Optimising Migraine Treatment PDF

Pomes et al. The Journal of Headache and Pain (2019) 20:56 https://doi.org/10.1186/s10194-019-1010-3 The Journal of Headache...

Pomes et al. The Journal of Headache and Pain (2019) 20:56 https://doi.org/10.1186/s10194-019-1010-3 The Journal of Headache and Pain REVIEW ARTICLE Open Access Optimising migraine treatment: from drug- drug interactions to personalized medicine Leda Marina Pomes1, Martina Guglielmetti2,3, Enrico Bertamino4, Maurizio Simmaco5,6, Marina Borro5,6 and Paolo Martelletti3,7* Abstract Migraine is the most disabling and expensive chronic disorders, the etiology of which is still not fully known. The neuronal systems, (glutammatergic, dopaminergic, serotoninergic and GABA-ergic) whose functionality is partly attributable to genetically determined factors, has been suggested to play an important role. The treatment of acute attacks and the prophylactic management of chronic forms include the use of different category of drugs, and it is demonstrated that not each subject has the same clinical answer to them. The reason of this is to be searched in different functional capacity and quantity of phase I enzymes (such as different isoforms of CYP P450), phase II enzymes (such as UDP-glucuronosyltransferases), receptors (such as OPRM1 for opioids) and transporters (such as ABCB1) involved in the metabolic destiny of each drug, all of these dictated by DNA and RNA variations. The general picture is further exacerbated by the need for polytherapies, often also to treat comorbidities, which may interfere with the pharmacological action of anti-migraine drugs. Personalized medicine has the objective of setting the optimal therapies in the light of the functional biochemical asset and of the comorbidities of the individual patient, in order to obtain the best clinical response. Novel therapeutic perspectives in migraine includes biotechnological drugs directed against molecules (such as CGRP and its receptor) that cause vasodilatation at the peripheral level of the meningeal blood vessels and reflex stimulation of the parasympathetic system. Drug-drug interactions and the possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale. Drug-drug interactions and their possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale. Keywords: Personalized medicine, Pharmacogenomic, Anti-migraine drugs, Polytherapies, Gepants, Ditans, CGRP monoclonal antibodies Introduction The disorder is more frequent in female (3,1 = F:M) According with World Health Report in 2001, migraine with a peak of prevalence between ages of 22 and 55 is the most disabling and expensive Chronic disorders years old. representing the major cause of non-fatal disease – Genetic factors have been implicated in many aspects related disability. of migraine: the aetiology, the tendency to become Migraine is a common disorder connoted by recurrent chronic, the sensitivity to pharmacological treatment. headache attacks with nausea, vomiting, hyper sensibility The last aspect offers the possibility to design personal- to light, sound and smell (defined as Migraine without ized treatments in order to achieve improved therapeutic aura, MO) and, in 25% of cases, neurological symptoms success. (defined as Migraine with aura, MA). Genetic roots of migraine * Correspondence: [email protected] Glutammatergic, dopaminergic, serotoninergic and 3 Department of Medical, Surgical and Experimental Sciences, University of GABA-ergic systems are implicated in the Migraine Sassari, Sassari, Italy Headache etiology. Genetic variations affecting expres- 7 Internal Medicine and Emergency Medicine Unit, Sant’Andrea Hospital, Rome, Italy sion in terms of quality and quantity of proteins, en- Full list of author information is available at the end of the article zymes, receptors and channels belonging to these © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Pomes et al. The Journal of Headache and Pain (2019) 20:56 Page 2 of 12 systems have been widely described [5–7] and the gen- non-appropriate drugs, choosing an alternative medication etic component of the disease is estimate around a 50%. in the same pharmacological class. Linkage analysis and genome-wide association studies Moreover, in the next future it will be possible to de- (GWAS) have been conducted on patients with common sign new drugs targeted on a patient’s genetic trait. migraine. However, linkage analyses have minimal power By cross-referencing the data relating to each drug of detection when studying genetic bases of complex traits used in a politreated patient, it is possible to predict and multifactorial disease such migraine (not showing a drug-drug interactions using web-based knowledgebases. simple Mendelian pattern of transmission), and most re- The same interactions impact differently on the meta- sults proved to be “false” positive, failing to be replicated bolic destiny of each of the other drugs included in the in larger cohorts or being contradictory. Differently, therapy, so it is possible, in light of the patient’s genomic GWAS are based on genome-wide data mining on auto- profile, to optimize the therapeutic choices by entrusting matic array platforms in which hundreds of thousand treatment to drugs that do not interfere with each other SNPs are queried and showed a high power to detect and do not interfere with the profile of the patient in common variants related to migraine. Among these, question. some are involved specifically in the susceptibility to the Many drugs are metabolized by isoforms of Cyto- development of the pathology [8, 9], as polymorphisms in chrome P450, membrane-associated proteins in the the encoding endothelin type A receptor (EDNRA), meth- endoplasmic reticulum , and different studies show ylenetetrahydrofolate reductase (MHTFR), endothelial ni- as they are particularly important in drugs used in mi- tric oxide synthase (NOS3), angiotensin-converting graine therapy. enzyme (ACE), β-2 transforming growth factor (TGFB2) Here we consider the most frequent pharmacological and its receptor (TGFB2R), neurogenic locus notch classes used in the treatment of migraine attacks such as homolog protein 3 (NOTCH3). NSAIDs, triptans and opioids, moreover we consider tricyc- Therapeutic failure could be traced back to the use of lic antidepressants most used in prophylactic therapy. drugs undergoing non-optimal metabolism in a specific patient. Treatment failure can in turn lead to overuse of NSAIDs acute medication, often without great results. Overuse of NSAIDs represent the most frequent drug’s class used acute medication is commonly identified as the most im- by migraine sufferers (with at first place Ketoprofen, portant risk factors for chronic headache (CH, group of used in 41% of cases in migraine attack). headaches occurring daily or almost daily) and a causa- This medications’ metabolism depends on the phase I tive factor for medications overuse headache (MOH) metabolic enzymes CYP P450, in particular CYP2C9 and. About the genetic liability of this last form of com- CYP2C8 and frequently on the phase II metabolic en- plication of migraine (MOH), such as for the common zyme UDP-glucuronosyltransferases [20, 21]. ones’, an involvement of some polymorphisms of 5HTT Among the SNPs indentified in the CYP2C9 gene, the (such as the 5-HTTLPR) [11, 12] has been hypothesized. *2 (rs1799853) and the *3 (rs1057910), coding for a Moreover, drug dependence has been associated to poly- change of amino-acid sequence, are those associated morphism in genes regulating monoaminergic transmis- with significant reductions of enzyme activity [22, 23]. sion. Approximately 35% of the human total CYP2C-encoded enzymes in the liver belong to the CYP2C8 subfamily Pharmacogenomics. Among the 16 allelic variants of CYP2C8, the *2, and The fact that only the 50% of migraine patients ad- *5 are clinically the most important , but also the *3 equately respond to acute and prophylaxis therapies sug- and the *4 are often detected, also if with different fre- gest that migraine patients react differently to given quencies between races. drugs. The patient’s response (efficacy and toxicity) In patients carriers of these variants a reduction in to a drug is affected by DNA and RNA variations in that therapeutic efficacy (by reducing metabolism or clear- patient, resulting in different rates of therapeutic effect ance), and an increase in dose-dependent adverse effects as in different risk of adverse events, also burdening the , are frequent, i.e. CYP2C8*3, CYP2C9*2, *3 and health expenses [15–17]. UGT2B7 coding for a low-activity enzyme are implicated The genomic characterization of the allelic variants car- in the hepatotoxic effects of Diclofenac [25, 27] [Fig. 1], ried by the patients allows identification of drug-interacting whereas the loss of function allele CYP2C9*3, is associ- proteins (metabolic enzymes, transporters, targets) with an ated to a reduction of celecoxib clearance compared to altered activity. Since alteration of the drug-protein interac- the wild type [Fig. 2]. tions can change both the pharmacokinetic and pharmaco- An example of the particular involvement of UGTs in dynamic profiles of the administered drug, recognition of the metabolism of some NSAIDs is represented by as- such alteration may be used to avoid administration of pirin. Aspirin is deacetylated to salicylic acid, which Pomes et al. The Journal of Headache and Pain (2019) 20:56 Page 3 of 12 Fig. 1 Diclofenac metabolic profile. In the left column there is the list of drug metabolizing enzymes and drug transporters, one for each row; in the right column relationship between corresponding transporter or enzyme of the row and diclofenac: is indicated by the symbol ‘S’ for substrate, ‘Inh’ for inhibitor and ‘Ind’ for inducer. Enzymes CYP 2C9, CYP2C8 and UGT and transporter MRP2 (ABCC2) are rimmed to emphasize their importance in diclofenac’s metabolic destiny. Related page at the website http://bioinformatics.charite.de/transformer Fig. 2 Celecoxib metabolic profile. In the left column there is the list of drug metabolizing enzymes and drug transporters, one for each row; in the right column relationship between corresponding transporter or enzyme of the row and celecoxib: is indicated by the symbol ‘S’ for substrate and ‘Inh’ for inhibitor. Enzyme CYP 2C9 is rimmed to emphasize their importance in celecoxib’s metabolic destiny. Related page at the website http://bioinformatics.charite.de/transformer Pomes et al. The Journal of Headache and Pain (2019) 20:56 Page 4 of 12 forms two hippuric acids (salicyluric and gentisuric) and constitution and migraine drug response have been two glucuronides. Salicylic acid accounts for 20–60% of showed also by Christensen et al. the product while metabolites from glucuronidation are At support of the heterogeneity in hepatic metabolism, 1–42%. Glucuronidations is supported by different likely due to MAO-A and CYP1A2, in different studies UGT isoforms including 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, conducted on in migraine patients outside attacks, dur- 1A9, 1A10, 2B4, 2B15 AND 2B17. So, the reduction ing attack and in healthy volunteers significant of the activity of UGTs can produce a reduction of a inter-individual variability was observed in the measured great part of the metabolism of the aspirin [Fig. 3]. plasma levels of different triptans in different situations It is also important to underline that some of the ABC such as Cmax after oral administration of Sumatriptan members (like ABCC2 and ABCC3) drug transporters (metabolised by MAO-A), rather than 2 h after the can modulate the hepatobiliary and renal transport and administration of Zolmitriptan (metabolised by excretion, i.e. loss of function of these proteins can pro- CYP1A2 and MAO-A) [Fig. 4]. duce accumulation of reactive diclofenac glucuronides It is very interesting to cite the observations of Gentile producing the effect of acute toxicity [31, 32] [Fig. 1]. et al. taking studying the CYP1A2, and in particular of the * 1F; they observed a higher frequency of -163A al- Triptans lele in abuser than non-abusers of drugs, hypothesizing Triptans are used for acute treatment of migraine at- that the -163A allele was associated to a faster degrad- tacks, and their pharmacological action is based on the ation of the drug. stimulation of serotonin receptors. Some individual genetic traits have been associated Opioids with the variability in triptans response, as SNPs in- Treatment of chronic pain is in someone entrusted to volved in transduction signal via HT1B/1D (i.e. rs5443 use of opioids. in the gene coding the G protein β3 subunit ) and This pharmacological category is even more compli- SNPs in metabolic genes involved in triptans’ degrad- cated than the previous ones because, in addition to the ation (MAO-A and CYP1A2 and 3A4). in particular, aspects related to the enzymatic stations involved in the Schürks et al. described as in a German sample rs5443 metabolism (mainly CYP2D6), the responsiveness to the in heterozygosity (C825TC) had a positive predictive opioid’s category is also related to the expression of ded- value for triptans response of 0.82 and a negative one of icated mu receptors (OPRM1), which also present poly- 0.35. Additionally, the association between genetic morphic alleles with differential functionality. Fig. 3 Aspirin metabolic profile. In the left column there is the list of drug metabolizing enzymes and drug transporters, one for each row; in the right column relationship between corresponding transporter or enzyme of the row and aspirin: is indicated by the symbol ‘S’ for substrate, ‘Inh’ for inhibitor and ‘Ind’ for inducer. Enzyme UGT is rimmed to emphasize their importance in aspirin’s metabolic destiny. Related page at the website http://bioinformatics.charite.de/transformer Pomes et al. The Journal of Headache and Pain (2019) 20:56 Page 5 of 12 Fig. 4 Sumatriptan and Zolmitriptan metabolic profile. From left to right, in the first column there is the list of drug metabolizing enzymes, one for each row; in the second and third columns relationship between corresponding enzyme of the row and Sumatriptan (second column) and Zolmitriptan (third column): is indicated by the symbol ‘S’ for substrate. Enzyme CYP1A2 is rimmed to emphasize their importance in these triptans’ metabolic destiny. Related page at the website http://bioinformatics.charite.de/transformer Genetic polymorphisms of CYP2D6 impact on the me- more noradrenergic effect) and secondary amines (with tabolism of this category when subjects are poor meta- a more serotoninergic effect). bolizers and when are ultra-rapid metabolizers. I.e. By CYP2C19, tertiary amines are metabolized (de- Tramadol is a pro-drug metabolized by CYP2D6 in to methylation) in secondary amines, both secondary and its active metabolite O- desmethyltramadol [Fig. 5]. tertiary amines are metabolized to less active metabolites There are experimental studies that show how patients by CYP2D6 (hydroxylation), so it’s clear as CYP2C19 poor metabolizers had little clinical effect related to a impacts the ratio of tertiary amines to secondary amines serum concentration of the active metabolite of the plasma concentration, but its weight on overall drug lower drug compared to the dosage of tramadol admin- clearance is lower than CYP2D6 [Figs. 6,7,8]. istered, ultra-rapid metabolizers tend to reduced experi- It is easy to guess why often interindividual differences mental pain concurrently with a wise increase in serum of plasma concentration, which are reflected in different levels of the drug [38, 39]. incidence of side effect and treatment response, are reg- In conditions of normal expression of OPRM1, poor istered. These differences are associated with the highly metabolizer, not metabolizing drug, will not use it, so polymorphic CYP2D6 (more of 100 allelic variants and therapeutic effect will not be obtained. Ultra-rapid one sub-variants identified) and CYP2C19 (more of 30 allelic can obtained the effect but for considerably shorter variants and sub-variants identified). In both cases, eth- times than normal, leading to an increase in the number nic differences were observed in the distribution of allele of administrations and doses, this could fuel an addictive frequencies [41, 42]. So, knowing CYP2D6 e CYP2C19 mechanism towards the drug. genomic variants of a patients we could modify pharma- About the receptor, SNP identified in the region of cotherapy (type and dosage of TCAs) potentially im- OPRM1 leads to a substitution of aspartate for aspara- proving clinical outcomes and reducing the rate of gine, altering N-glycosilation of the receptor protein, this treatment’s failure. influence patients’ response to therapeutic effect of opi- There are documented cases of CYP2D6 ultrarapid pa- oids. Moreover, there are discordant opinions about the tients who received large doses of tricyclic to achieve tendency of subjects with OPRM1 rs1799971 to make a therapeutic concentrations exposing the patient himself higher use of opioids [40, 20]. to increased risks of adverse effects , likely in CYP2D6 poor patients in which a therapeutic dosage of Tricyclic antidepressants (TCAs) plasma concentrations was not proportionally raised Still used to treat depression, their main therapeutic use. In similar situation, in both cases, therapeutic drug is in pain management. TCAs are mixed serotonin and monitoring is strongly recommended. norepinephrine reuptake inhibitors distinguished accord- In patients CYP2C19 ultrarapid, by extrapolated phar- ing to the chemical structure in tertiary amines (with a macokinetic data, it could be said that they need Fig. 5 Tramadol metabolic profile. In the left column there is the list of drug metabolizing enzymes and drug transporters, one for each row; in the right column relationship between corresponding transporter or enzyme of the row and tramadol: is indicated by the symbol ‘S’ for substrate and ‘Inh’ for inhibitor. Enzyme CYP2D6 is rimmed to emphasize its importance in tramadol’s metabolic destiny. Related page at the website http://bioinformatics.charite.de/transformer Pomes et al. The Journal of Headache and Pain (2019) 20:56 Page 6 of 12 Fig. 6 Metabolic destiny of secondary and tertiary amines. Tertiary amines trough a reaction of demethylation supported by CYP2C19 are metabolized in Secondary amines; both tertiary and secondary amines are metabolized in less active metabolites by a reaction of hydroxylation supported by CYP2D6 increased doses of tertiary amine , as well as poor down between each drug. In fact, it must be also consid- ones are expected to have an increase of plasma concen- ered how the risk of toxicity and inefficacy of a polyther- tration if given the same dose. apeutic regime is partly attributable to the mechanism Therefore, combination of traits different from exten- for which the pharmacological effect of a drug varies sive one, of both CYP and in the same patient could due to the simultaneous biological action of an add- produce additive pharmacokinetic effects in tricyclic’s itional drug on the metabolic stations used for the me- proprieties. tabolism of the first drug, but equally and with reversed roles applies to the second drug too: the efficacy or pos- Politherapy: the obstacles between DDI and the genetic sible toxicity of a pharmacological cocktail is partly at- trait tributable to the drug-drug interactions (DDIs) that are According with how until now explained and in consid- established between the various drugs in therapy. eration of the fact that, as reported by the studies of Fer- It’s clear that the more drugs are present into the thera- rari et al. , it’s common practice to treat migraine peutic regimen, the more DDIs need to be considered. with multiple types of medications, the limit of patient’s Therefore, it is evident that the multiple comorbidities genetic is compounded by interaction that can settle that frequently occur in specific subsets of patients with Fig. 7 Tertiary amines metabolic profile From left to right, in the first column there is the list of drug metabolizing enzymes, one for each row; in the second, third, fourth, fifth and sixth columns relationship between corresponding enzyme of the row and different Tricyclic: is indicated by the symbol ‘S’ for substrate, ‘Inh’ for inhibitor and ‘Ind’ for inducer. Enzymes CYP2C19 and 2D6 are rimmed to emphasize their importance in these tertiary amines’ metabolic destiny. Related page at the website http://bioinformatics.charite.de/transformer Pomes et al. The Journal of Headache and Pain (2019) 20:56 Page 7 of 12 Fig. 8 Secondary amines metabolic profile. From left to right, in the first column there is the list of drug metabolizing enzymes, one for each row; in the second and third columns relationship between corresponding enzyme of the row and different Tricyclic: is indicated by the symbol ‘S’ for substrate, ‘Inh’ for inhibitor and ‘Ind’ for inducer. Enzyme 2D6 is rimmed to emphasize their importance in these secondary amines’ metabolic destiny. Related page at the website http://bioinformatics.charite.de/transformer migraine (cardiovascular, cerebrovascular, psychiatric In fact, it’s evident as drugs present in the proposed regi- and musculoskeletal) [47–49] and which require the men impact in a different way (as substrate, inhibitors introduction of other drugs into therapy, further compli- and inductors) on differently enzymatic stations vari- cate the situation. ously important for the drug category considered. Moreover, as previously demonstrated, genetic trait of pa- If to that an unfavourable genetic trait is added, as in tient impacts further on the efficacy and toxicity of a drug. the example patient (poor metabolizer for CYP 2D6 and When a therapy is based on more than one drug, the ther- CYP2C19, and with reduction of activity of CYP 2C9), apist has to consider the situation in all its completeness. it’s clear that therapeutic regimen is not well thought Unfavourable drug-drug and/or drug-drug-genome inter- out. Probably Amitriptyline will not work (it’s a tertiary action can represent greats risk factor in the development amine that need to be transformed by CYP2C19 in sec- of adverse drug reaction (ADRs), related to deficient thera- ondary to be then hydrossilated by 2D6), the same for peutic effect or toxicity. And in these ADRs the pos- Captopril (substrate of CYP2D6), Carvedilol (substrate sible real motivation of many of the therapeutic failures of CYP2C9 and 2D6), Ibuprofen (substrate and inhibi- that aggravate already complicated clinical pictures is to be tors of CYP2C9), Losartan (inhibitor and substrate of found, they maintain the pathogenetic processes and induce CYP2C9, inhibitor of CYP2C19), Omeprazol (primary the chronification of the pathology. substrate, inductor and inhibitor of CYP2C19, but more- For the explanatory purpose of the above-mentioned, over substrate and inhibitor of CYP2C9 and inhibitor of let consider the plausible situation of a patient suffering 2D6) and Torasemide (substrate of CYP2C9 and inhibi- from arterial hypertension and chronic migraine. The tor of 2C19). These only citing the enzymatic stations patient in question is treated for the arterial hyperten- that would show a reduced activity on the basis of the sion with a sartan (Losartan), a β-blocker (Carvedilol), genetic trait. an Ace-inhibitor (Captopril), a diuretic (Torasemide); for A therapeutic approach based on the personalized the prophylactic treatment of migraine, he takes a tricyc- medicine allows to remedy similar situation by setting lic (Amitriptyline); during migraine attacks he uses an from the beginning a therapy based on drugs metabolic- NSAID (Ibuprofen); to complete this therapeutic regi- ally non-interfering with each other and with the func- men employs a PPI (Omeprazol) [Fig. 9]. tional biochemical profile of the patient, or alternatively, Without information about the genetic profile of the in the case of already established therapies, adjusting the patient, it is possible to state that the therapeutic regi- shot making the therapeutic regime more effective and men is not the best under the metabolic point of view. avoiding the ADRs that can develop due to unfavourable Pomes et al. The Journal of Headache and Pain (2019) 20:56 Page 8 of 12 Fig. 9 Drug-drug interaction involved in a polytherapy for hypertension, prophylactic therapy for chronic migraine and episodes of acute attacks. From left to right, in the first column there is the list of drug metabolizing enzymes, one for each row, each following column represent a drug the relationship between a drug and an enzyme/transporter is indicated by the symbol ‘S’ for substrate, ‘Inh’ for inhibitor and ‘Ind’ for inducer. The colours of different rows indicate the increase in metabolic pressure passing by the various colours ranging from yellow to orange, to red, to dark red. Related page at the website http://bioinformatics.charite.de/transformer drug-drug and/or drug-drug-genome interactions. In re- CYP2C19 and is not substrate and inhibitor of CYP2C9 ferring to previous example, the therapeutic regimen and inhibitor of 2D6), at last in case of acute attacks as could be optimized choosing drugs compatible both with NSAIDs Ketorolac (that differently from Ibuprofen is biochemical profile of the patient and with his clinical not substrate and inhibitors of CYP2C9). Moreover, in necessity, for example selecting as sartan Eprosartan this way, drug-drug interactions that can be unfavour- (that differently from Losartan is only inhibitor, but not able on other metabolic stations are drastically reduced. substrate of CYP2C9, ant it is not inhibitor of [Fig. 10]. CYP2C19), as β-blocker Esmolol (that differently from Carvedilol not is substrate of CYP2C9 and CYP2D6), as New therapeutic perspectives Ace-inhibitor Enalapril (that differently from Captopril The possibility of a personalized pharmacological poly- is not substrate of CYP2D6), as diuretic Furosemide pharmacy, calibrated on the patient’s functional bio- (that differently from Torasemide not is substrate of chemical abilities and on the further therapeutic CYP2C9 and inhibitor of CYP2C19), as tricyclic Mapro- necessities dictated by the comorbidities of the same, tyline (that differently from Amitriptyline it is only sub- seems to contrast with some biotechnological drugs, al- strate but not inhibitor of CYP2D6 and is not substrate beit with the limit of being mostly still under study. It’s a of CYP2C19), as PPI Esomeprazole (that differently from matter of monoclonal antibodies, antagonist molecules Omeprazol is only inhibitor but not substrate of and agonist molecules crucial in migraine mechanism. Pomes et al. The Journal of Headache and Pain (2019) 20:56 Page 9 of 12 Fig. 10 Drug-drug interaction involved in optimized polytherapy for hypertension, prophylactic therapy for chronic migraine and episodes of acute attacks optimization of previous therapy. From left to right, in the first column there is the list of drug metabolizing enzymes, one for each row, each following column represent a drug the relationship between a drug and an enzyme/transporter is indicated by the symbol ‘S’ for substrate, ‘Inh’ for inhibitor and ‘Ind’ for inducer. The colours of different rows indicate the increase in metabolic pressure passing by the various colours ranging from yellow to orange, to red, to dark red. X = link to related scientific articles about the items in the first column accessible through the related page at the website http://bioinformatics.charite.de/transformer These not having a metabolic destiny, or rather not be- against CGPR have been developed for prophylactic ing subjected to enzymatic transformations or substrates purposes. of membrane transporters, allow to bypass the obstacles dictated by different functional biochemical settings of Gepants each individual patient and by the metabolically Gepants are non –peptide CGRP able to reduce the unfavourable drug interactions, common in the activity of the trigeminal- vascular system. Their ef- polytherapies. fectiveness is similar to the triptans one, but differ- One of the pathogenetic mechanisms under study for ently from triptans not inducing vasoconstriction, the structuring of the drugs in question is represented gepants have no side effect related to this event. by the activation of trigeminal neurons which involves Moreover, they show a prolonged effect of action the release of some neuropeptides (CGRP substance P, compared to the triptans. PACAP and nitric oxide). These cause at the peripheral Among these, olcegepant (BIBN4096BS) is the first level vasodilatation of the meningeal blood vessels and neuropeptide antagonist of CGRP receptor used with reflex stimulation of the parasympathetic system. In success since 10 years. This drug binds a part of the particular, to date, therapeutic drugs interfere with the CGRP receptor (RAMP1), competing with endogenus vasodilatory mechanism induced by the CGRP are in use CGRP. Unfortunately, the bioavailability is reduced and object of study. Regarding the use in the acute by oral abministration because this drug has a poor phase, two categories of drugs have been designed penetration across the Blood-brain barrier (BBB), in fact (Gepants and Ditans), whereas monoclonal antibodies it proves effective after intravenous administration, this Pomes et al. The Journal of Headache and Pain (2019) 20:56 Page 10 of 12 constitutes an obstacle to the common use from migrai- antibodies are to be found in the protective role of neurs. CGRP. This is able to counteract the development of Telcagepant (MK - 0974) is the oral CGRP receptor hypertension, because it has a direct action on smooth antagonist developed following in the footsteps of the muscle cells in the vessel wall, particularly marked at the olcegepant. It is rapidly absorbed, with a Tmax of 1.5 h microvascular level, to which it is attributed the estab- and terminal half-life 6 h , it proves effective in treat- lishment of peripheral resistance and so of the blood ing migraine associated symptoms, such as photophobia, pressure. In the same way, having CGRP an vasodilatory phonophobia and nausea. But the most important side effect, the use of this monoclonal antibodies induces a effect is a hepatotoxicity that may be dose- and reduction of CGRP’s in cardio-protective mechanisms time-dependent in consideration to an observed increase during ischemia. The unique drug directed against in transaminases. the receptor is Erenumab, the other ones (Galcanezumab, Ubrogepant (MK-1602) and Rimegepant (BMS-927711) Fremanezumab and Eptinezumab) are directed against actually at phase III of study, represents the latest gepants CGRP. object of study, but there are currently no definitive data Erenumab is a human immunoglobulin G2 monoclo- regarding efficacy, bioavailability of side effects of such nal antibody designed specifically to bind and antagonize drugs. the calcitonin gene-related peptide receptor (CGRPR). The most common side effects of erenumab include Ditans pain, redness, or swelling at the injection site, and Ditans are agonist of 5-HTR selective for the type 1F, constipation. this one decreases the release of excitatory transmitters Galcanezumab is a fully humanized monoclonal anti- and CGRP in a trigeminal-vascular system. Differently body against human calcitonin gene-related peptide from triptans, that bind to the 5HT 1B e 5HT 1D recep- (CGRP), is administered as a subcutaneous injection. tors, they do not induce peripheral vasoconstriction des- There are clinical evidence that shown a significant re- pite having a similar therapeutic efficacy on the duction in the mean number of migraine headache days migraine. So, they are better tolerated and with less con- and a drug’s good tolerability profile. The most traindications related to the peripheral vasoconstriction commonly reported adverse events are headache, naso-. The most used today is Lasmiditan, that was shown pharyngitis, hematuria, dermatitis, diarrhea, toothache, to be efficacious and well tolerated in the treatment of and increased alanine aminotransferase (ALT). acute migraine in patients with a high level of cardiovas- Fremanezumab is a genetically engineered humanized cular risk factors. monoclonal antibody against human calcitonin gene-related peptide (CGRP). Ongoing clinical trials CGRP monoclonal antibodies for the agent are directed to people with episodic and The use with a prophylaxis purpose is supported by their chronic migraine as well as cluster headaches. It is adminis- lower onset of action and much longer half-life, differ- trated in a monthly subcutaneous injection. The most ently from CGRP receptor antagonist. Compared to commonly reported adverse events included injection site other drugs used in prophylaxis CGRP monoclonal anti- erythema, injection site induration, diarrhea, anxiety, and bodies might be administrated less frequently, in fact depression. previous drugs (like triptans) are recommended orally Eptinezumab is a fully humanized IgG1 antibody man- one to three times daily, antibodies one up to once a ufactured using yeast. It is currently in clinical trials month. Compared from CGRP’s receptor antago- for preventing migraine attacks. It has been specifically nists these monoclonal antibodies are highly selective, designed to bind to both alpha and beta forms of the hu- this avoids the reported toxic effects of CGRP’s receptor man calcitonin gene-related peptide (CGRP). The most antagonists. Moreover, different studies, as early clinical frequent adverse events include upper respiratory tract trials, have also shown that humanized monoclonal anti- infection, urinary tract infection, fatigue, back pain, arth- bodies against CGRP have proven successful in reducing ralgia, and nausea and vomiting. the frequency of migraine headaches as a preventative therapeutic. However, there are polymorphism in Conclusions the CGRP receptor pathway, which have been investi- A personalized approach for setting the therapies that gated, that increase the risk of migraine evolution into every patient needs, dictated by the evaluation of the co- the complication of medication oversue. We also morbidities and the functional biochemical structure of have to mention a negative study on this matter reveal- the same, represents a goal in the therapeutic field by re- ing that polymorphism in CGRP pathaways might be the ducing the possibility of establishing side effects related signal of differences between CGRP mAB responders vs. to therapies that affect the clinical course of each pa- non-responders. The side effects of this monoclonal tient. The new biotechnological drugs currently being Pomes et al. The Journal of Headache and Pain (2019) 20:56 Page 11 of 12 studied could represent a valid alternative that needs to Received: 18 January 2019 Accepted: 5 May 2019 be further refined to date, with the aim of reducing the already highlighted limitations of the same correlated to the contraindications linked to the comorbidities and to References the adverse effects recorded. 1. World Health organization. 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