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ScienceDirect Understanding the pharmacology of headache Paul Edward Rolan1,2,3 Migraine continues to be the most common of the debilitating headaches. Existing acute headache treatments are not always satisfactory, and current research is focussed on targeting neuroinflammatory pathways with drugs that are devoid of vascular action. Current prophylactic drugs are largely centred around antihypertensive, anticonvulsant and antidepressant drugs, although not all drugs of all sub-classes in these categories are effective. Selective agents which target the neuroinflammatory process including targets such as calcitonin gene related peptide, and PANNEXIN 1 may have clinical utility. Addresses 1 Clinical Pharmacology, Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia 2 Pain Management Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia 3 Pain and Anaesthesia Research Clinic, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia Corresponding authors: Rolan, Paul Edward (
[email protected])
Current Opinion in Pharmacology 2014, 14:30–33 This review comes from a themed issue on Neurosciences Edited by David G Trist and Alan Bye For a complete overview see the Issue and the Editorial Available online 22nd November 2013 1471-4892/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.coph.2013.10.005
Introduction Headache is one of the commonest symptoms in the community. Although there are many effective treatments, the relatively small proportion of patients who do not have a satisfactory outcome with current treatments still represents a large number of people with unsatisfactory outcomes. Given that headache patients are generally younger people of working age, this additionally represents a large economic burden to society and hence there is an important unmet medical need to address [1]. However, for several reasons, developing new treatments for headache on a pharmacologically rational basis is difficult. The first problem is that for the main types of headache we still do not have good mechanistic understanding of the condition. For migraine, by far the most studied condition, there is reasonable consensus that this is a disorder of neuronal excitability causing paroxysmal spreading depression which leads to a sterile inflammatory Current Opinion in Pharmacology 2014, 14:30–33
response with pain [2]. Very recently one part of the missing link describing how aura could cause the inflammatory response has been established by activation of pannexin-1 channels and this may represent a new therapeutic target [3]. However, for the more common condition of tension-type headache, apart from a general consensus that this somehow represents a state of acquired central sensitisation with some peripheral involvement, the pathways by which this occurs are unclear [4]. The much rarer but clinically dramatic presentation of cluster headache can bring extreme suffering to the patient, such that an American survey showed that more than half the patients have considered suicide to exit the condition [5]. Despite the strikingly unusual phenotype, there has been little research into the mechanisms involved in cluster headache and most treatments have been found opportunistically.
Pathophysiology of headache Much of the lack of understanding the mechanisms of headache is due to the absence of suitable animal models. Various animal models have been proposed for migraine including neurovascular [6] and inflammatory [7] models, but these do not replicate most of the aspects of the condition. For migraine, the development of new treatments has been fairly rational. The first mechanistically plausible hypothesis for migraine was that of Wolff who hypothesised that migraine was due to cerebral vasoconstriction causing aura, and cerebral vasodilation causing pain [8]. It is now recognised that low cerebral blood flow is a consequence rather than a cause of aura [9] and intracranial and extracranial blood vessels are not dilated in migraine [10]. However, the initial Wolff hypothesis was plausible and the hunt for selective cerebral vasoconstrictors initially led to the ergots. These drugs have complex pharmacology, interacting at a wide range of receptors but undoubtedly have some vasoconstrictor properties [11]. Indeed the main clinical problem with this class of drugs when used too frequently is peripheral vasoconstriction and tissue ischaemia [11]. The multiple receptor activities are also a mixed blessing. For example, methysergide is probably an effective migraine prophylactic drug although its agonist activity at 5HT2B receptors is probably responsible for the occasional serious but irreversible complications of cardiac valve and retroperitoneal fibrosis [12].
Acute treatments The story of the discovery of the triptans has been well documented by the discoverer of sumatriptan, Pat Humphrey [13]. It had been noted in the 1960s that intravenous serotonin appeared to be effective in migraine, but was unsuitable as a treatment due to widespread adverse www.sciencedirect.com
Understanding the pharmacology of headache Rolan 31
effects in the vascular and pulmonary systems. However, it was hypothesised that a selective cerebral vasoconstrictor mimicking some but not all of the effects of 5-HT would be effective. In early clinical development, sumatriptan was noted to cause chest pain reminiscent of angina and given its putative vasoconstrictor properties this was of concern. It is now clear that this is a class effect and only very rarely ever associated with true cardiac ischaemia and hence the nature of this class of symptoms is still unknown. Given that sumatriptan is relatively polar, early studies confirmed that little drug entered the brain [14]; the striking clinical efficacy of injected sumatriptan was taken as confirmation of the vascular hypothesis of migraine and that a selective cerebral vasoconstrictor was a rational treatment. However, subsequent research demonstrated that triptans are not selective cerebral vasoconstrictors but cause a modest reduction of around 15% in conductance vessels throughout the body, and is not selective for the cerebral vasculature [15]. Additionally, a number of unequivocally central phenomena have been ascribed to sumatriptan (and other triptans) and in clinical practice the drug is accompanied by CNS-type adverse effects such as lethargy as reflected in the product information. It is now accepted that at least some of the effects of sumatriptan and other triptans are due to modulation of the ascending central pathways from the trigeminal tract [16]. Although there have been attempts to make triptans with superior pharmacokinetic or pharmacodynamic properties, this is not translated to any one drug being clearly the best in class although individual patients may favour one or the other [17]. Agonists targeted at other non-vasocontrictor 5HT receptors, 5HT1F and 5HT7, show promise [18]. Another class of anti-migraine therapies with rational basis is the small molecule receptor antagonist calcitonin gene-related peptide (CGRP) [19]. CGRP was known to reside in peripheral nerve terminals in the vasculature and confirmation of their role in migraine was confirmed by Goadsby et al. who showed an increase in plasma concentration of CGRP in the internal jugular vein in a patient in the ipsilateral headache side in patients suffering from migraine, and that normalisation of such levels occurred following successful attenuation of the treatment with sumatriptan [20]. Several orally bioavailable small molecule receptor antagonists of CGRP have been in development, but their route to market has been hampered by hepatic toxicity and it is unclear whether any of these will reach commercial success [18,21]. An interesting alternative approach is the use of monoclonal antibodies against the CGRP receptor [21,22]. The potential attractiveness of this approach is a ‘vaccination’ approach in which patients could receive a single injection which may provide prophylaxis for a month or more. However, such antibodies will clearly not cross the blood–brain barrier and www.sciencedirect.com
we await the results of phase II studies to see whether such compounds are effective. In addition to the migraine-specific treatments mentioned above, non-specific analgesics and antiemetics are still the best choice for some patients. Paracetamol, aspirin, other non-steroidal anti-inflammatory drugs are effective [23]. There is a general consensus that opioids and combination products containing opioids, including codeine, are best avoided except for very infrequent use when other acute treatments have failed [24]. Most classes of acute headache therapy have been associated with an increasing frequency of headache, which reduces once the medication is withdrawn, a condition known as medication overuse headache (MOH) [25]. However the class of drugs which has by this far the strongest association with medication overuse headache is the opioid class [26]. We have hypothesised that this is due to paradoxical glial activation causing a chronic neuroinflammatory state [26].
Prophylactic drugs A wide range of drugs has been shown to be efficacious in reducing the frequency of migraine. Generally such drugs reduce the frequency but do not significantly change the attack phenotype although this can occur. There is no currently accepted unifying mechanism by which such drugs work. The majority of migraine prophylactic drugs come from cardiovascular or antidepressant and anticonvulsant classes. Indeed the success of some of the early cardiovascular drugs such as propranolol was taken as confirmation of the vascular hypothesis of migraine. The efficacy of propranolol does appear to be due to its beta blocking action, not from off target effects, as all beta blockers without intrinsic sympathomimetic activity appeared to be effective [27]. Other antihypertensive drugs which are shown efficacy in migraine include candesartan [28] and lisinopril [28]; how the mechanism of action of these drugs are not clear and it is also uncertain whether other drugs of these therapeutic classes are effective. Although all tricyclic antidepressants appear to have some efficacy in migraine [29], this appears to be independent of the antidepressant action and patients did not need to be depressed for them to work. However the selective serotonin reuptake inhibitors appear not to be generally effective in migraine [30] and in a significant number of patients make them worse. The role of the SNRIs is unclear [31]. Tricyclics are the treatment of first choice in tension-type headache, where in fact very few treatments have been shown to be effective [29]. Several anticonvulsants such as valproate [32] and topiramate [33] have been shown in multiple studies to be effective in migraine. These two drugs are approved by regulatory authorities for use in migraine. However this Current Opinion in Pharmacology 2014, 14:30–33
32 Neurosciences
efficacy does not extend generally to other anticonvulsants, and anticonvulsants which have efficacy in neuropathic pain such as the gabapentinoids, are not effective [34]. Hence the mechanisms by which these drugs are effective is unclear. Of the wide range of prophylactic drugs, generally no one drug produces much more than a 50% reduction in headache frequency in about 50% of patients. However although this has not been demonstrated by clinical trials, clinical experience suggests that is not the same patients who respond to all of these medications and others are non-responders. In practice it is worth cycling through several runs of different classes of prophylactic therapy, often failing, before a successful drug is found. This suggests that with the heterogeneous mechanisms by which such drugs are likely to act, different mechanisms may play different roles in individual patients and thus there may not be a unifying mechanism of action. The above prophylactic drugs are rarely disease modifying in an individual patient. Typically when a patient ceases prophylaxis, headache frequency will increase. It is commonly seen in clinical practice that patients may have transformed from an infrequent pattern of migraine to an accelerated phase where they tend to have headache on more days than not. Although medication overuse may be a complicating factor, this acceleration can occur in the absence of medication overuse. The factors that have caused such acceleration have been poorly understood. Recently I and others have hypothesised that activation of the central nervous immune system through microglia may be causing acquired central sensitisation with bilateral communication between activated glia and sensitive neurons. Targeting the central nervous immune system is an entirely novel approach which has the potential to be disease modifying and with treatments that may not produce the typical CNS adverse effects with more neuronally-directed therapies [26]. Additional therapies continue to be discovered even when a clear rational basis does not exist. Botulinum toxin was initially explored in a range of headache conditions and found to be ineffective. On the somewhat flawed rationale that tension-type headache was due to excessive muscle tension, botulinum toxin was trialled in chronic tension-type headache but failed to be efficacious [35]. Without any clear rationale it was tried in migraine again without efficacy [35]. However, when tried in this recently recognised phenotype of ‘chronic migraine’, that is, this accelerated phase of migraine in which patients have headache more days than not, it showed a modest statistically significant superiority to placebo [35]. How a drug which works at the neuromuscular junction is effective in pain without evidence of muscle spasm is unclear but there is some early evidence of the drug being Current Opinion in Pharmacology 2014, 14:30–33
transported centrally after peripheral administration and this may be responsible for this effect. Hence, research in the pharmacology of headache has led to a number of highly effective new treatments benefitting patients. However, there is still major unmet medical need and progress is somewhat difficult through a relative paucity of mechanistic understanding of the various headache phenotypes, however, progress is being made.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, AMPP Advisory Group: Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007, 68: 343-349.
Eikermann-Haerter K, Negro A, Ayata C: Spreading depression and the clinical correlates of migraine. Rev Neurosci 2013, 24:353-363. This paper summarises the current state of knowledge on the relationship between alterations in cerebral calcium channels and cortical spreading depression.
2.
3.
Karatas H, Erdener SE, Gursoy-Ozdemir Y, Lule S, Eren-Koc¸ak E, Sen ZD, Dalkara T: Spreading depression triggers headache by activating neuronal Panx1 channels. Science 2013, 339:10921095. This paper, for the first time, demonstrated that activation of the neuronal Pannexin 1 channel is a plausible link between cortical spreading depression and the sterile inflammatory response which accompanies migraine. 4.
Bendtsen L, Ferna´ndez-de-la-Pen˜as C: The role of muscles in tension-type headache. Curr Pain Headache Rep 2011, 15:451458.
5.
Rozen TD, Fishman RS: Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache 2012, 52:99-113.
6.
Akerman S, Holland PR, Hoffmann J: Pearls and pitfalls in experimental in vivo models of migraine: dural trigeminovascular nociception. Cephalalgia 2013, 33:577-592.
7.
Oshinsky ML, Luo J: Neurochemistry of trigeminal activation in an animal model of migraine. Headache 2006, 46(Suppl 1):S39S44.
8.
Graham JR, Wolff HG: Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 1938, 39:737-763.
9.
Goadsby PJ: The vascular theory of migraine — a great story wrecked by the facts. Brain 2008, 132:6-7.
10. Amin FM, Asghar MS, Hougaard A, Hansen AE, Larsen VA, de Koning PJH, Larsson HBW, Olesen J, Ashina M: Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol 2013, 12:454-461. This paper definitely showed the lack of important vascular changes in migraine. 11. Tfelt-Hansen P, Saxena PR: Ergot alkaloids in the acute treatment of migraines. In The Headaches, 3rd edn.. Edited by Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA.Philadelphia: Lippincott Williams and Wilkins; 2006:459-467. 12. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL: Evidence for possible involvement of 5HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 2000, 102:2836-2841. www.sciencedirect.com
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13. Humphrey PP: The discovery and development of the triptans, a major therapeutic breakthrough. Headache 2008, 48:685-687. 14. Dallas FA, Dixon CM, McCulloch RJ, Saynor DA: The kinetics of 14C-GR43175 in rat and dog. Cephalalgia 1989, 9(Suppl 9):53-56. 15. Dixon RM, Meire HB, Evans DH, Watt H, On N, Posner J, Rolan PE: Peripheral vascular effects and pharmacokinetics of the antimigraine compound, zolmitriptan, in combination with oral ergotamine in healthy volunteers. Cephalalgia 1997, 17:639646. 16. Saxena PR, Tfelt-Hansen P: Triptans, 5-HT1B/1D receptor agonists in the acute treatment of migraines. In The Headaches, 3rd edn.. Edited by Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA.Philadelphia: Lippincott Williams and Wilkins; 2006:469-503. 17. Lipton RB, Cutrer FM, Goadsby PJ, Ferrari MD, Dodick DW, McCrory D, Liberman JN, Williams P: How treatment priorities influence triptan preferences in clinical practice: perspectives of migraine sufferers, neurologists, and primary care physicians. Curr Med Res Opin 2005, 21:413-424. 18. Ramı´rez Rosas MB, Labruijere S, Villalo´n CM, VanDenBrink AM: Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs. Expert Opin Pharmacother 2013, 14:1599-1610. This thorough study showed no clinically significant difference in diameter of extra-cranial or intra-cranial vessels during migraine, further diminishing any change in blood vessel diameter as a minor and not core pathology in migraine. This paper is a thorough review of the mechanism of action of the serotonin-directed acute therapies of migraine. 19. Goadsby PJ: Calcitonin gene-related peptide antagonists as treatments of migraine and other primary headaches. Drugs 2005, 65:2557-2567. 20. Goadsby PJ, Evinsson L, Ekman R: Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990, 28:183-187. 21. Bigal ME, Walter S, Rapoport AM: Calcitonin gene-related peptide (CGRP) and migraine current understanding and state of development. Headache 2013 http://dx.doi.org/10.1111/ head.12179. [Epub ahead of print]. This paper summarises the rationale for the selection of calcitonin gene related peptide as a target for both the acute treatment and prophylaxis of migraine. 22. Greb E: Could an antibody prevent migraine? Neurol Rev 2013, 21 1,30. 23. Tfelt-Hansen P, Rolan P: Nonsteroidal anti-inflammatory drugs in the acute treatment of migraines. In The Headaches, 3rd edn.. Edited by Olesen J, Goadsby PJ, Ramadan NM, TfeltHansen P, Welch KMA.Philadelphia: Lippincott Williams and Wilkins; 2006:449-457.
www.sciencedirect.com
24. Kelley NE, Tepper DE: Rescue therapy for acute migraine, Part 3: opioids, NSAIDs, steroids, and post-discharge medications. Headache 2012, 52:467-482. 25. Katsarava Z, Obermann M: Medication-overuse headache. Curr Opin Neurol 2013, 26:276-281. 26. Johnson JL, Hutchinson MR, Williams DB, Rolan P: Medication overuse headache and opioid-induced hyperalgesia: a review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment. Cephalalgia 2013, 33:52-64. This publication summarises the potential immunological mechanisms by which analgesics, especially opioids, may cause medication overuse headache and potential pathways to inhibit this action. 27. Tfelt-Hansen P, Rolan P: b-Adrenoceptor blocking drugs in migraine prophylaxis. In The Headaches, 3rd edn. Edited by Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA.Philadelphia: Lippincott Williams and Wilkins; 2006:519-528. 28. Rapoport AM, Bigal ME: Preventive migraine therapy: what is new. Neurol Sci 2004, 25:S177-S185. 29. Jackson JL, Shimeall W, Sessums L, DeZee KJ, Becher D, Diemer M, Berbano E, O’Malley PG: Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ 2010, 341:c5222. 30. Moja L, Cusi C, Sterzi R, Canepari C: Selective serotonin reuptake inhibitors (SSRIs) for preventing migraine and tensiontype headaches. Cochrane Datab Systematic Rev 2005 http:// dx.doi.org/10.1002/14651858.CD002919.pub2. Art No: CD002919. 31. Smitherman TA, Brooke Walters A, Maizels M, Penzien DB: The use of antidepressants for headache prophylaxis. CNS Neurosci Ther 2011, 17:462-469. 32. Linde M, Mulleners WM, Chronicle EP, McCrory DC: Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. Cochrane Datab Systematic Rev 2013 http://dx.doi.org/10.1002/ 14651858.CD010611. Art No: CD010611. 33. Linde M, Mulleners WM, Chronicle EP, McCrory DC: Topiramate for the prophylaxis of episodic migraine in adults. Cochrane Datab Systematic Rev 2013 http://dx.doi.org/10.1002/ 14651858.CD010610. Art No: CD010610. 34. Linde M, Mulleners WM, Chronicle EP, McCrory DC: Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults. Cochrane Datab Systematic Rev 2013 http://dx.doi.org/ 10.1002/14651858.CD010609. Art No: CD010609. 35. Jackson JL, Kuriyama A, Hayashino Y: Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults. JAMA 2012, 307:1736-1745.
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