Increased activity of serotonin uptake in platelets in medication overuse headache following regular intake of analgesics and triptans
© Springer-Verlag 2008
Received: 1 December 2007
Accepted: 18 January 2008
Published: 11 March 2008
The Erratum to this article has been published in The Journal of Headache and Pain 2008 9:37
We investigated the effect of chronic administration of different pain medications on the activity of the serotonin transporter (SERT) in patients with medication overuse headache (MOH). We measured the kinetic of platelet 5-HT uptake (maximal velocity, Vmax and the Michaelis–Menten constant, Km) in patients with overuse of triptans (tMOH, n = 15) or analgesics (aMOH, n = 14) before and after drug withdrawal, as well as in headache-free healthy subjects (n = 15) and patients with episodic migraine (EM, n = 16). Vmax was increased similarly in both, tMOH and aMOH compared to healthy subjects and patients with EM and normalized after withdrawal in parallel to the improvement of headache frequency. Average Km was similar in all groups at baseline and not affected by the withdrawal. The data demonstrate a transient increase of SERT activity in patients with analgesic and triptan induced MOH but do not allow to differentiate whether the increase of serotonin uptake is caused by regular intake of analgesics or triptans or is a consequence of frequent headache attacks.
Transformation of episodic migraine to chronic daily or near-daily headache caused by an excessive use of medication taken for symptomatic headache relief is a well known phenomenon. Medication overuse headache (MOH) has developed into the third most common type of headache after tension-type headache (TTH) and migraine . All anti-headache drugs, such as triptans, analgesics, ergots, and opioids can induce MOH.
Clinically, triptan induced chronic migraine differs from chronic migraine following the overuse of analgesics. Overuse of triptans can cause migraine-like daily headaches (as opposed to analgesics that usually cause tension type like daily headache) but also might solely cause a considerable increase in migraine attack frequency without necessarily causing daily headache. Additionally, the overuse of triptans leads to MOH faster and with lower dosages compared to ergots or analgesics, while it is also characterized by shorter and easier withdrawal with lower relapse rates compared to analgesics overuse .
Despite a growing scientific interest, the pathophysiological mechanisms associated with the development of MOH are still insufficiently understood. One of the key pathophysiological mechanisms could involve the alteration of the serotonin metabolism. Abnormalities of 5-HT turnover have been demonstrated in patients with chronic headache due to analgesic overuse [3–6]. It is not known, however, whether the overuse of triptans leads to the alteration of the serotonin metabolism as well.
In the present study we aimed to investigate the serotonin metabolism in patients with triptan- and analgesics induced MOH. We therefore studied the functional properties of the platelet serotonin transporter (SERT) in patients with triptan MOH (tMOH) and analgesic MOH (aMOH) and compared it to patients with episodic migraine and headache-free healthy subjects. We used the platelet model for several reasons: SERT in all tissues and organs, including brain, gut and platelets are encoded by the same gene and to date, there is no definitive evidence for the existence of a distinct tissue-specific SERT . Therefore, platelets have been widely used as a practical, easily accessible and reproducible peripheral model for the study of SERT functions and its alterations. A recent study indicated that there is a relationship between the SERT measures in platelets and in the human midbrain .
Given the prior reports, we hypothesized that overuse of triptans and analgesics may cause alterations in SERT function, which would be reversible after drug withdrawal. We moreover aimed to find differences between patients overusing analgesics and patients overusing triptans.
The study protocol was approved by the ethics committee of the University of Duisburg-Essen. Subjects were recruited from our headache clinic; healthy controls consisted of University of Duisburg-Essen medical students and faculty members. All participants gave their written informed consent according to the Declaration of Helsinki. All participants received a standard interview and neurological examination. Inclusion criteria were: age between 18 and 65 years and primary migraine type of headache according to the IHS criteria . Exclusion criteria were suspicion for symptomatic headache, primary tension-type headache, co-morbid depression (>18 according to Beck depression scale), overuse of two or more different types of acute headache drugs simultaneously and previous or actual treatment with antidepressants. Patients with chronic migraine with probable medication overuse headache who did not improve 6–8 weeks after withdrawal therapy were excluded as well.
Group 1—healthy controls (n = 15)
Group 2—episodic migraine without aura (n = 16)
Group 3—analgesics induced medication overuse headache (aMOH) (n = 14)
Group 4—triptan induced medication overuse headache (tMOH) (n = 15).
The variables were tested for normal distribution using the Kolmogoroff-Smirnoff test. One factorial ANOVA was used to compare mean values of Vmax and Km between groups. Factor = GROUP: healthy controls versus episodic migraine versus analgesics induced MOH (aMOH) versus triptan induced MOH (tMOH). Post-hoc comparisons were performed using the least statistical significances. A paired t-test was used to compare the results of patients with analgesics and triptans induced MOH before and after withdrawal. Spearman correlation coefficients were calculated for testing for possible relationships between headache frequency and kinetic characteristics of 5HT uptake in platelets. All statistics were calculated with SPSS 13.0 (SPSS Inc. Chicago, IL, USA). The level of significance was set at p < 0.05.
General group characteristics
Demography and clinical characteristics of the study population
Duration of migraine (years)
Duration of MOH (years)
Headache frequency (days/month)
Medication intake frequency (days/month)
39.6 ± 12.4
37.4 ± 12.2
5.1 ± 2.7
21.4 ± 10.4
4.37 ± 1.82
Analgesic induced MOH
39.3 ± 16.5
6.9 ± 3.9
23.3 ± 9.6
3.99 ± 3.34
23.7 ± 4.7
23.5 ± 4.6
Triptan induced MOH
40.9 ± 11.8
6.3 ± 4.4
24.9 ± 10.3
3.44 ± 3.1
22.1 ± 6.0
19.1 ± 7.6
5HT uptake in platelets
We investigated the serotonin turnover in platelets in patients with MOH following overuse of triptans and analgesics before and after withdrawal. The main findings of our study are: (a) patients with both, analgesic or triptan induced medication overuse headache had higher 5-HT uptake rates than patients with episodic migraine and controls; (b) this normalized again after withdrawal in both groups; (c) there were no differences between patients with analgesic induced MOH and triptan induced MOH.
Acute administration of both, acetaminophen and acetylsalycilic acid caused significant increase of brain serotonin (5-HT) content and decrease of the number of 5-HT2 receptors in cortical brain membranes [11, 12]. Serotonergic mechanisms are thought to play an important role as brain serotonin depletion prevented the antinociceptive effect of acetaminophen. The chronic administration of acetaminophen however, resulted in a significant decrease in the maximum number of 5-HT2A binding sites and an increase in the maximum number of 5-HT transporter binding sites in frontal cortical membrane , which is line with our results. Reduced serotonin levels and diminished endogenous cannabinoid levels in platelets of chronic migraine and MOH patients were shown by other groups only recently and provide further evidence for a dysfunctioning of these systems in chronic headache .
Clinical efficacy of triptans is related to their vascular, neuronal and central effects at the 5HT1B/1D/1F receptors . As observed in different experimental conditions, triptan-sensitive 5HT1B/1Dreceptors are predominantly terminal autoreceptors inhibiting 5HT release and/or synthesis and decreasing brain 5HT level [14, 15]. Acute, systemic application of sumatriptan and zolmitriptan in rats was found to decrease the 5HT synthesis in many brain regions, including the dorsal raphe nucleus. Chronically applied, the drugs induced a significant increase of 5HT synthesis in many projection areas but not in the dorsal raphe nucleus . Reuter et al.  demonstrated that chronic sumatriptan and zolmitriptan treatment (2 weeks) significantly reduces 5HT1B/1D/1F mRNA in trigeminal ganglion cells. Thus, excessive use of anti-migraine medication may result in alterations of serotonergic neurotransmission. However, to our knowledge there are no studies investigating the effect of chronic triptan administration on serotonin uptake.
Alternatively, changes of serotonin metabolism may reflect the consequence of pain chronification in headache patients. Serotonin release during the migraine attack is a well known phenomen and platelets serotonin depletion was demonstrated in chronic headache due to analgesics overuse previously. After withdrawal the headache frequency decreased and platelet serotonin normalized [4, 5, 17]. Similarly in our study we demonstrated up-regulation of serotonin uptake in MOH patients before withdrawal and its normalization after withdrawal with no differences between the analgesic and triptan group. This observation is in line with a recent, in vivo 123I-ADAM SPECT study that demonstrated significantly higher SERT binding in the brainstem of migraine patients during attack-free period compared to healthy subjects: the monthly migraine days, ranged from 2 to 17 days, and the ADAM binding ratio in the brainstem correlated significantly .
We therefore conclude that: (a) SERT activity is increased in patients with medication overuse headache; (b) it is reversible and normalizes after withdrawal; (c) based on our data we are not able to differentiate whether the increase of serotonin uptake is caused by regular use of analgesics or triptans or is a consequence of frequent headache attacks. Further studies are needed to identify the precise mechanism responsible for the demonstrated SERT up-regulation in MOH.
- Celentano DD, Stewart WF, Lipton RB et al (1992) Medication use and disability among migraineurs: a national probability sample. Headache 32:223–228View ArticlePubMedGoogle Scholar
- Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC (2002) Features of medication overuse headache following overuse of different acute headache drugs. Neurology 59:1011–1014View ArticlePubMedGoogle Scholar
- Goadsby PJ (2000) The pharmacology of headache. Prog Neurobiol 62:502–525View ArticleGoogle Scholar
- Hering R, Glover V, Pattichis k, Catarci T, Steiner TJ (1993) 5HT in migraine patients with medication-induced headache. Cephalalgia 13:410–412View ArticlePubMedGoogle Scholar
- Srikiatkhachorn A, Maneesri S, Govitrapong P, Kasantikul V (1998) Derangement of serotonin system in migraineous patients with analgesic abuse headache: clues from platelets. Headache 38:43–49View ArticlePubMedGoogle Scholar
- Rossi C, Pini LA, Cupini ML, Calabresi P, Sarchielli P (2007) Endocannabinoids in platelets of chronic migraine patients and medication-overuse headache patients: relation with serotonin levels. Eur J Clin Pharmacol Nov 15; [Epub ahead of print]Google Scholar
- Malmgren R, Hasselmark L (1988) The platelet and the neuron: two cells in focus in migraine. Cephalalgia 8:7–24View ArticlePubMedGoogle Scholar
- Uebelhack R, Franke L, Herold N, Plotkin M, Amthauer H, Felix R (2006) Brain and platelet serotonin transporter in humans-correlation between [123I]-ADAM SPECT and serotonergic measurements in platelets. Neurosci Lett 406(3):153–158View ArticlePubMedGoogle Scholar
- The international classification of headache disorder (2004) 2nd Edn. Cephalalgia 24(Suppl 1):9–160Google Scholar
- Thies-Flechtner K, Weigel I, Muller-Oerlinghausen B (1994) 5-HT uptake in platelets of lithium-treated patients with affective disorders and of healthy controls. Pharmacopsychiatry 27(Suppl 1):4–6View ArticlePubMedGoogle Scholar
- Pini LA, Sandrini M, Vitale G (1996) The antinociceptive action of paracetamol is associated with changes in the serotonergic system in the rat brain. Eur J Pharmacol 308(1):31–40View ArticlePubMedGoogle Scholar
- Pini LA, Vitale G, Sandrini M (1997) Serotonin and opiate involvement in the antinociceptive effect of acetylsalicylic acid. Pharmacology 54(2):84–91View ArticlePubMedGoogle Scholar
- Srikiatkhachorn A, Tarasub N, Govitrapong P (2000) Effect of chronic analgesic exposure on the central serotonin system: a possible mechanism of analgesic abuse headache. Headache 40:343–350View ArticlePubMedGoogle Scholar
- Dobson CF, Tohyama Y, Diksic M, Hamel E (2004) Effects of acute or chronic administration of anti-migraine drugs sumatriptan and zolmitriptan on serotonin synthesis in the rat brain. Cephalalgia 24:2–11View ArticlePubMedGoogle Scholar
- Mitsikostas DD, Papadopoulou-Daifotis Z, Sfikakis A, Varonos D (1996) The effect of sumatriptan on brain monoamines in rats. Headache 36(1):29–31View ArticlePubMedGoogle Scholar
- Reuter U, Salomone S, Ickstein GW, Waeber C (2004) Effects of chronic sumatriptan and zolmitriptan treatment on 5-HAT receptor expression and function in rats. Cephalalgia 24:398–407View ArticlePubMedGoogle Scholar
- Srikiatkhachorn A, Anthony M (1996) Platelet serotonin in patients with analgesic-induced headache. Cephalalgia 16:423–426View ArticlePubMedGoogle Scholar
- Schuh-Hofer S, Richter M, Geworski L, Villringer A, Israel H, Wenzel R, Munz DL, Arnold G (2007) Increased serotonin transporter availability in the brainstem of migraineurs. J Neurol 254(6):789–796View ArticlePubMedGoogle Scholar