Dimos D. Mitsikostas

EFNS guideline on the treatment of tension‐type headache – Report of an EFNS task force

Background:  Tension‐type headache (TTH) is the most prevalent headache type and is causing a high degree of disability. Treatment of frequent TTH is often difficult.

The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis

&NA; The effect of the N‐methyl‐d‐aspartate (NMDA) receptor antagonist (5R,10S)‐(+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclo‐hepten‐5,10‐imine hydrogen maleate (MK‐801) was examined on c‐fos‐like immunoreactivity (c‐fos‐LI) in urethane‐anesthetized Sprague‐Dawley rats using a polyclonal antibody. C‐fos, an indicator of neuronal activation, was assessed within the trigeminal nucleus caudalis (TNC), area postrema, lateral reticular and solitary tract nuclei 2 h after intracisternal injection of capsaicin. C‐fos‐positive cells were counted at three representative levels corresponding to obex, −2.05 mm and −6.45 mm in 18 tissue sections (50 &mgr;m). A weighted average was obtained reflecting total brainstem expression within lamina I, II of TNC using a recently validated method. Capsaicin (0.1, 1, 5, 10 and 15 nmol) caused a dose‐dependent labeling of cells in lamina I, II at obex similar to that previously reported after intracisternal blood or carrageenin administration in rats and guinea pigs. MK‐801 (0.3, 1 and 3 mg/kg) administered i.p. 30 min before capsaicin (5 nmol in 100 &mgr;l artificial CSF) reduced significantly and dose‐dependently (12%, 36% and 47%, respectively) the c‐fos‐LI cells in TNC at each level from rostral to caudal but not in solitary tract, area postrema and lateral reticular nuclei, and for unexplained reasons, increased c‐fos‐LI within the inferior olive. These results suggest that NMDA receptors provide a potential therapeutic target for cephalic pain (e.g. migraine) due to trigeminovascular activation from meningeal afferents.

Animal models of migraine: looking at the component parts of a complex disorder.

Animal models of human disease have been extremely helpful both in advancing the understanding of brain disorders and in developing new therapeutic approaches. Models for studying headache mechanisms, particularly those directed at migraine, have been developed and exploited efficiently in the last decade, leading to better understanding of the potential mechanisms of the disorder and of the action for antimigraine treatments. Model systems employed have focused on the pain‐producing cranial structures, the large vessels and dura mater, in order to provide reproducible physiological measures that could be subject to pharmacological exploration. A wide range of methods using both in vivo and in vitro approaches are now employed; these range from manipulation of the mouse genome in order to produce animals with human disease‐producing mutations, through sensitive immunohistochemical methods to vascular, neurovascular and electrophysiological studies. No one model system in experimental animals can explain all the features of migraine; however, the systems available have begun to offer ways to dissect migraines component parts to allow a better understanding of the problem and the development of new treatment strategies.

Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine

In intracranial structures unmyelinated C- and Adelta-fibers of the trigeminal nerve transmit pain stimuli from meninges to the trigeminal nucleus caudalis (Sp5C). Peripheral nerve endings surround meningeal vessels (the so-called trigeminovascular system) and contain vasoactive neuropeptides (calcitonin gene-related peptide, substance P and neurokinin A). Activation of the trigeminovascular system promotes a meningeal sterile inflammatory response through the release of neuropeptides by peripheral endings. Orthodromic conduction along trigeminovascular fibers transmits information centrally with induction of immediate early c-fos gene within post-synaptic Sp5C neurons, as a marker of neuronal activity within central nociceptive pathways. In laboratory animals the system is activated by either electrical stimulation of the TG, chemical stimulation of the meninges, electrical or mechanical stimulation of the superior sagittal sinus or by induction of cortical spreading depression. All these techniques induce c-fos within Sp5C and are used as a rodent/feline model of vascular headache in humans. Up-to-date there is evidence that at least ten receptors (5-HT(1B), 5-HT(1D), 5-HT(lF), 5-HT(2B), NK-1, GABA(A), NMDA, AMPA, class III metabotropic glutamate receptors, and opioids mu receptors) modulate c-fos expression within Sp5C. These receptors represent potential targets for anti-migraine drugs as shown by triptans (5-HT(1B/1D/1F)) and ergot alkaloids (5-HT(1A1B/1D/1F)). This review discusses the importance of c-fos expression within Sp5C as a marker of cephalic nociception, the different cephalic pain models that induce c-fos within Sp5C, the receptors involved and their potential role as targets for anti-migraine drugs.

The Role of Glutamate and its Receptors in Migraine

Glutamate (Glu) is the principal excitatory neurotransmitter in the central nervous system. Its receptors are classified into ionotropic receptors, which are ion channels and include NMDA, AMPA and kainate receptors, named after the agonists that selectively bind to them, and metabotropic receptors, which are G-protein coupled receptors. The trigeminal system is considered to play a key role in migraine pathophysiology, trafficking pain signals from the head and face to the trigeminal nucleus caudalis. The role of glutamate in the pathophysiology of migraine is implicated by data from animal and human studies. Animal studies include experiments of cortical spreading depression, studies of c-fos protein expression in trigeminal nucleus caudalis, studies of plasma protein extravasation and electrophysiological studies. Human studies investigating the role of Glu in migraine pathogenesis measured the levels of Glu in plasma, platelets and cerebrospinal fluid, studied its effect on migraine symptoms and examined the effect of Glu in modulating sensitization. Findings from both the animal and the human studies suggest a link between glutamate and migraine and further suggest that glutamate plays a key role in migraine mechanisms. In the future, efforts should be made to further investigate the role of glutamate in migraine pathogenesis and, subsequently, in migraine treatment.

Non-NMDA glutamate receptors modulate capsaicin induced c-fos expression within trigeminal nucleus caudalis.

We examined the effects of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate receptor antagonists 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) and 1,2,3,4‐tetrahydro‐6‐nitro‐2,3‐dioxo‐benzol[f]quinoxaline‐7‐sulphonamide (NBQX), the kainate receptor antagonists γ‐(R‐)‐glutamylaminomethanesulphonic acid (GAMS) and 6,7,8,9‐tetrahydro‐5‐nitro‐1H‐benz[g]indole‐2,3‐dione‐3‐oxime (NS‐102), and the group III metabotropic glutamate receptor (mGluR) agonist 2‐amino‐4‐phosphono‐S‐butanoic acid (L‐AP4) on c‐fos‐like immunoreactivity (c‐fos LI) in trigeminal caudalis (Sp5C), lateral reticular (LRt), medullary reticular (Md) and solitary tract (Sol) nuclei, after intracisternal injection of capsaicin in urethane anaesthetized Sprague‐Dawley rats. Few c‐fos labelled cells were observed within Sp5C in capsaicin‐vehicle treated animals. The number of positive c‐fos cells increased by 17 fold after intracisternal capsaicin (5 nmol) administration. Pretreatment with CNQX (0.02, 0.1, 0.6, 3 and 15 mg kg−1) or NBQX (0.01, 0.1 and 1 mg kg−1), administered intraperitoneally 15 min before capsaicin, significantly reduced labelled cells within Sp5C by a maximum of 45 and 34%, respectively. The number of c‐fos LI cells within LRt, Md and Sol was not affected. Pretreatment with  L‐AP4 (1, 3 and 10 mg kg−1) decreased the number of Sp5C c‐fos LI cells by a maximum of 30%, whereas GAMS (1 and 10 mg kg−1) and NS‐102 (1 and 5 mg kg−1) did not show any significant effect. These results suggest that blockade of AMPA receptors, but not kainate receptors, or the activation of group III mGluRs, decrease the response of Sp5C neurons to trigeminovascular activation. Thus, in addition to NMDA receptors, mGluRs and AMPA receptors may modulate cephalic pain and may provide a potential therapeutic target for antimigraine drugs.

Guidelines for controlled trials of drugs in tension-type headache: second edition.

The Clinical Trials Subcommittee of the International Headache Society published its first edition of the guidelines on controlled trials of drugs in tension-type headache in 1995. These aimed ‘to improve the quality of controlled clinical trials in tension-type headache’, because ‘good quality controlled trials are the only way to convincingly demonstrate the efficacy of a drug, and form the basis for international agreement on drug therapy’. The Committee published similar guidelines for clinical trials in migraine and cluster headache. Since 1995 several studies on the treatment of episodic and chronic tension-type headache have been published, providing new information on trial methodology for this disorder. Furthermore, the classification of the headaches, including tension-type headache, has been revised. These developments support the need for also revising the guidelines for drug treatments in tension-type headache. These Guidelines are intended to assist in the design of well-controlled clinical trials in tension-type headache.

Both 5-HT1B and 5-HT1F receptors modulate c-fos expression within rat trigeminal nucleus caudalis

A possible mechanism of action of antimigraine drugs such as sumatriptan is inhibition of the trigeminovascular pathway. Sumatriptans effects might be mediated by 5-HT1B, 5-HT1D or 5-HT1F receptors. To establish the relative importance of these subtypes, we compared the effects of sumatriptan with those of a selective 5-HT1F receptor agonist (LY 344864) on c-fos protein expression in the trigeminal nucleus caudalis. c-fos expression was induced in urethane-anaesthetized rats by intracisternal capsaicin administration. Sumatriptan and LY 344864 decreased the number of capsaicin-induced c-fos-like immunoreactive cells within trigeminal nucleus caudalis (ID50 = 0.04 and 0.6 mg kg(-1)). The effect of sumatriptan, but not of LY 344864, was prevented by pretreatment with the antagonist SDZ 21-009, which displays high affinity for rat 5-HT1B receptors. LY 344864 appears to attenuate c-fos-like immunoreactivity via 5-HT1F receptors, while sumatriptan acts via 5-HT1B receptors. The fact that activation of 5-HT1F receptors is sufficient to modulate the activity of the trigeminal system suggests that this receptor may be a target for antimigraine drugs with improved safety profile.

Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for practice.

Background:  Nocebo refers to adverse effects (AEs) generated by negative expectations that medical treatment will likely harm instead of heal and can be assessed in placebo‐controlled randomized clinical trials (RCTs). We examined AEs following placebo administration in RCTs for fibromyalgia (FM), a condition characterized by patients’ poor medication adherence, which may affect outcome and/or increase healthcare costs.

Refractory Chronic Headache Associated with Obstructive Sleep Apnoea Syndrome

The aim was to investigate the comorbidity of chronic refractory headache with obstructive sleep apnoea syndrome (OSAs). Seventy-two patients (51 women and 21 men) with chronic and refractory headaches, whose headache occurred during sleep or whose sleep was accompanied by snoring, were submitted to polysomnography. Patients diagnosed with OSAs (respiratory disturbance index > 10) began continuous positive airway pressure (C-PAP) treatment and were followed up for ≥ 6 months. Twenty-one cases of OSAs were identified (29.2% of the total investigated, 13.7% of the women and 66.6% of the men). Headaches were classified into several headache disorders, medication overuse headache and cluster headache being the most prevalent (nine and six of the 21 cases, respectively). In one case (1.4% of the total sample, 4.7% of all the men), the criteria for hypnic headache were fulfilled. Multivariate regression analysis revealed that age, male gender and body mass index were associated with OSAs. C-PAP treatment improved both sleep apnoea and headache in only a third of the cases. Patients suffering from chronic refractory headache associated with sleep or snoring, in particular those who are also middle-aged, overweight men, should be considered for polysomnography. C-PAP treatment alone does not seem to improve headache, but further investigation is needed.