prestudy doses of nonsteroidal anti-inflammatory
drugs (NSAID), antidepressants, and opioids was allowed. Levetiracetam was started at 500 mg/day and titrated upward (if tolerated) by 500 mg/week to a maximum of 1,500 mg BID. Visits 3 to 6
took place after 2, 4, 8, and 12 weeks of study medication.
Results. The four women and six men had PHN pain in the
cervical or thoracic dermatomes for an average of 4 years (see
table E-1 in the supplementary material on the Neurology Web
site; go to www.neurology.org). All 10 had previously tried gabapentin and NSAID, and 9 of 10 had tried opioids. During levetiracetam treatment, three subjects continued on opioids. Two subjects
continued on selective serotonin reuptake inhibitor antidepressants for depression. Three subjects were considered levetiracetam responders and three as partial responders. Four subjects
were treatment failures who reported no relief of pain and exited
before study completion. Maximum doses ranged from 1,500 to
3,000 mg/day (mean 2,200 mg/day).
The three treatment responders had less pain (67 to 75% improvement), improved sleep, less allodynia (reduced 61 to 64%),
and shrinkage in their areas of pain and allodynia by 40 to 80%.
PGIC ratings were “much improved” or “very much improved.”
The three partial responders also had less pain (11 to 50% improvement) and improved sleep. Subject 1 exhibited reduced allodynia severity without change in pain area; Subjects 5 and 8 had
slightly increased allodynia in a pain area that was 50% smaller.
PGIC ratings were “improved.” The four treatment failures took
levetiracetam for ⬍30 days. Pain intensity and allodynia severity
were either worse or unimproved, but the areas of pain and allodynia were unchanged in size. PGIC ratings were “unchanged” to
“very much worse.”
Common adverse events were mild to moderate drowsiness
and lack of energy. Subject 2 presented with marked hypertension
(190/109 mm Hg) of uncertain origin on treatment day 27. Levetiracetam was withdrawn and oral antihypertensive medication
Discussion. Considering the duration of pain and its resistance to treatment, a partial or full response to levetiracetam in 6
of 10 subjects is encouraging. All 10 had received multiple prior
treatments for PHN, including gabapentin. Drowsiness and lack
of energy were usually manageable by dose reduction, although
dose reduction usually led to increased pain. Hypertension has not
been observed in prior studies of levetiracetam.7
Observational studies of PHN patients have shown stable allo-
Michael C. Rowbotham, MD; Nira S. Manville, MS, RN; and
Junlong Ren, MD
Postherpetic neuralgia (PHN) is defined as pain persisting for ⬎3
months after acute herpes zoster (“shingles”).1,2 Tricyclic antidepressants, opioids, gabapentin, and the lidocaine patch have been
proven effective, but many patients fail to achieve relief.2 Levetiracetam (Keppra; UCB Pharma, Lake Smyrna, GA), approved in
the USA as adjunctive therapy for partial-onset seizures, has an
incompletely characterized mechanism of action that includes inhibition of N-type calcium channels and modulation of
␥-aminobutyrate and glycine receptors.3-5 Levetiracetam is active
in animal models of neuropathic pain.6 There are no case reports
or prospective studies of levetiracetam for chronic neuropathic
Methods. Ten subjects in stable health without significant
pain besides PHN were recruited for this prospective open-label
tolerability and effectiveness study of levetiracetam, approved by
the University of California San Francisco Committee on Human
Research. A 1-week baseline period was followed by a 12-week
treatment period. Subjects were seen a total of six times.
Diary measures consisted of daily diary pain rating (0 to 10
Likert scale) of average pain over the previous 24 hours, interfering effect of PHN pain on sleep (0 to 10 Likert scale), and concomitant medication use. Visit measures included average pain over
previous 7 days (written 100-mm Visual Analog Scale [VAS]),
current pain (hand-held 100-mm VAS), and severity of allodynia
from three foam-brush strokes in the area of greatest pain (handheld 100-mm VAS). On the first and last visits, photographs of the
areas of greatest pain and allodynia were taken and routine hematology/chemistry tests performed. On the final visit, the Patient
Global Impression of Change (PGIC; seven categories, from very
much improved to very much worse) was conducted.
At Visit 2, subjects began study medication if baseline period
pain exceeded 3 of 10. Muscle relaxants, anticonvulsants, and
Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Contents for the September 23 issue to find the title link for this article.
September (2 of 2) 2003
From the Michigan Head-Pain and Neurological Institute, Ann Arbor.
Received March 31, 2003. Accepted in final form May 12, 2003.
Address correspondence and reprint requests to Dr. Todd D. Rozen, Michigan Head-Pain and Neurological Institute, 3120 Professional Drive, Ann
Arbor, MI 48104; e-mail: firstname.lastname@example.org
Copyright © 2003 by AAN Enterprises, Inc.
1. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial
neuralgias and facial pain. Cephalalgia 1988;8(suppl 7):1–96.
2. Piovesan EJ, Zukerman E, Kowacs PA, Werneck LC. COX-2 inhibitor for
the treatment of idiopathic stabbing headache secondary to cerebrovascular diseases. Cephalalgia 2002;22:197–200.
3. Dodick DW. Indomethacin responsive headache syndromes: a hypothesis
on the mechanisms(s) underlying the efficacy of indomethacin in these
disorders. Neurology 1999;52:A210. Abstract.
4. Peres MP, Stiles MA, Oshinsky M, Rozen TD. Remitting form of hemicrania continua with seasonal pattern. Headache 2001;41:592–594.
5. El-Shenawy SM, Abdel-Salam OM, Baiuomy AR, El-Batran S, Arbid MS.
Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Pharmacol Res 2002;46:235–243.
6. Leone M, D’Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin
versus placebo in the prophylaxis of cluster headache: a double-blind
pilot study with parallel groups. Cephalalgia 1996;16:494 – 496.
7. 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.