Caracterización de la problemática y elaboración de un plan de acción previo a la

Most medications that reduce headache (section 3.7) inhibit the production of second messengers that may reduce the generation and propagation of action potentials in the excitatory pathways of nociception. They may also facilitate neural pathways that inhibit nociception. Medications can act as an agonist (a drug that binds and activates a receptor) or an antagonist (a drug that binds and prevents the agonist binding to the receptor) depending on the actions of the receptor. If the receptor results in an increase in second messenger production when stimulated (e.g. β receptors) then medications reducing headache may be antagonists (e.g. β blockers) and if the receptor results in a subsequent reduction in second messengers when stimulated (e.g. 5HT1) then an agonist (triptans) may alleviate headache (Figure 5.4). Many receptors have subtypes, some of which increase second messengers and some which reduce second messengers e.g. serotonin 5HT1 receptor stimulation reduces second messengers and 5HT2 receptor stimulation increases production of second messengers, therefore medications with serotonin agonist properties (triptans acting via 5HT1 receptors) may reduce headache activity while medication with serotonin antagonist activity (methysergide and cyproheptadine via 5HT2 receptors) may reduce headache activity.

The central nervous system stress response includes the release of noradrenaline, adrenaline, serotonin and histamine. Medications that alleviate headache act at several receptor sites (Table 5.1) including histamine receptors, serotonin receptors, β receptors and α2 receptors, to reduce the production of second messengers and subsequent formation of an action potential. Medications can also act directly at the ion channel e.g. sodium valproate to block inflow of ions needed for the generation and propagation of an action potential (Table 5.1).

Reduces

Inhibition of ion channel opening

Inhibitory postsynaptic potential (IPSP) > Excitatory postsynaptic potential (EPSP) Overall reduction in second

messengers

Summation

Axon Hillock

sodium gated voltage channels remain closed

Preventative medications Reduce central and peripheral sensitisation

No Action Potential Headache medication

agonist or antagonist

Direct action on ion channel Headache medication

Acute analgesics Reduction in headache

Headache disorder medication is used both to abort acute attacks and as a preventative measure. The acute treatment of headache disorder (migraine and/or TTH) medications includes the use of ergotamine, the triptans, anti-nausea medications and NSAIDs or combinations of the aforementioned. While triptans are mostly reserved for migraine they also have efficacy for TTH (Cady, et al., 1997; Lipton, et al., 2000). Ergotamine has both α2 adrenergic and serotoninergic agonist activity (Table 5.1). Both ergotamine and

dihydroergotamine are agonists at the serotonin 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F receptors. When these drugs bind to their specific receptors, it results in the reduction of

adenyl cyclase activity and the subsequent reduction in cAMP production (Silberstein, Freitag & Bigal, 2008).

Non steroidal anti-inflammatory medications reduce the production of second messengers by inhibiting the production of prostaglandins. Prostaglandin E2 (PGE2) binds to the prostaglandin E2 receptor (EP2) to increase the subsequent production of cAMP (Hata & Breyer, 2004), therefore a reduction of prostaglandins reduces generation of second messengers and transmission of pain in the pathways of nociception.

Preventative medication is prescribed for people who suffer frequent headache symptoms (section 3.7). Preventative medication is not effective for a proportion of patients. This may reflect the inability to tolerate the medication due to side effects, or may reflect the

heterogeneous population of people enrolled in a clinical trial of headache disorders. Some patients diagnosed with primary headache disorder may have undiagnosed pathology that is causing their headache and will not respond to preventative medication (Figure 5.5).

Triptans Agonist 5HT1B,1D,1F, reduces cAMP

Ergotamine/dihydroergotamineAgonist 5HT1A,1B,1E,1F, reduces cAMP

Agonist α2 reduces cAMP

NSAID Antagonist EP2 reduces cAMP

B Blocker Antagonist β2 reduces cAMP

Amitriptyline/desipramine Antagonist H1 reduces cGMP

Antagonist M3 reduces cGMP

Reduces β receptor densityβ reduces cAMP sodium reduces sodium calcium reduces calcium

Buspirone Agonist 5HT1A reduces cAMP

Alprazolam Agonist GABAA increases chloride

Calcium channel blocker calcium reduces calcium sodium valproate sodium reduces sodium

messengers or ion channel

second messenger

or ion change

receptor or

ion channel

Spontaneous generation of action potential in pathways of nociception Unidentified secondary headache e.g. Cervicogenic medications Primary Headache Preventative Medication Decreases

Unlikely to alleviate headache

Preventative medication that has support for migraine prevention include β blockers without partial agonist activity (Tfelt-Hansen, 2006), sodium valproate (D’Amico, 2007), and some calcium channel blockers (Tfelt-Hansen, 2006). The other properties of β blockers such as cardioselectivity, penetration into the central nervous system, or

membrane stabilising activity are not important in their ability to prevent migraine attacks (Tfelt-Hansen & Shanks, 2000). Beta blockers block adrenaline binding to both β1 and β2 receptors and hence stop the production of cAMP and may reduce subsequent formation of action potentials in the pathways of nociception. A review of RCTs of β blockers for migraine prevention has concluded that they are superior to placebo (Weerasuriya, Patel, & Turner, 1982). There are no RCTs of β blockers for CTTH.

The mechanism of action of β blockers has been elusive in the management of migraine and the mode or even the site of action of these drugs is unknown (Weerasuriya, et al., 1982) in relation to the management of headache pain. Only those β blockers without partial agonist properties have been found effective. The Adrenaline Model of Headache Causation explains the benefits of β blockade as this reduces the production of cAMP and ensuing neural sensitisation (Figure 5.3).

A RCT for migraine prevention showed a combination of cyproheptadine and propanolol (Rao, Das, Taraknath, & Sarma, 2000) was found to be superior to placebo and both propanolol or cyproheptadine taken individually. Cyproheptadine has antihistamine, antiserotonergic (5-HT2 receptor antagonist) and blocks calcium channels. This

combination of medication improving migraine is consistent with the Adrenaline Model of Headache Causation.

Headache prevention medication may act directly on ion channels to inhibit action

potentials and nerve transmission. Calcium channel blockers reduce the influx of calcium into cells while sodium valproate suppresses the sodium channel. Both will reduce the membrane potential of the neuron and reduce the likelihood of action potential generation and propagation, therefore helping prevent the transmission of pain.

Amitriptyline, the most effective preventative medication in CTTH prevention trials (sections 3.7, 3.71 and 3.72), has the following actions;

1. H1 receptor antagonist that blocks histamine action and reduces the production of intracellular cGMP.

2. Anticholinergic, blocking muscarinic (M3) receptors on the vasculature, reducing nitric oxide and subsequent production of cGMP.

3. α1 receptor antagonist, reducing intracelullar IP3 and calcium production (α1 receptors found throughout the central and peripheral nervous system.)

4. Inhibits the reuptake of noradrenaline and serotonin, increasing both noradrenaline and serotonin at the synapse. Noradrenaline binding to the α2 receptor and serotonin

second messengers.

5. Decreased β adrenoreceptor density (Silberstein, et al., 2007) which will result in a subsequent reduction of cAMP.

6. Inhibits sodium channels and calcium channels that further inhibit nerve transmission.

Amitriptyline therefore reduces second messengers through several receptors and also directly inhibits ion channels to inhibit generation of action potentials and subsequent transmission of pain thus accounting for its effectiveness in several clinical trials of CTTH (section 3.71). The effect of amitriptyline is only modest and reduces headache activity between 30% (Bendtsen, 2000) and 60% (Bettucci, et al., 2006). This may reflect the development of tolerance to medication, or that neural sensitisation only plays a role in a proportion of people with CTTH. In a proportion of people with CTTH an unidentified source of nociception such as the cervical spine (section 3.5) may be the significant source of pain with sensitisation playing a lesser role in the generation of headache pain.

A series of studies have shown neurons in the thalamic nuclei are inhibited in reaching the threshold of -55mV to generate action potentials by propanolol (β blocker) through the β adrenoreceptor (Shields & Goadsby, 2005), triptans through 5-HT1B/1D receptors (Shields & Goadsby, 2006) and anxiolytics (alprazolam) through GABA receptors (Shields, Kaube, & Goadsby, 2003). These studies are consistent with the Adrenaline Model of Headache Causation (Figure 5.3).