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Il trattamento della “medication

overuse headache”Dr. Francesco Perini

Ospedale S. Bortolo VICENZA AULSS 8 VENETO

Il trattamento della “medication overuse headache”

• Classificazione

• Diagnosi differenziale

• Patogenesi

• Fattori prognostici

• Linee guida

• Nuove evidenze

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8.2 Cefalea da uso eccessivo di farmaci (CUEF)

8.2.1 Cefalea da uso eccessivo di ergotaminici

8.2.2 Cefalea da uso eccessivo di triptani

8.2.3 Cefalea da uso eccessivo di analgesici semplici

8.2.3.1 Cefalea da uso eccessivo di paracetamolo (acetaminofene)

8.2.3.2 Cefalea da uso eccessivo di acido acetilsalicilico

8.2.3.3 Cefalea da uso eccessivo di altri FANS

8.2.4 Cefalea da uso eccessivo di oppioidi

8.2.5 Cefalea da uso eccessivo di prodotti di combinazione di analgesici

8.2.6 Cefalea da uso eccessivo di farmaci sintomatici in combinazione

8.2.7 Cefalea da uso eccessivo non verificabile di più classi farmacologiche

8.2.8 Cefalea da uso eccessivo di altri farmaci

8.3 Cefalea attribuita a sospensione di sostanze

8.3.1 Cefalea da sospensione di caffeina

8.3.2 Cefalea da sospensione di oppioidi

8.3.3 Cefalea da sospensione di estrogeni

8.3.4 Cefalea attribuita a sospensione dell'uso cronico di altre sostanze

8.2 Cefalea da uso eccessivo di farmaci

A. Cefalea presente per ≥15 giorni al mese in un

soggetto con una cefalea preesistente

B. Uso eccessivo regolare da ≥ 3 mesi di uno o più

farmaci che possono essere utilizzati per il trattamento

acuto o sintomatico della cefalea

C. Non meglio inquadrata da altra diagnosi ICHD-3.

≥ 10 al mese per più di 3 mesi: triptani, ergot, oppioidi o

combinazioni

≥ 15 al mese per più di 3 mesi: analgesici semplici

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8.2.5 Cefalea da uso eccessivo di prodotti di combinazione di analgesici

• acido acetilsalicilico + paracetamolo + caffeina (Neocibalgina)

• Indometacina + Caffeina + Proclorperazina (neurolettico fenotiazinico antiemetico:

abbassa la soglia convulsiva, effetti extrapiramidali, anticolinergici, allungamento del QT ect) (Difmetrè)

• Ergotamina Tartrato + Caffeina + Aminofenazone (Virdex)

• Propifenazone (fans) + Caffeina + Butalbital (Optalidon)

• Propifenazone (fans) + Caffeina + Paracetamolo (Neoptalidon)

• Paracetamolo + Codeina (Tachidol)

• Tramadolo + dexketoprofene (Lenizak)

• Tramadolo + paracetamolo (Patrol)

• Ossicodone + paracetamolo (Depalgos)

• Ossicodone + Naloxone (Targin)

Diagnosi Differenziale

• Vanno sempre escluse forme secondarie (es.

pseudotumor senza papilledema, glaucoma ect…)

• Le caratteristiche della cefalea vanno rivalutate dopo la

sospensione dell’eccessivo uso di analgesici

a)Emicrania

b)Cefalea tensiva ?

c)Cefalea a grappolo cronica?

d)Cefalea persistente di nuovo esordio?

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Diagnosi Differenziale

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Appendice

1.3 Emicrania cronica: NOTELa causa più comune di emicrania cronica è l’uso eccessivo di farmaci sintomatici.

Il 50% dei pazienti affetti da emicrania cronica ritornano ad un sottotipo di emicrania

episodica dopo la sospensione dell’abuso di farmaci sintomatici.

Molti pazienti che abusano di trattamenti sintomatici non migliorano dopo la

sospensione nell’assunzione di analgesici e quindi i pazienti che soddisfino i criteri

diagnostici per 1.3 Emicrania cronica e per 8.2 Cefalea da uso eccessivo di farmaci

dovrebbero ricevere entrambe le diagnosi.

Forme refrattarie o farmacoresistenti

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Cefalea da Uso Eccessivo di Farmaci?

• Un paziente emicranico assume 10 triptani al mese con beneficio perché ha

10 crisi di emicrania al mese (con 5 gg di tensiva associata) da più di 3 mesi.

Quindi rientra nel criterio di CUEF. E’ una emicrania cronica in quanto rispetta

i criteri per la cronica, non c’è un problema di diagnosi differenziale tanto che

risponde ad analgesici specifici per l’emicrania.

• Che terapia ?

Possibili meccanismi fisiopatogeneticiDr Domenico Damico

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Cephalalgia. 2013 Aug;33(11):932-7. doi: 10.1177/0333102413480755. Epub 2013 Mar 14.

The role of tyrosine metabolism in the pathogenesis of chronic migraine.D'Andrea G1, D'Amico D, Bussone G, Bolner A, Aguggia M, Saracco MG, Galloni E, De Riva V, Colavito D, Leon A, Rosteghin V, Perini F

Author information

AbstractOBJECTIVE:

The pathogenesis of chronic migraine (CM) remains largely unknown. We hypothesized that anomalies of tyrosine metabolism, fou

METHODS:

To test our hypothesis we measured the plasma levels of dopamine (DA), noradrenaline (NE) and trace amines, including tyramin

RESULTS:

The plasma levels of DA and NE were several-fold higher in CM patients compared with control subjects ( P  > 0.001). The plasma

CONCLUSIONS:

Our data support the hypothesis that altered tyrosine metabolism plays an important role in the pathogenesis of CM. The high

TYROSINE

DOPA

DOPAMINE

EPINEPHRINE

NOREPINEPHRINE

Tyrosine

Hydroxylase

DOPA

Decarboxylase

Dopamineβ-hydroxylase

Phenylethanolamine

N-methyltranferase

TYRAMINE

OCTOPAMINE

Dopamineβ-hydroxylase

Tyrosine

Decarboxylase

Phenylethanolamine

N-methyltranferase

SYNEPHRINE

MAO

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Prognostic factors for CM

• Patients who suffer 5–9 days of migraine may

have a six-fold more likely chance to develop CM

compared to patients with ,4 days of headache

per month.Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for

chronicity of headache in patients with episodic migraine. Neurology.

2004;62(5):788–790.

• Cutaneous allodynia is a marker of central

sensitization and an independent predictor for

migraine chronificationLouter MA, Bosker JE, van Oosterhout WP, et al. Cutaneous allodynia as a predictor of

migraine chronification. Brain. 2013;136(Pt 11):3489–3496

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Natural History CM

In a study of nearly 400 CM patients, only 26%

had CM remission at 2 years. Remission was

defined as fewer than 10 days of headache per

month, and reported remission predictors were

the absence of allodynia and having a lower

baseline headache frequency

Manack A, Buse DC, Serrano D, Turkel CC, Lipton RB.

Rates, predictors, and consequences of remission from

chronic migraine to episodic migraine. Neurology.

2011;76(8):711–718.

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Chronic headache with medication overuse: Long-term prognosis after withdrawal

therapy.

Bøe MG; Thortveit E; Vatne A; Mygland Å, Cephalalgia, 2017 Nov; Vol. 37 (13), pp. 1215-1221;

Background Knowledge about long-term outcomes after medication withdrawal therapy for chronic headache, including tension type and migraine headache is lacking. Methods We re-examined 56 patients an average of nine years after they participated in a medication withdrawal study with a one-year follow-up. We collected and compared data on headache, use of medication, quality of life, quality of sleep, anxiety, depression, and labor participation one and nine years after the start of withdrawal therapy. Results Headache days per month decreased from 16.7 (14.0-19.3) at one year to 13.3 (10.6-15.9) at nine years (P = 0.007). The proportion of patients meeting the criteria for chronic headache decreased from 27/56 (48%) at one year to 18/56 (32%) at nine years (P = 0.004). Medication overuse was reported in seven (13%) patients at one year and 18 (32%) at nine years (P = 0.013). The majority of patients overusing medication at nine years (10/18) belonged to a group of 14 patients who had a poor early response to withdrawal therapy and had sustained chronic headache after nine years. After excluding patients receiving retirement pensions, the proportion who received disability benefits increased from 21/55 (38%) at one year to 30/49 (61%) at nine years (P = 0.003). Conclusion Improvements after withdrawal therapy for chronic headache last at least nine years, with a parallel increase in the use of disability benefits. However, a high proportion of patients with a poor initial response to withdrawal therapy and sustained chronic headache overuse medication.

Trattamento della CUEF

Interruzione dell’eccessivo uso di analgesici:

•Come? brusca o graduale?

•Dove? ambulatoriale, ricovero?

•Sempre? è sufficiente iniziare una profilassi efficace?

•Quando? profilassi prima o dopo la sospensione?

•Cosa usare?

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Caso Clinico

Paziente maschio di 50 aa con storia di emicrania senza aura che

assumeva da un anno un grammo di paracetamolo al giorno con

beneficio. Nessuna comorbilità o FR per cronicizzazione.

Informato

Motivato

Prescritto terapia per la cefalea da rimbalzo (cortisone 1gr pro kg per os) e

profilassi combinata con triciclico e beta-bloccante.

Dopo un anno torna. Aveva sospeso gli analgesici con miglioramento

della frequenza delle crisi senza assumere alcuna terapia, ne cortisone ne

di profilassi.

Aveva una frequenza di crisi di 3-4 al mese per le quali assumeva

paracetamolo che però non sempre funzionava.

Voleva un consiglio su cosa potesse assumere al posto del paracetamolo.

2010 Management of medication overuse

• achieve withdrawal from the overused medication.

• which should follow, is recovery from MOH.

• review and reassess the underlying primary headache disorder (migraine or tension type headache),

• prevent relapse, which has a rate of around 40% within five years and is most likely to occur within the first year after withdrawal.

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AGENAS 2011:

terapia durante la disassuefazione

• GPP-La sospensione degli analgesici andrebbe

tentata in tutti i pz con cefalea associata a cefalea

da eccessivo uso di analgesici

• B-prednisone 100 mg/die x 5 gg risulta efficace

nella cefalea da rimbalzo

• B-La terapia con topiramato andrebbe valutata in

pazienti con cefalea associata ad eccessivo uso di

analgesici allo scopo di ridurre il numero

complessivo di giorni di cefalea

• I pz dovrebbero essere informati e incoraggiati alla sospensione (B)

• La sospensione può essere brusca eccetto che per oppioidi, BDZ,

barbiturici (GPP)

• La sospensione ambulatoriale, da ricoverato o con semplice

informazione non influenza il tasso di successo (A)

• In pz con severa comorbilità o fallimento di precedenti tentativi

ambulatoriali va offerto il ricovero (GPP)

• La profilassi va iniziata il primo giorno della sospensione

o anche prima (B).

• Il cortisone è possibile che sia efficace (GPP)

• I pz dovrebbero essere seguiti per prevenire le ricadute (GPP).

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2013

2014 AAN guidelines ASSESSMENT OF MEDICATION OVERUSE IN THE TREATMENT

OF

PRIMARY HEADACHE DISORDERS

Headache

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D’Amico D. Neurol. Sci. 2010

Acta Neurologica Taiwanica Vol 26 No 1 March 2017

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Raccomandazione per la fase acuta della sospensione degli analgesici

Somministrazione di fluidi

Ansiolitici

Neurolettici

Amitriptilina

Valproato

Ossigeno

Antiemetici

Diidroergotamina e.v.

Steroidi

Halker RB Cephalalgia 2013,33.149-151

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Flunarizine versus topiramate for chronic migraine prophylaxis:

a randomized trial.

Lai KL et Al Acta Neurol. Scand. 2017 Apr;135(4):476-483

OBJECTIVES:

Chronic migraine (CM) is a prevalent and devastating disorder with limited therapeutic options. This study explored the efficacy of 10 mg/d flunarizine for CM prophylaxis as compared with 50 mg/d topiramate.METHODS:

We conducted a prospective, randomized, open-label, blinded-endpoint trial. Patients with CM were randomized to flunarizine and topiramate treatment. The primary outcomes assessed were the reductions in the total numbers of headache days and migraine days after 8 weeks of treatment. Secondary outcomes were reductions in the numbers of days of acute abortive medication intake and acute abortive medication tablets taken, and the 50% responder rate.RESULTS:

Sixty-two subjects were randomized (n=31/group). Patients treated with flunarizine showed significant reductions in the numbers of total headache days (-4.9 vs -2.3, P=.012) and migraine days (-4.3 vs -1.4, P=.001) compared with those treated with topiramate. Patients treated with flunarizine also showed significant reductions in the numbers of days of acute abortive medication intake (-2.3 vs -0.2, P=.005) and acute abortive medication tablets taken (-4.6 vs -0.5, P=.005) and had a higher 50% responder rate in terms of total headache days (58.6% vs 25.9%, P=.013) and migraine days (75.9% vs 29.6%, P=.001), compared with topiramate-treated patients. Flunarizine was generally well tolerated and had a safety profile comparable to that of topiramate.CONCLUSIONS:

Our results suggest that, in an 8-week study, 10 mg/d flunarizine is more effective than 50 mg/d topiramate for CM prophylaxis.

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Eur Neuropsychopharmacol. 2014 Aug;24(8):1289-97.

Sodium valproate in migraine without aura and medication overuse headache: a

randomized controlled trial.

Sarchielli P et Al.

OBJECTIVE: To assess the efficacy, safety and tolerability of sodium valproate

(800mg/die) compared with placebo in medication-overuse headache patients with a

history of migraine without aura.

METHODS: This is a multicenter, randomized, double-blind, placebo-controlled

study enrolled medication-overuse headache patients for a 3-month treatment

period with sodium valproate (800mg/day) or placebo after a 6 day outpatient

detoxification regimen, followed by a 3-month follow-up. Primary outcome was

defined by the proportion of patients achieving ≥50% reduction in the number of

days with headache per month (responders) from the baseline to the last 4 weeks

of the 3-month treatment. Multivariate logistic regression models were used on

the primary endpoint, adjusting for age, sex, disease duration, comorbidity and

surgery. The last-observation-carried-forward method was used to adjust for

missing values.

RESULTS: Nine sites enrolled 130 patients and, after a 6-day detoxification

phase, randomized 88 eligible patients. The 3-month responder rate was higher in

the sodium valproate (45.0%) than in the placebo arm (23.8%) with an absolute

difference of about 20% (p=0.0431). Sodium valproate had safety and tolerability

profiles comparable to placebo.

CONCLUSIONS: The present study supports the efficacy and safety of sodium

valproate in the treatment of medication overuse headache with history of

migraine after detoxification.

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Altri approcci terapeutici

• Agopuntura

• Blocchi farmacologici del GON

• TMS

• Elettrostimolazione GON, vago ect

Acupuncture versus topiramate in chronic migraine prophylaxis: a randomized

clinical trial.

Yang CP1, Chang MH, Liu PE, Li TC, Hsieh CL, Hwang KL, Chang HH.

Cephalalgia. 2011 Nov;31(15):1510-21BACKGROUND:The aim of this study was to investigate the efficacy and tolerability of acupuncture

compared with topiramate treatment in chronic migraine (CM) prophylaxis.METHODS:A total of 66 consecutive and prospective CM patients were randomly divided into two

treatment arms: 1) acupuncture group: acupuncture administered in 24 sessions over 12

weeks (n = 33); and 2) topiramate group: a 4-week titration, initiated at 25 mg/day and

increased by 25 mg/day weekly to a maximum of 100 mg/day followed by an 8-week

maintenance period (n = 33).RESULTS:A significantly larger decrease in the mean monthly number of moderate/severe headache

days (primary end point) from 20.2 ± 1.5 days to 9.8 ± 2.8 days was observed in the

acupuncture group compared with 19.8 ± 1.7 days to 12.0 ± 4.1 days in the topiramate

group (p < .01) Significant differences favoring acupuncture were also observed for all

secondary efficacy variables. These significant differences still existed when we focused

on those patients who were overusing acute medication. Adverse events occurred in 6% of

acupuncture group and 66% of topiramate group.CONCLUSION:We suggest that acupuncture could be considered a treatment option for CM patients

willing to undergo this prophylactic treatment, even for those patients with medication

overuse.

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Greater occipital nerve block in the treatment of triptan-overuse headache:

a randomized comparative study.

Acta Neurol Scand. 2017 Apr;135(4):426-433.

Karadaş Ö1, Özön AÖ2, Özçelik F3, Özge A4.Acta Neurol Scand. 2017 Apr;135(4):426-433.

Acta Neurol Scand. 2017 Apr;135(4):426-433. OBJECTIVES:

This study aims to investigate the efficiency of a single and repeated greater occipital nerve (GON) block

using lidocaine in the treatment of triptan-overuse headache (TOH), whose importance has increased

lately.

MATERIALS AND METHODS:

In the study, 105 consecutive subjects diagnosed with TOH were evaluated. The subjects were randomized

into three groups. In Group 1 (n=35), only triptan was abruptly withdrawn. In Group 2 (n=35), triptan was

abruptly withdrawn and single GON block was performed. In Group 3 (n=35), triptan was abruptly

withdrawn and three-stage GON block was performed. All patients were injected bilaterally with a total

amount of 5 cc 1% lidocaine in each stage. During follow-up, the number of headache days per month, the

severity of pain (VAS), the number of triptans used, and hsCRP and IL-6 levels were recorded three times;

in the pretreatment period, in the second month post-treatment, and in the fourth month post-treatment.

They were then compared.

RESULTS:

There was a statistically significant difference in the post-treatment fourth month in comparison with the

pretreatment period in Group 3 (P<.05). Compared to Group 1, the number of headache days, VAS, and

decrease in triptan need in Group 3 was statistically significant compared to Group 2 (P<.05). Compared to

pretreatment, in the fourth month post-treatment, both hsCRP and IL-6 levels were lower only in Group 3

(P<.05).

CONCLUSIONS:

We are of the opinion that repeated GON block in addition to the discontinuation of medication has

significant efficacy for TOH cases.

We report the efficacy of three versus single session of 10 Hz repetitive transcranial magnetic stimulation (rTMS) in chronic migraine (CM) and chronic tension-type headache (CTTH). Ninety-eight patients with CM or CTTH were included and their headache frequency, severity, functional disability and number of abortive medications were noted. Fifty-two patients were randomly assigned to group I (three true sessions) and 46 to group II (one true and two sham rTMS sessions) treatment. 10 Hz rTMS comprising 600 pulses was delivered in 412.4 s on the left frontal cortex. Outcomes were noted at 1, 2 and 3 months. The primary outcome was 50 % reduction in headache frequency, and secondary outcomes were improvement in severity, functional disability, abortive drugs and side effects. The baseline headache characteristics were similar between the two groups. Follow up at different time points revealed significant improvement in headache frequency, severity, functional disability and number of abortive drugs compared to baseline in both group I and group II patients, although these parameters were not different between the two groups. In group I, 31 (79.4 %) had reduction of headache frequency and 29 (74.4 %) converted to episodic headache. In group II, these were 24 (64.8 %) and 22 (59.2 %), respectively. In chronic migraine, the severity of headache at 2 months reduced in group I compared to group II (62.5 vs 35.3 %; P = 0.01). Both single and three sessions of 10 Hz rTMS were found to be equally effective in CM and CTTH, and resulted in conversion of chronic to episodic headache in 67.1 % patients.

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NEUROSTIMOLAZIONE GON

Perini F. Neurol. Sci. 2012

Dopo il 2012?

Safety and Efficacy of Occipital Nerves Stimulation for the Treatment of Chronic Migraines: Randomized, Double-blind,

Controlled Single-center Experience.

Mekhail NA, Estemalik E, Azer G, Davis K, Tepper SJ.

Pain Pract. 2017 Jun;17(5):669-677

Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine:

long-term results from a randomized, multicenter, double-blinded, controlled study.

Dodick DW, Silberstein SD, Reed KL, Deer TR, Slavin KV, Huh B, Sharan AD, Narouze S, Mogilner AY, Trentman TL,

Ordia J, Vaisman J, Goldstein J, Mekhail N.

Cephalalgia. 2015 Apr;35(4):344-58

Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine:

results from a randomized, multicenter, double-blinded, controlled study.

Silberstein SD, Dodick DW, Saper J, Huh B, Slavin KV, Sharan A, Reed K, Narouze S, Mogilner A, Goldstein J,

Trentman T, Vaisman J, Ordia J, Weber P, Deer T, Levy R, Diaz RL, Washburn SN, Mekhail N.

Cephalalgia. 2012 Dec;32(16):1165-79. doi: 10.1177/0333102412462642. Epub 2012 Oct 3. Erratum in: Cephalalgia.

2014 Oct;34(11):944. Vaisma, Julien [corrected to Vaisman, Julien]. Cephalalgia. 2014 Oct;34(11):944.

Martelletti P, Jensen RH, Antal A, et al. Neuromodulation of chronic headaches: position statement from the European

Headache Federation. J Headache Pain. 2013;14(1):86.

Hann S, Sharan A. Dual occipital and supraorbital nerve stimulation for chronic migraine: a single-center experience,

review of literature, and surgical considerations. Neurosurg Focus. 2013;35:E9.

Serra G, Marchioretta F. Occipital nerve stimulation for chronic migraine: a randomized trial. Pain Physician.

2012;15(3):245–253.

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Cephalalgia. 2017 Jan 1:333102417728873. Distribution of CGRP and CGRP receptor components in the rat brain.Warfvinge K1,2, Edvinsson L1,2.

Background Calcitonin gene-related peptide and its receptor, consisting of

receptor activity-modifying protein 1 and calcitonin receptor-like receptor, are of

considerable interest because of the role they play in migraine and recently

developed migraine therapies. Methods To better understand the function of this

neuropeptide, we used immunohistochemistry to determine a detailed

distribution of calcitonin gene-related peptide, receptor activity-modifying protein

1 and calcitonin receptor-like receptor in the rat brain in a region of 0.5-1.5 mm

lateral to the midline. We found calcitonin gene-related peptide immunoreactivity

in most of the neurons of the cerebral cortex, hippocampus, cerebellum,

thalamic nuclei, hypothalamic nuclei and brainstem nuclei. In contrast, receptor

activity-modifying protein 1 and calcitonin receptor-like receptor

immunoreactivity were found almost exclusively in the neuronal processes in the

investigated regions. Conclusion Overall, the degree of expression of calcitonin

gene-related peptide and calcitonin gene-related peptide receptor components

in the central nervous system is astonishingly complex and suggestive of many

different brain functions, including a possible role in migraine. However,

currently, the presence of calcitonin gene-related peptide and the nature of its

receptors throughout the brain is an enigma yet to be solved.

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Conclusioni

• I limiti della classificazione dell’emicrania

cronica si ripropongono anche per la MOH

• Fisiopatologia della MOH non chiara

• Ci sono poche evidenze per il trattamento dei

sintomi da sospensione degli analgesici

• Il 50%-70% migliora con la sospensione dei

sintomatici e la profilassi adeguata.

• Possibile approccio non farmacologico

• Difficoltà di trattamento delle forme refrattarie

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Sistemi neurotrasmettitoriali

Network GLU-ASP/Gaba Ramadan NM Cephalagia 2014

Serotoninergico: 5HT/TRY D'Andrea G Neurol Sci. 2014

Adrenergico: NE/OCT-SYN D'Andrea G Cephalalgia 2013

Dopaminergico: DA/TYR D’Andrea G Headache 2012

Istaminergico: IST Alstadhaug KB Headache 2014

RAS: REN (neuronal renin receptor) Tronvik E Curr Pain Head Rep 2014

Acetilcolinergico: ACH Ikeda K Inter Med 2009

Calcitoninergico: CRGP Warfvinge K Cephalalgia 2017

Sistemi neurotrasmettitoriali

GLU-ASP/Gaba: neuromodulatori: Topiramato, Valproato

Serotoninergico: triciclici (Amitriptilina, Nortriptilina)

Adrenergico: beta bloccanti, Tizanidina, Clonidina

Dopaminergico: triciclici,

Istaminergico: Ciproeptadina, Cinnarizina

RAS: ACEI, ARB (Lisinopril, Candesartan)

Acetilcolinergici: Diidroergotamina

Ca antagonisti: Verapamile, Flunarizina,

Cinnarizina, Acetazolamide

CGRP antagonisti: Erenumab, Fremanezumab

Antinfiammatori: steroidi immunomodulatori