Role of voltage-gated sodium channel blockers in the treatment of chronic pain: Potential uses in clinical practice based on available evidence | Revista Española de Anestesiología y Reanimación (English Edition)

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Alcántara Montero, C.I. Sánchez Carnerero" "autores" => array:2 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Alcántara Montero" "email" => array:1 [ 0 => "a.alcantara.montero@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "C.I." 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Long-term opioid treatment for chronic pain has increased dramatically in recent years, particularly in the United States, despite insufficient evidence of long-term benefits and increasing evidence of harmful effects.<a class="elsevierStyleCrossRef" href="#bib0260">3</a> There are no studies comparing long term (over 1 year) opioid therapy versus placebo, treatment without opioids, or other therapies.<a class="elsevierStyleCrossRef" href="#bib0260">3</a> Tapering opioids can be a challenge for both patients and doctors. In clinical practice, long-term opioid treatment is only discontinued in 8–35% of patients, according to cohort studies.<a class="elsevierStyleCrossRef" href="#bib0265">4</a> However, there is little evidence to guide clinicians through the process of tapering opioid therapy.<a class="elsevierStyleCrossRef" href="#bib0270">5</a> In addition, the number of alternative therapeutic options is limited, and many clinicians have difficulty distinguishing between non-opioid analgesics.It is imperative to approach and treat chronic pain with specific therapies for each pain syndrome. Although opioids may be indicated in some patients, it is difficult to control pain and reduce dependence on opioids without fully understanding which non-opioid drug therapies to choose. Therefore, it is essential to understand the risks and benefits of each therapeutic alternative and each adjuvant drug, in order to combat the current opioid epidemic and offer adequate treatment for chronic pain.Nowadays, clinicians tend to base chronic pain management on the pathogenesis of pain. Therefore, in addition to, clinicians are urged not only to evaluate the pathology that triggers the pain, but also to characterise the type of pain based on the neurophysiological mechanisms involved, differentiating between nociceptive and neuropathic pain.<a class="elsevierStyleCrossRef" href="#bib0275">6</a> Once this has been determined, the next key step is to choose the right drug for each type of pain. Many clinicians are generally familiar with first-line treatments for inflammatory pain and neuropathic pain. However, once first-line treatment has failed, many doctors admit that they lack the knowledge necessary to differentiate between or effectively administer second-line treatment options.Voltage-gated sodium channel blockers, specifically, carboxamides, which include carbamazepine (CBZ), oxcarbazepine (OXC) and, more recently, eslicarbazepine acetate (ESL), could be one of the most under-prescribed pain management alternatives. This could be due to the limited amount of experience and data available on these drugs compared to first line treatments. However, good pain management depends on familiarity with second- and third-line treatment, and understanding the role of each therapeutic class in the treatment regimen. In order to choose between alternative therapies, clinicians must understand the pharmacology and pharmacokinetics of each drug, and be aware of the available evidence supporting specific treatments for various chronic pain conditions. The aim of this article is to update evidence for the clinical use of voltage-gated sodium channel blockers, clarify misconceptions surrounding their use, and highlight emerging research on better pain targets that warrant further analysis.For this purpose, we searched PubMed and Google Scholar for the most significant studies on this topic, using the following search criteria: “carbamazepine”, “oxcarbazepine” and “eslicarbazepine acetate” in combination with “neuropathic pain”, “inflammatory pain”, and “chronic pain management”. We also consulted the summary of product characteristics of CBZ, OXC and ESL to ascertain the adverse reactions, bioavailability, pharmacological and pharmacokinetic data of each drug.Voltage-gated sodium channels as therapeutic targets in pain managementVoltage-gated sodium channels (Nav) contribute to pain syndromes by facilitating electric transmission and increasing the density of sodium channels around the lesion; both these mechanisms cause hyperexcitability and enhanced sensory transmission.<a class="elsevierStyleCrossRefs" href="#bib0280">7,8</a> Nine voltage-gated sodium channels subtypes have been identified (Nav1.1-1.9), and several Navs have been linked to the transmission of inflammatory, nociceptive and neuropathic pain<a class="elsevierStyleCrossRefs" href="#bib0280">7–11</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Researchers have recently identified specific Navs that correlate with specific types of pain. This shows that targeting hyperactive channels may oversimplify the complex biological processes involved in pain signalling.<a class="elsevierStyleCrossRefs" href="#bib0290">9,11</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Nav1.9 mainly occurs in the peripheral nervous system, whereas Nav1.8 is mostly found in the C fibres of the dorsal root ganglion. However, evidence supporting the presence of Nav1.7, Nav1.8 and Nav1.9 channels in small-diameter dorsal root ganglion neurons, most of which are nociceptive,<a class="elsevierStyleCrossRefs" href="#bib0295">10,12</a> has highlighted their involvement in the transmission of pain signals. Sodium channels subtypes are classified as tetrodotoxin-resistant (TTX-R) or tetrodotoxin-sensitive. Nav1.8 and Nav1.9 are TTX-R.<a class="elsevierStyleCrossRef" href="#bib0295">10</a> Studies have shown that TTX-R currents carry the majority of charge during action potentials in nociceptive neurons, and this is dynamically regulated in response to injury<a class="elsevierStyleCrossRefs" href="#bib0295">10,11</a>. Increased TTX-R channel activity has been observed after inflammation associated with dorsal root ganglion neurons.<a class="elsevierStyleCrossRef" href="#bib0295">10</a> Similarly, inflammatory mediators have been shown to regulate Nav1.8 and Nav1.7. These mediators are associated with increased expression and enhanced electrical activity of Nav 1.9, which suggests they play a role in maintaining the inflammatory response.<a class="elsevierStyleCrossRefs" href="#bib0295">10,11</a> Likewise, elevated Nav1.8 protein levels have been observed in dorsal root ganglion neurons surrounding the inflamed limbs.<a class="elsevierStyleCrossRef" href="#bib0300">11</a> Several studies mention the association between Nav1.7 and mechanical and inflammatory pain, Nav1.8 and visceral pain, and Nav1.9 and the transmission of inflammatory pain signals.<a class="elsevierStyleCrossRef" href="#bib0300">11</a> Evidence also suggests that Nav1.8 could participate in neuropathic pain.<a class="elsevierStyleCrossRef" href="#bib0300">11</a>Nav expression and alteration also occurs in certain disease conditions and pain syndromes. It has been hypothesised that up-regulation of the sodium channel beta2-subunit is associated with allodynia.<a class="elsevierStyleCrossRef" href="#bib0300">11</a> It has been reported that Nav1.3 is only detectable in injured nerves, and expression increases in dorsal root ganglion neurons due to nerve lesions.<a class="elsevierStyleCrossRefs" href="#bib0280">7,11</a> Nav1.3, Nav1.6, Nav1.7 and Nav1.9 have been shown to increase in diabetic neuropathic pain.<a class="elsevierStyleCrossRef" href="#bib0300">11</a> Nav1.3 expression was reported to increase at the site of peripheral nerve damage and in the nociceptive dorsal horn neurons after an experimental spinal cord injury<a class="elsevierStyleCrossRef" href="#bib0280">7</a>; it is also believed that Nav1.3 could be involved in neuropathic pain after nerve and spinal cord injuries. Nav1.2 is mainly expressed in unmyelinated axons, and has been associated with multiple sclerosis.<a class="elsevierStyleCrossRef" href="#bib0300">11</a>Nav mutations are also associated with various pain syndromes.<a class="elsevierStyleCrossRefs" href="#bib0280">7,12,13</a> A Nav1.7 mutation has been linked to erythromelalgia in humans.<a class="elsevierStyleCrossRefs" href="#bib0280">7,12</a> Mutations in Nav1.7, Nav1.8 and Nav1.9 have been closely and specifically liked to neuropathic pain.<a class="elsevierStyleCrossRefs" href="#bib0290">9,13,14</a> Nav1.8 is expressed in Purkinje neurons in multiple sclerosis, and deletions in the SCN10A gene have been shown to predict the degree of cerebellar dysfunction in this disease.<a class="elsevierStyleCrossRef" href="#bib0285">8</a> Finally, in patients with paroxysmal extreme pain disorder, there is evidence that Nav1.7, despite being activated by normal stimuli, does not deactivate correctly, which leads to persistent sodium influx.<a class="elsevierStyleCrossRef" href="#bib0300">11</a>Targeted treatment for specific pain conditions using an associated sodium channel subtype is a promising field of research, and has the potential to transform both the state of the knowledge and clinical pain management. There is no guarantee that pharmacological compounds that selectively inhibit individual Navs can be designed successfully. However, research is currently under way into 2 drugs, one that selectively targets Nav1.7, and another that selectively targets Nav1.8.<a class="elsevierStyleCrossRefs" href="#bib0285">8,15,16</a> Recently, a Nav1.7 selective sodium channel blocker (BIIB074) was evaluated in patients with trigeminal neuralgia in a Phase 2a trial.<a class="elsevierStyleCrossRef" href="#bib0330">17</a> The sample size was small, and the results were not statistically significant, but there were almost twice as many treatment failures in the placebo group compared to BIIB074.<a class="elsevierStyleCrossRef" href="#bib0330">17</a> On the basis of these promising results, new clinical trials are currently being conducted in both trigeminal neuralgia and other pain syndromes (such as small fibre neuropathy, erythromelalgia and lumbosacral radiculopathy).This shows the need for further research to determine the receptor subtypes associated with each of the current pharmacological compounds, and could guide research towards specific types of pain for which there are currently no evidence-based treatment guidelines.Pharmacological profile of voltage-gated sodium channel blockersPharmacokinetic and pharmacodynamic profilesSodium channels are closed and inactive at rest, but undergo structural changes in response to membrane depolarisation, leading to cycling of the channel through activated (open), inactive, and repriming states.<a class="elsevierStyleCrossRef" href="#bib0280">7</a> Drugs must selectively inhibit hyperactive Navs.All drugs in the carboxamide class of sodium channel blockers bind to the alpha subunit of the Nav. All 3 selectively inhibit inactivated sodium channels, the affinity of CBZ and OXC for inactive channels is 10 times that of resting channels, while the affinity of ESL is about 3 times greater than that of CBZ.<a class="elsevierStyleCrossRef" href="#bib0335">18</a>CBZ, OXC and ESL share similar chemical structures (<a class="elsevierStyleCrossRef" href="#sec0045">Appendix Banexo figure supplementary material available in the online version</a>). OXC was designed to avoid the 10,1-epoxide metabolite of CBZ, to which many of its serious side effects are attributed.<a class="elsevierStyleCrossRef" href="#bib0340">19</a> ESL is the (s)-isomer of the monohydroxy derivative (MHD), which is the active metabolite of OXC and is mainly responsible for its action.<a class="elsevierStyleCrossRef" href="#bib0345">20</a> According to the current literature, there is no evidence that CBZ, OXC and ESL have an affinity to any particular NAV.Due to the similarity between their chemical structures, many clinicians have assumed that the pharmokinetic profile and side effects of CBZ and OXC are also similar. However, it is essential to understand these differences in order to prescribe them correctly. OXC differs from CBZ in a key substitution that intentionally avoids the epoxide metabolite of CBZ and improve its general tolerability. As a result, OXC is metabolised very differently from CBZ. CBZ uses the CYP450 enzyme system as a primary metabolic pathway; this leads to various drug interactions, including the induction of its own metabolism.<a class="elsevierStyleCrossRefs" href="#bib0340">19,21</a> Unlike CBZ, OXC has only minimal interaction with the CYP450 enzyme system.<a class="elsevierStyleCrossRef" href="#bib0345">20</a>Traditionally, OXC, like CBZ, has been considered a potent inducer of CYP3A4. Pharmacokinetic studies have shown no enzymatic induction or autoinduction.<a class="elsevierStyleCrossRef" href="#bib0345">20</a> In pharmacodynamic studies in which the effect of OXC was specifically evaluated on 2 known CYP substrates – erythromycin and cimetidine – no changes in serum concentrations of these substrates were observed in comparison with monotherapy.<a class="elsevierStyleCrossRef" href="#bib0345">20</a> In contrast, other pharmacodynamic studies have questioned the reputed induction properties of CYP3A4. OXC has been shown to reduce the area under the curve of felodipine by approximately 28%, and it also improves the metabolism of quinidine.<a class="elsevierStyleCrossRef" href="#bib0345">20</a> Many clinicians had accepted that OXC was an inducer of CYP450 enzymes, until it was suggested that induction might be dose-dependent. The results of this study confirmed the hypothesis that OXC only induces CYP3A4 at a daily dose of 900mg or higher, and even at higher doses it is considered a weak inducer.<a class="elsevierStyleCrossRef" href="#bib0345">20</a> It is not entirely clear whether the MHD metabolite underlies the inductive effects of OXC; however, since OXC is almost entirely metabolised to MHD, this is very likely to be the case. Studies with ESL in fresh human hepatocytes have shown no in vitro induction effect, but the observed reduction in serum levels of simvastatin and contraceptives raises questions about its true pharmacodynamic profile.<a class="elsevierStyleCrossRefs" href="#bib0355">22,23</a> A once-daily dose of 800mg or higher were used in studies evaluating ESL induction of CYP3A4, suggesting a similar dose-dependent effect as that observed with OXC. However, this has not been conclusively confirmed in the literature.<a class="elsevierStyleCrossRef" href="#bib0355">22</a>The MHD metabolite of OXC inhibits CYP2C19 in normal concentrations and CYP2C9 in above normal concentrations.<a class="elsevierStyleCrossRef" href="#bib0345">20</a> Similarly, ESL has been shown to inhibit CYP2C19.<a class="elsevierStyleCrossRef" href="#bib0355">22</a> Few drugs are metabolised by CYP2C19; therefore, this inhibition is not clinically important. As expected, the metabolism of ESL, the s-isomer of MHD, is almost identical to that of OXC.<a class="elsevierStyleCrossRef" href="#bib0365">24</a>Pharmacodynamic studies have also evaluated use of OXC and ESL in combination with warfarin. OXC, even at doses of 900mg daily or more, had no clinical impact on the INR.<a class="elsevierStyleCrossRef" href="#bib0345">20</a> Studies have shown that ESL doses of 1200mg daily reached the level of statistical significance, but hardly affected serum S-warfarin levels, and had no clinically significant effect on the INR.<a class="elsevierStyleCrossRefs" href="#bib0355">22,25</a> Both OXC and ESL at high doses have been shown to decrease serum levels of contraceptives.<a class="elsevierStyleCrossRefs" href="#bib0345">20,22,23</a> This may be due to CYP3A4 induction, but it has also been suggested that this interaction is due to inhibited absorption or accelerated metabolic clearance. This is why pharmacodynamic studies have shown that OXC and ESL do not carry the same risk of clinically significant drug interactions that have been described in CBZ.<a class="elsevierStyleCrossRefs" href="#bib0340">19,20,23</a>SafetyCognitive impairment associated with CBZ has been directly linked to the concentration of the main drug as well as the epoxide metabolite.<a class="elsevierStyleCrossRef" href="#bib0340">19</a> Since OXC does not form an epoxide intermediate, it would be expected to be better tolerated. Although real world data are ambiguous, an analysis of active treatment trials in patients receiving CBZ and OXC has shown that OXC is generally better tolerated.<a class="elsevierStyleCrossRef" href="#bib0375">26</a>CBZ has been linked to haematological side effects, specifically agranulocytosis and aplastic anaemia.<a class="elsevierStyleCrossRef" href="#bib0340">19</a> It is not fully understood why the same is not true of OXC and ESL, however, it is often suggested that this might be due to the absence of an epoxide intermediate. Others, however, attribute this to CBZ's affinity for and effect on peripheral benzodiazepine receptors, which are found in lymphocytes.<a class="elsevierStyleCrossRef" href="#bib0340">19</a> There is no definitive evidence to show whether it is the main drug or the epoxide intermediate of CBZ that acts on these receptors, but it is evident that OXC and ESL do not exhibit the same activity. The action of CBZ in these peripheral benzodiazepine receptors is also thought to mitigate its propensity to induce the syndrome of inappropriate antidiuretic hormone secretion. Both OXC and CBZ carry a warning for drug-induced hyponatraemia and syndrome of inappropriate antidiuretic hormone secretion; however, this is dose-dependent, and far less common in OXC than CBZ.<a class="elsevierStyleCrossRefs" href="#bib0340">19,20</a>These drugs also carry a warning for adverse cutaneous reactions. It is recommended that patients of Asian descent be tested for the HLA-B*15: 02 and HLA-A*31: 01 genes, since these have been associated with a 10-fold increased risk of Stevens-Johnson syndrome.<a class="elsevierStyleCrossRefs" href="#bib0340">19,20</a> Although OXC and ESL carry a warning for possible adverse dermatological events, they seem to be better tolerated.<a class="elsevierStyleCrossRefs" href="#bib0345">20,23</a> ESL causes moderate side effects, similar to those of OXC, notably dizziness, nausea, vomiting, drowsiness and diplopia, and occasionally hyponatremia.<a class="elsevierStyleCrossRef" href="#bib0360">23</a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarises the main pharmacological characteristics of voltage-dependent sodium blockers.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Each improvement made in the development of these drugs is accompanied by a corresponding improvement in their toxicological profile. Previously, improved tolerability was thought to be due to different metabolic pathways, but the key might lie in isolating the active fraction of these drugs.Evidence for voltage-gated sodium channel blockers in analgesiaCBZ is currently the drug of choice in the pharmacological treatment of trigeminal neuralgia.<a class="elsevierStyleCrossRefs" href="#bib0380">27–29</a> It is also indicated in epilepsy, manic episodes, and prophylactic treatment of bipolar affective disorder, glossopharyngeal neuralgia, and alcohol withdrawal syndrome.<a class="elsevierStyleCrossRef" href="#bib0340">19</a>Although the only European Medicines Agency (EMA) approved indication for CBZ as an analgesic is in the treatment of trigeminal neuralgia, some studies support its benefits in other indications, such as tabetic lightning pain, postsympathectomy neuralgia, diabetic neuropathy, glossopharyngeal neuralgia, and phantom limb pain.<a class="elsevierStyleCrossRefs" href="#bib0395">30–34</a> OXC is not approved by the EMA for trigeminal neuralgia; instead, it is indicated for the treatment of partial epileptic seizures with or without secondary generalisation with tonic-clonic seizures.<a class="elsevierStyleCrossRef" href="#bib0345">20</a> However, some guidelines for trigeminal neuralgia consider OXC to be a reasonable first line option.<a class="elsevierStyleCrossRef" href="#bib0390">29</a> Both a double-blind randomised trial and a meta-analysis have compared CBZ with OXC, but these have only been published as abstracts. These studies found that both drugs are equally effective (88%, with a pain reduction greater than 50%), but OXC is better tolerated.<a class="elsevierStyleCrossRef" href="#bib0380">27</a>OXC has also been effective in allodynia, diabetic neuropathy, paroxysmal symptoms in multiple sclerosis, and peripheral neuropathy. Some case reports support its use in postherpetic neuralgia refractory to gabapentin, in complex regional pain syndrome refractory to gabapentin, and in radiculopathy refractory to gabapentin.<a class="elsevierStyleCrossRefs" href="#bib0420">35–40</a>Apart from evidence as an analgesic, recent studies have shown that the efficacy OXC may be maximised in patients with a specific pain phenotype.<a class="elsevierStyleCrossRef" href="#bib0450">41</a> In a study evaluating response to OXC, the “irritable nociceptor” phenotype responded better to OXC for total pain, deep dull pain, lancinating pain and pressure-induce pain, compared to the “non-irritable nociceptor” phenotype. The authors also reported a reduction in pain-related sleep disturbances.<a class="elsevierStyleCrossRef" href="#bib0450">41</a> Similarly, a recent study evaluated the effect of CBZ on 2 patients with inherited erythromelalgia and the S241T Nav1.7 mutation.<a class="elsevierStyleCrossRef" href="#bib0455">42</a> The authors observed that CBZ reduced heat-induced hyperactivity in the dorsal root ganglion neurons of these patients, as predicted in the genomic analysis. Patients also reported lower pain scores.<a class="elsevierStyleCrossRef" href="#bib0455">42</a> These studies are encouraging, and should encourage further research in the field of pain management guided by genomic analysis.ESL was approved by the EMA in 2009, and has been available in Spain since February 2011. The drug is currently indicated as monotherapy for the treatment of partial onset seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy, and as adjuvant therapy in adults, adolescents and children over 6 years of age with partial onset seizures, with or without secondary generalization.<a class="elsevierStyleCrossRef" href="#bib0360">23</a> Very few studies have reported the analgesic effects of ESL. However, there is evidence for its use in multiple sclerosis with refractory trigeminal neuralgia, and in diabetic neuropathy.<a class="elsevierStyleCrossRefs" href="#bib0460">43,44</a> Some authors have published their experience with ESL in case series with different types of pain. These, however, are small, open-label observational studies with no control group.<a class="elsevierStyleCrossRef" href="#bib0470">45</a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarises the evidence for the use of carboxamide class of sodium channel blockers in pain management. Only drugs currently available in Spain are shown.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>All the latest clinical practice guidelines consulted recommend tricyclic, dual antidepressants (venlafaxine/duloxetine) and gabapentin/pregabalin antiepileptics as first-line drugs in the treatment of neuropathic pain, reserving sodium channel blockers as a second-line option, along with many other drugs.<a class="elsevierStyleCrossRef" href="#bib0475">46</a> The failure of some guidelines, such as the American Academy of Neurology (AAN),<a class="elsevierStyleCrossRef" href="#bib0480">47</a> or the Cochrane library,<a class="elsevierStyleCrossRefs" href="#bib0485">48,49</a> to support the use of CBZ or OXC in neuropathy diabetic peripheral has led numerous clinicians to question the effectiveness of these drugs in pain management. However, these findings should be weighed up against a more recent meta-analysis (2015) on neuropathic pain carried out by the International Association for the Study of Pain (IASP), which suggests, based on the results of various studies, that OXC might be significantly more effective in a subgroup of patients with a specific pain phenotype.<a class="elsevierStyleCrossRef" href="#bib0475">46</a>In the 3 clinical trials cited by the AAN, pain scores were reduced in patients receiving>1200mg/day OXC.<a class="elsevierStyleCrossRef" href="#bib0480">47</a> There is currently insufficient evidence to confirm a dose-dependent effect, but the available literature suggests that the main benefits of OXC in peripheral neuropathy are observed at doses of >900mg/day. Although studies supporting the use of first- and second-line drugs for various pain conditions vary greatly in terms of quantity and quality, the latest continue to describe the potential for voltage-gated sodium channel blockers in the treatment of pain, an indication which is still underestimated.<a class="elsevierStyleCrossRef" href="#bib0475">46</a>The is little evidence in the literature for the superiority of Nav over gabapentinoids in neuropathic pain, but most studies evaluating these drugs for pain management involve patients with neuropathic pain syndromes. It is interesting to note that many Navs have been associated with the transmission of neuropathic pain,<a class="elsevierStyleCrossRef" href="#bib0295">10</a> and some have also been associated with inflammatory pain, with evidence that prostaglandins increase the activity of Nav1.9 and Nav.1.7.<a class="elsevierStyleCrossRefs" href="#bib0295">10,12</a> However, there is no evidence voltage-gated sodium channel blockers can replace non-steroidal anti-inflammatory drugs for inflammatory pain management. However, the pharmacological characteristics indicate that a trial with sodium channel blockers could be effective in patients who cannot tolerate or are contraindicated for NSAIDs due to gastrointestinal or cardiovascular complications. Clinical trials are necessary to fully assess and characterise the targeted use of voltage-dependent sodium channel blockers and their place in the treatment of inflammatory pain.Treatment targeting specific Nav subtypes could greatly affect the development of drugs to treat chronic pain, and is an area that merits further research. Researchers are currently attempting to design drugs that selectively inhibit specific Nav subtypes; however, this can be complicated because of the structural similarities between the different channels.Traditionally, the use of CBZ has been limited, due to its pharmacokinetic profile and undesirable side effects, and the use of OXC has decreased by association and due to the assumption that it will have similar effects. Research has validated the improved pharmacokinetic profile and adverse side effects of OXC compared to CBZ, but research into their use in pain management has not been given the priority it merits. The recent launch ESL has generated new and promising evidence on sodium channels blockers as a drug class. More research is needed to identify the different sodium channels subtypes, their role in the underlying causes of pain and their application in clinical practice.ConclusionsThe global effort to minimise and reduce dependence on opioids has been undermined by the limited availability of effective treatment alternatives. The evidence for various first- and second-line drugs for neuropathic pain is conflicting, and must be clarified by further research into specific pain conditions. Targeted sodium channel blocker therapy for musculoskeletal and neuroinflammatory disorders may be a new frontier in research into pain management. Identifying and converting sodium channels subtypes associated with specific pain conditions into pharmacological targets is just one example of the potential of truly individualised treatments and the new approach needed in pain care. Evidence has shown that voltage-gated sodium channels blockers are underutilised. However, emerging research has shown these drugs to be a promising field for clinical trials that can guide future trends in clinical practice.Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1024771" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec982669" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1024770" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec982670" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Voltage-gated sodium channels as therapeutic targets in pain management" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Pharmacological profile of voltage-gated sodium channel blockers" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Pharmacokinetic and pharmacodynamic profiles" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Safety" ] ] ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Evidence for voltage-gated sodium channel blockers in analgesia" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-09-16" "fechaAceptado" => "2018-01-22" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec982669" "palabras" => array:6 [ 0 => "Eslicarbazepine acetate" 1 => "Sodium channel blockers" 2 => "Carbamazepine" 3 => "Chronic pain management" 4 => "Oxcarbazepine" 5 => "Adjunct therapy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec982670" "palabras" => array:6 [ 0 => "Acetato de eslicarbazepina" 1 => "Bloqueadores de los canales de sodio" 2 => "Carbamazepina" 3 => "Manejo del dolor crónico" 4 => "Oxcarbazepina" 5 => "Tratamiento adyuvante" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Once patients have failed first line therapy, there is an apparent lack of knowledge on how to proceed with choosing subsequent therapy. To choose amongst alternative agents, an understanding of pharmacology, pharmacokinetics, and available evidence in targeting various pain conditions is necessary. This article focuses on the use of the carboxamide class of voltage-gated sodium channel blockers (carbamazepine, oxcarbazepine, eslicarbazepine acetate) for adjunct pain medication management; including research updates in pharmacology, pharmacokinetics, and evidence for pain along on this therapeutic group with promising future areas of research.Although evidence for voltage-gated sodium channel blockers in chronic pain management is limited, emerging research has identified this area as promising for additional clinical trials to better guide clinical practice." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Una vez que ha fracasado el tratamiento de primera línea en los pacientes con dolor crónico, parece haber una laguna de conocimiento sobre cómo proceder en la elección de un tratamiento posterior. Este artículo se centra en el uso de los bloqueadores de los canales de sodio dependientes de voltaje que pertenecen a la clase de las carboxamidas (carbamazepina, oxcarbazepina, acetato de eslicarbazepina) como tratamiento analgésico adyuvante; e incluye actualizaciones sobre farmacología, farmacocinética y evidencias en dolor de este grupo terapéutico, así como prometedoras futuras líneas de investigación.Aunque la evidencia de los bloqueadores de los canales de sodio dependientes de voltaje en el manejo del dolor crónico es limitada, la investigación emergente ha identificado esta área como esperanzadora para que ensayos clínicos adicionales guíen mejor nuestra práctica clínica." ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Alcántara Montero A, Sánchez Carnerero CI. Papel de los bloqueadores de los canales de sodio dependientes de voltaje en el tratamiento del dolor crónico: usos potenciales en la práctica clínica según la evidencia disponible. Rev Esp Anestesiol Reanim. 2018;65:275–283." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "This article is part of the Anaesthesiology and Resuscitation Continuing Medical Education Program. An evaluation of the questions on this article can be made through the Internet by accessing the Education Section of the following web page: <a class="elsevierStyleInterRef" target="_blank" id="intr0110" href="http://www.elsevier.es/redar">www.elsevier.es/redar</a>" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0050" ] ] ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3265 "Ancho" => 2499 "Tamanyo" => 282844 ] ] "descripcion" => array:1 [ "en" => "Voltage-dependent sodium channels subtypes and associated pain syndromes." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "CYP450: cytochrome p450 enzyme system; MHD: 10-monohydroxy derivative, active metabolite of oxcarbazepine; OXC: oxcarbazepine.Sources: Carbamazepine<a class="elsevierStyleCrossRef" href="#bib0340">19</a>; oxcarbazepine<a class="elsevierStyleCrossRef" href="#bib0345">20</a>; eslicarbazepine acetate<a class="elsevierStyleCrossRef" href="#bib0360">23</a>." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Carbamazepine \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Oxcarbazepine \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Eslicarbazepine acetate \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bioavailability \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">70% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>95% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>90% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Plasma protein binding \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">70–80% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40% (MHD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><40% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metabolism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepatic: phase I * CYP3A4 (major), responsible for the formation of pharmacologically active 10,11-carbamazepine epoxide * CYP2C8 (minor) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Step 1: OXC metabolised by arylketone reductase to MHD Step 2: MHD metabolism: hepatic: phase I (CYP450-minor)∼4% inactive metabolite Hepatic: phase II: glucuronidation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepatic: phase II Esterases, glucuronidation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Half-life \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36h (after several administrations: 16–24h) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.3–2.3h 9.3±1.8h (MHD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10–20h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Excretion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">72% in urine and 28% in stools \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>95% in urine and <4% in stools \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">∼90% in urine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CYP450 interaction \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Potent inducer of CYP3A4 and other phase I and phase II hepatic enzyme systems \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">OXC and MHD are weak in vitro and in vivo inducers of CYP3A4 and CYP3A5 In vitro, OXC and MHD are weak inducers of UDP-glucuronyltransferases OXC and MHD inhibit CYP2C19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Weak inducer of CYP3A4 at ≥800mg/day Minor inhibition of CYP2C19 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Different side effects \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↑ Haematological and dermatological adverse effects \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↑ Hyponatraemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">∼ to OXC (less hyponatraemia) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1742374.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Pharmacokinetic and pharmacodynamic comparison of sodium channel blockers." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "CBZ: carbamazepine." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Pain syndrome \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Carbamazepine \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Oxcarbazepine \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Eslicarbazepine acetate \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Level of evidence<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tabetic pain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">800mg/day<a class="elsevierStyleCrossRef" href="#bib0395">30</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Trigeminal neuralgia</td><td class="td" title="table-entry " align="left" valign="top">400–1200mg/day<a class="elsevierStyleCrossRefs" href="#bib0380">27–29</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">600–2400mg/day<a class="elsevierStyleCrossRefs" href="#bib0380">27–29</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Moderate \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Multiple sclerosis with refractory trigeminal neuralgia: 400mg/day<a class="elsevierStyleCrossRef" href="#bib0460">43</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Postimpactomy neuralgia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">600mg/day<a class="elsevierStyleCrossRef" href="#bib0410">33</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Diabetic neuropathy</td><td class="td" title="table-entry " align="left" valign="top">200–600mg/day (often requires >600mg/day)<a class="elsevierStyleCrossRef" href="#bib0415">34</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Moderate \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">150–1200mg/day (often requires>600mg/day; average dose∼800mg/day)<a class="elsevierStyleCrossRef" href="#bib0420">35</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Second line treatment: 400–800mg/day<a class="elsevierStyleCrossRef" href="#bib0465">44</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glossopharyngeal neuralgia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">400–800mg/day<a class="elsevierStyleCrossRef" href="#bib0400">31</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Phantom limb pain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">800mg/day<a class="elsevierStyleCrossRef" href="#bib0405">32</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Central neuropathic pain with allodynia after spinal cord injury \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">900mg/day<a class="elsevierStyleCrossRef" href="#bib0425">36</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Postherpetic neuralgia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Refractory to CBZ and gabapentin: 900mg/day<a class="elsevierStyleCrossRef" href="#bib0430">37</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Paroxysmal symptoms in multiple sclerosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1000mg/day<a class="elsevierStyleCrossRef" href="#bib0435">38</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Complex regional pain syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Refractory to gabapentin: 150–2000mg/day<a class="elsevierStyleCrossRef" href="#bib0440">39</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Radiculopathy  \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Refractory to gabapentin: 150–900mg/day<a class="elsevierStyleCrossRef" href="#bib0445">40</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1742375.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "GRADE evidence quality classification system." ] ] ] "descripcion" => array:1 [ "en" => "Summary of evidence for sodium channel blockers in pain management." ] ] 3 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.pdf" "ficheroTamanyo" => 456418 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:49 [ 0 => array:3 [ "identificador" => "bib0250" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "H. 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Role of voltage-gated sodium channel blockers in the treatment of chronic pain: Potential uses in clinical practice based on available evidence

Papel de los bloqueadores de los canales de sodio dependientes de voltaje en el tratamiento del dolor crónico: usos potenciales en la práctica clínica según la evidencia disponible

A. Alcántara Monteroa,

Corresponding author

a.alcantara.montero@hotmail.com

Corresponding author.

, C.I. Sánchez Carnererob

a Unidad del Dolor, Hospital Don Benito-Villanueva de la Serena, Don Benito, Badajoz, Spain

b Complejo Hospitalario Universitario de Cáceres, Hospital San Pedro de Alcántara, Cáceres, Spain

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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Voltage-dependent sodium channels subtypes and associated pain syndromes&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">It is estimated that 1 in 5 Europeans &#40;19&#37;&#41; suffer from chronic pain&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">1</span></a> Although few epidemiological studies have been performed at the national level&#44; recent data suggest that prevalence in Spain is slightly lower than the European average &#40;17&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">2</span></a> Chronic pain not only has a major impact on work&#44; and social and family life&#44; but also places a considerable financial burden on the health system&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The lack of good therapeutic and management strategies for chronic pain is part of the problem&#59; however&#44; a limited knowledge of adequate treatments&#44; specifically non-opioid analgesic drugs&#44; is an important factor&#46; Long-term opioid treatment for chronic pain has increased dramatically in recent years&#44; particularly in the United States&#44; despite insufficient evidence of long-term benefits and increasing evidence of harmful effects&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">3</span></a> There are no studies comparing long term &#40;over 1 year&#41; opioid therapy versus placebo&#44; treatment without opioids&#44; or other therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">3</span></a> Tapering opioids can be a challenge for both patients and doctors&#46; In clinical practice&#44; long-term opioid treatment is only discontinued in 8&#8211;35&#37; of patients&#44; according to cohort studies&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">4</span></a> However&#44; there is little evidence to guide clinicians through the process of tapering opioid therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">5</span></a> In addition&#44; the number of alternative therapeutic options is limited&#44; and many clinicians have difficulty distinguishing between non-opioid analgesics&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">It is imperative to approach and treat chronic pain with specific therapies for each pain syndrome&#46; Although opioids may be indicated in some patients&#44; it is difficult to control pain and reduce dependence on opioids without fully understanding which non-opioid drug therapies to choose&#46; Therefore&#44; it is essential to understand the risks and benefits of each therapeutic alternative and each adjuvant drug&#44; in order to combat the current opioid epidemic and offer adequate treatment for chronic pain&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Nowadays&#44; clinicians tend to base chronic pain management on the pathogenesis of pain&#46; Therefore&#44; in addition to&#44; clinicians are urged not only to evaluate the pathology that triggers the pain&#44; but also to characterise the type of pain based on the neurophysiological mechanisms involved&#44; differentiating between nociceptive and neuropathic pain&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">6</span></a> Once this has been determined&#44; the next key step is to choose the right drug for each type of pain&#46; Many clinicians are generally familiar with first-line treatments for inflammatory pain and neuropathic pain&#46; However&#44; once first-line treatment has failed&#44; many doctors admit that they lack the knowledge necessary to differentiate between or effectively administer second-line treatment options&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Voltage-gated sodium channel blockers&#44; specifically&#44; carboxamides&#44; which include carbamazepine &#40;CBZ&#41;&#44; oxcarbazepine &#40;OXC&#41; and&#44; more recently&#44; eslicarbazepine acetate &#40;ESL&#41;&#44; could be one of the most under-prescribed pain management alternatives&#46; This could be due to the limited amount of experience and data available on these drugs compared to first line treatments&#46; However&#44; good pain management depends on familiarity with second- and third-line treatment&#44; and understanding the role of each therapeutic class in the treatment regimen&#46; In order to choose between alternative therapies&#44; clinicians must understand the pharmacology and pharmacokinetics of each drug&#44; and be aware of the available evidence supporting specific treatments for various chronic pain conditions&#46; The aim of this article is to update evidence for the clinical use of voltage-gated sodium channel blockers&#44; clarify misconceptions surrounding their use&#44; and highlight emerging research on better pain targets that warrant further analysis&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">For this purpose&#44; we searched PubMed and Google Scholar for the most significant studies on this topic&#44; using the following search criteria&#58; &#8220;<span class="elsevierStyleItalic">carbamazepine</span>&#8221;&#44; &#8220;<span class="elsevierStyleItalic">oxcarbazepine</span>&#8221; and &#8220;<span class="elsevierStyleItalic">eslicarbazepine acetate</span>&#8221; in combination with &#8220;<span class="elsevierStyleItalic">neuropathic pain</span>&#8221;&#44; &#8220;<span class="elsevierStyleItalic">inflammatory pain</span>&#8221;&#44; and &#8220;<span class="elsevierStyleItalic">chronic pain management</span>&#8221;&#46; We also consulted the summary of product characteristics of CBZ&#44; OXC and ESL to ascertain the adverse reactions&#44; bioavailability&#44; pharmacological and pharmacokinetic data of each drug&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Voltage-gated sodium channels as therapeutic targets in pain management</span><p id="par0035" class="elsevierStylePara elsevierViewall">Voltage-gated sodium channels &#40;Nav&#41; contribute to pain syndromes by facilitating electric transmission and increasing the density of sodium channels around the lesion&#59; both these mechanisms cause hyperexcitability and enhanced sensory transmission&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">7&#44;8</span></a> Nine voltage-gated sodium channels subtypes have been identified &#40;Nav1&#46;1-1&#46;9&#41;&#44; and several Navs have been linked to the transmission of inflammatory&#44; nociceptive and neuropathic pain<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">7&#8211;11</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Researchers have recently identified specific Navs that correlate with specific types of pain&#46; This shows that targeting hyperactive channels may oversimplify the complex biological processes involved in pain signalling&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">9&#44;11</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Nav1&#46;9 mainly occurs in the peripheral nervous system&#44; whereas Nav1&#46;8 is mostly found in the C fibres of the dorsal root ganglion&#46; However&#44; evidence supporting the presence of Nav1&#46;7&#44; Nav1&#46;8 and Nav1&#46;9 channels in small-diameter dorsal root ganglion neurons&#44; most of which are nociceptive&#44;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">10&#44;12</span></a> has highlighted their involvement in the transmission of pain signals&#46; Sodium channels subtypes are classified as tetrodotoxin-resistant &#40;TTX-R&#41; or tetrodotoxin-sensitive&#46; Nav1&#46;8 and Nav1&#46;9 are TTX-R&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">10</span></a> Studies have shown that TTX-R currents carry the majority of charge during action potentials in nociceptive neurons&#44; and this is dynamically regulated in response to injury<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">10&#44;11</span></a>&#46; Increased TTX-R channel activity has been observed after inflammation associated with dorsal root ganglion neurons&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">10</span></a> Similarly&#44; inflammatory mediators have been shown to regulate Nav1&#46;8 and Nav1&#46;7&#46; These mediators are associated with increased expression and enhanced electrical activity of Nav 1&#46;9&#44; which suggests they play a role in maintaining the inflammatory response&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">10&#44;11</span></a> Likewise&#44; elevated Nav1&#46;8 protein levels have been observed in dorsal root ganglion neurons surrounding the inflamed limbs&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">11</span></a> Several studies mention the association between Nav1&#46;7 and mechanical and inflammatory pain&#44; Nav1&#46;8 and visceral pain&#44; and Nav1&#46;9 and the transmission of inflammatory pain signals&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">11</span></a> Evidence also suggests that Nav1&#46;8 could participate in neuropathic pain&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Nav expression and alteration also occurs in certain disease conditions and pain syndromes&#46; It has been hypothesised that up-regulation of the sodium channel beta2-subunit is associated with allodynia&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">11</span></a> It has been reported that Nav1&#46;3 is only detectable in injured nerves&#44; and expression increases in dorsal root ganglion neurons due to nerve lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">7&#44;11</span></a> Nav1&#46;3&#44; Nav1&#46;6&#44; Nav1&#46;7 and Nav1&#46;9 have been shown to increase in diabetic neuropathic pain&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">11</span></a> Nav1&#46;3 expression was reported to increase at the site of peripheral nerve damage and in the nociceptive dorsal horn neurons after an experimental spinal cord injury<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">7</span></a>&#59; it is also believed that Nav1&#46;3 could be involved in neuropathic pain after nerve and spinal cord injuries&#46; Nav1&#46;2 is mainly expressed in unmyelinated axons&#44; and has been associated with multiple sclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">11</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Nav mutations are also associated with various pain syndromes&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">7&#44;12&#44;13</span></a> A Nav1&#46;7 mutation has been linked to erythromelalgia in humans&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">7&#44;12</span></a> Mutations in Nav1&#46;7&#44; Nav1&#46;8 and Nav1&#46;9 have been closely and specifically liked to neuropathic pain&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">9&#44;13&#44;14</span></a> Nav1&#46;8 is expressed in Purkinje neurons in multiple sclerosis&#44; and deletions in the SCN10A gene have been shown to predict the degree of cerebellar dysfunction in this disease&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">8</span></a> Finally&#44; in patients with paroxysmal extreme pain disorder&#44; there is evidence that Nav1&#46;7&#44; despite being activated by normal stimuli&#44; does not deactivate correctly&#44; which leads to persistent sodium influx&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">11</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Targeted treatment for specific pain conditions using an associated sodium channel subtype is a promising field of research&#44; and has the potential to transform both the state of the knowledge and clinical pain management&#46; There is no guarantee that pharmacological compounds that selectively inhibit individual Navs can be designed successfully&#46; However&#44; research is currently under way into 2 drugs&#44; one that selectively targets Nav1&#46;7&#44; and another that selectively targets Nav1&#46;8&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">8&#44;15&#44;16</span></a> Recently&#44; a Nav1&#46;7 selective sodium channel blocker &#40;BIIB074&#41; was evaluated in patients with trigeminal neuralgia in a Phase 2a trial&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">17</span></a> The sample size was small&#44; and the results were not statistically significant&#44; but there were almost twice as many treatment failures in the placebo group compared to BIIB074&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">17</span></a> On the basis of these promising results&#44; new clinical trials are currently being conducted in both trigeminal neuralgia and other pain syndromes &#40;such as small fibre neuropathy&#44; erythromelalgia and lumbosacral radiculopathy&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">This shows the need for further research to determine the receptor subtypes associated with each of the current pharmacological compounds&#44; and could guide research towards specific types of pain for which there are currently no evidence-based treatment guidelines&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pharmacological profile of voltage-gated sodium channel blockers</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pharmacokinetic and pharmacodynamic profiles</span><p id="par0065" class="elsevierStylePara elsevierViewall">Sodium channels are closed and inactive at rest&#44; but undergo structural changes in response to membrane depolarisation&#44; leading to cycling of the channel through activated &#40;open&#41;&#44; inactive&#44; and repriming states&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">7</span></a> Drugs must selectively inhibit hyperactive Navs&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">All drugs in the carboxamide class of sodium channel blockers bind to the alpha subunit of the Nav&#46; All 3 selectively inhibit inactivated sodium channels&#44; the affinity of CBZ and OXC for inactive channels is 10 times that of resting channels&#44; while the affinity of ESL is about 3 times greater than that of CBZ&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">18</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">CBZ&#44; OXC and ESL share similar chemical structures &#40;<a class="elsevierStyleCrossRef" href="#sec0045">Appendix Banexo figure supplementary material available in the online version</a>&#41;&#46; OXC was designed to avoid the 10&#44;1-epoxide metabolite of CBZ&#44; to which many of its serious side effects are attributed&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">19</span></a> ESL is the &#40;s&#41;-isomer of the monohydroxy derivative &#40;MHD&#41;&#44; which is the active metabolite of OXC and is mainly responsible for its action&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">20</span></a> According to the current literature&#44; there is no evidence that CBZ&#44; OXC and ESL have an affinity to any particular NAV&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Due to the similarity between their chemical structures&#44; many clinicians have assumed that the pharmokinetic profile and side effects of CBZ and OXC are also similar&#46; However&#44; it is essential to understand these differences in order to prescribe them correctly&#46; OXC differs from CBZ in a key substitution that intentionally avoids the epoxide metabolite of CBZ and improve its general tolerability&#46; As a result&#44; OXC is metabolised very differently from CBZ&#46; CBZ uses the CYP450 enzyme system as a primary metabolic pathway&#59; this leads to various drug interactions&#44; including the induction of its own metabolism&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">19&#44;21</span></a> Unlike CBZ&#44; OXC has only minimal interaction with the CYP450 enzyme system&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">20</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Traditionally&#44; OXC&#44; like CBZ&#44; has been considered a potent inducer of CYP3A4&#46; Pharmacokinetic studies have shown no enzymatic induction or autoinduction&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">20</span></a> In pharmacodynamic studies in which the effect of OXC was specifically evaluated on 2 known CYP substrates &#8211; erythromycin and cimetidine &#8211; no changes in serum concentrations of these substrates were observed in comparison with monotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">20</span></a> In contrast&#44; other pharmacodynamic studies have questioned the reputed induction properties of CYP3A4&#46; OXC has been shown to reduce the area under the curve of felodipine by approximately 28&#37;&#44; and it also improves the metabolism of quinidine&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">20</span></a> Many clinicians had accepted that OXC was an inducer of CYP450 enzymes&#44; until it was suggested that induction might be dose-dependent&#46; The results of this study confirmed the hypothesis that OXC only induces CYP3A4 at a daily dose of 900<span class="elsevierStyleHsp" style=""></span>mg or higher&#44; and even at higher doses it is considered a weak inducer&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">20</span></a> It is not entirely clear whether the MHD metabolite underlies the inductive effects of OXC&#59; however&#44; since OXC is almost entirely metabolised to MHD&#44; this is very likely to be the case&#46; Studies with ESL in fresh human hepatocytes have shown no <span class="elsevierStyleItalic">in vitro</span> induction effect&#44; but the observed reduction in serum levels of simvastatin and contraceptives raises questions about its true pharmacodynamic profile&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">22&#44;23</span></a> A once-daily dose of 800<span class="elsevierStyleHsp" style=""></span>mg or higher were used in studies evaluating ESL induction of CYP3A4&#44; suggesting a similar dose-dependent effect as that observed with OXC&#46; However&#44; this has not been conclusively confirmed in the literature&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">22</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The MHD metabolite of OXC inhibits CYP2C19 in normal concentrations and CYP2C9 in above normal concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">20</span></a> Similarly&#44; ESL has been shown to inhibit CYP2C19&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">22</span></a> Few drugs are metabolised by CYP2C19&#59; therefore&#44; this inhibition is not clinically important&#46; As expected&#44; the metabolism of ESL&#44; the s-isomer of MHD&#44; is almost identical to that of OXC&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">24</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Pharmacodynamic studies have also evaluated use of OXC and ESL in combination with warfarin&#46; OXC&#44; even at doses of 900<span class="elsevierStyleHsp" style=""></span>mg daily or more&#44; had no clinical impact on the INR&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">20</span></a> Studies have shown that ESL doses of 1200<span class="elsevierStyleHsp" style=""></span>mg daily reached the level of statistical significance&#44; but hardly affected serum S-warfarin levels&#44; and had no clinically significant effect on the INR&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">22&#44;25</span></a> Both OXC and ESL at high doses have been shown to decrease serum levels of contraceptives&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">20&#44;22&#44;23</span></a> This may be due to CYP3A4 induction&#44; but it has also been suggested that this interaction is due to inhibited absorption or accelerated metabolic clearance&#46; This is why pharmacodynamic studies have shown that OXC and ESL do not carry the same risk of clinically significant drug interactions that have been described in CBZ&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">19&#44;20&#44;23</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Safety</span><p id="par0100" class="elsevierStylePara elsevierViewall">Cognitive impairment associated with CBZ has been directly linked to the concentration of the main drug as well as the epoxide metabolite&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">19</span></a> Since OXC does not form an epoxide intermediate&#44; it would be expected to be better tolerated&#46; Although real world data are ambiguous&#44; an analysis of active treatment trials in patients receiving CBZ and OXC has shown that OXC is generally better tolerated&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">26</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">CBZ has been linked to haematological side effects&#44; specifically agranulocytosis and aplastic anaemia&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">19</span></a> It is not fully understood why the same is not true of OXC and ESL&#44; however&#44; it is often suggested that this might be due to the absence of an epoxide intermediate&#46; Others&#44; however&#44; attribute this to CBZ&#39;s affinity for and effect on peripheral benzodiazepine receptors&#44; which are found in lymphocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">19</span></a> There is no definitive evidence to show whether it is the main drug or the epoxide intermediate of CBZ that acts on these receptors&#44; but it is evident that OXC and ESL do not exhibit the same activity&#46; The action of CBZ in these peripheral benzodiazepine receptors is also thought to mitigate its propensity to induce the syndrome of inappropriate antidiuretic hormone secretion&#46; Both OXC and CBZ carry a warning for drug-induced hyponatraemia and syndrome of inappropriate antidiuretic hormone secretion&#59; however&#44; this is dose-dependent&#44; and far less common in OXC than CBZ&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">These drugs also carry a warning for adverse cutaneous reactions&#46; It is recommended that patients of Asian descent be tested for the HLA-B&#42;15&#58; 02 and HLA-A&#42;31&#58; 01 genes&#44; since these have been associated with a 10-fold increased risk of Stevens-Johnson syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">19&#44;20</span></a> Although OXC and ESL carry a warning for possible adverse dermatological events&#44; they seem to be better tolerated&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">20&#44;23</span></a> ESL causes moderate side effects&#44; similar to those of OXC&#44; notably dizziness&#44; nausea&#44; vomiting&#44; drowsiness and diplopia&#44; and occasionally hyponatremia&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">23</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarises the main pharmacological characteristics of voltage-dependent sodium blockers&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">Each improvement made in the development of these drugs is accompanied by a corresponding improvement in their toxicological profile&#46; Previously&#44; improved tolerability was thought to be due to different metabolic pathways&#44; but the key might lie in isolating the active fraction of these drugs&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Evidence for voltage-gated sodium channel blockers in analgesia</span><p id="par0120" class="elsevierStylePara elsevierViewall">CBZ is currently the drug of choice in the pharmacological treatment of trigeminal neuralgia&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">27&#8211;29</span></a> It is also indicated in epilepsy&#44; manic episodes&#44; and prophylactic treatment of bipolar affective disorder&#44; glossopharyngeal neuralgia&#44; and alcohol withdrawal syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">19</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Although the only European Medicines Agency &#40;EMA&#41; approved indication for CBZ as an analgesic is in the treatment of trigeminal neuralgia&#44; some studies support its benefits in other indications&#44; such as tabetic lightning pain&#44; postsympathectomy neuralgia&#44; diabetic neuropathy&#44; glossopharyngeal neuralgia&#44; and phantom limb pain&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">30&#8211;34</span></a> OXC is not approved by the EMA for trigeminal neuralgia&#59; instead&#44; it is indicated for the treatment of partial epileptic seizures with or without secondary generalisation with tonic-clonic seizures&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">20</span></a> However&#44; some guidelines for trigeminal neuralgia consider OXC to be a reasonable first line option&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">29</span></a> Both a double-blind randomised trial and a meta-analysis have compared CBZ with OXC&#44; but these have only been published as abstracts&#46; These studies found that both drugs are equally effective &#40;88&#37;&#44; with a pain reduction greater than 50&#37;&#41;&#44; but OXC is better tolerated&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">27</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">OXC has also been effective in allodynia&#44; diabetic neuropathy&#44; paroxysmal symptoms in multiple sclerosis&#44; and peripheral neuropathy&#46; Some case reports support its use in postherpetic neuralgia refractory to gabapentin&#44; in complex regional pain syndrome refractory to gabapentin&#44; and in radiculopathy refractory to gabapentin&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">35&#8211;40</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Apart from evidence as an analgesic&#44; recent studies have shown that the efficacy OXC may be maximised in patients with a specific pain phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">41</span></a> In a study evaluating response to OXC&#44; the &#8220;irritable nociceptor&#8221; phenotype responded better to OXC for total pain&#44; deep dull pain&#44; lancinating pain and pressure-induce pain&#44; compared to the &#8220;non-irritable nociceptor&#8221; phenotype&#46; The authors also reported a reduction in pain-related sleep disturbances&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">41</span></a> Similarly&#44; a recent study evaluated the effect of CBZ on 2 patients with inherited erythromelalgia and the S241T Nav1&#46;7 mutation&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">42</span></a> The authors observed that CBZ reduced heat-induced hyperactivity in the dorsal root ganglion neurons of these patients&#44; as predicted in the genomic analysis&#46; Patients also reported lower pain scores&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">42</span></a> These studies are encouraging&#44; and should encourage further research in the field of pain management guided by genomic analysis&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">ESL was approved by the EMA in 2009&#44; and has been available in Spain since February 2011&#46; The drug is currently indicated as monotherapy for the treatment of partial onset seizures&#44; with or without secondary generalisation&#44; in adults with newly diagnosed epilepsy&#44; and as adjuvant therapy in adults&#44; adolescents and children over 6 years of age with partial onset seizures&#44; with or without secondary generalization&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">23</span></a> Very few studies have reported the analgesic effects of ESL&#46; However&#44; there is evidence for its use in multiple sclerosis with refractory trigeminal neuralgia&#44; and in diabetic neuropathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">43&#44;44</span></a> Some authors have published their experience with ESL in case series with different types of pain&#46; These&#44; however&#44; are small&#44; open-label observational studies with no control group&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">45</span></a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarises the evidence for the use of carboxamide class of sodium channel blockers in pain management&#46; Only drugs currently available in Spain are shown&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0145" class="elsevierStylePara elsevierViewall">All the latest clinical practice guidelines consulted recommend tricyclic&#44; dual antidepressants &#40;venlafaxine&#47;duloxetine&#41; and gabapentin&#47;pregabalin antiepileptics as first-line drugs in the treatment of neuropathic pain&#44; reserving sodium channel blockers as a second-line option&#44; along with many other drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">46</span></a> The failure of some guidelines&#44; such as the American Academy of Neurology &#40;AAN&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">47</span></a> or the Cochrane library&#44;<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">48&#44;49</span></a> to support the use of CBZ or OXC in neuropathy diabetic peripheral has led numerous clinicians to question the effectiveness of these drugs in pain management&#46; However&#44; these findings should be weighed up against a more recent meta-analysis &#40;2015&#41; on neuropathic pain carried out by the International Association for the Study of Pain &#40;IASP&#41;&#44; which suggests&#44; based on the results of various studies&#44; that OXC might be significantly more effective in a subgroup of patients with a specific pain phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">46</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">In the 3 clinical trials cited by the AAN&#44; pain scores were reduced in patients receiving<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1200<span class="elsevierStyleHsp" style=""></span>mg&#47;day OXC&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">47</span></a> There is currently insufficient evidence to confirm a dose-dependent effect&#44; but the available literature suggests that the main benefits of OXC in peripheral neuropathy are observed at doses of &#62;900<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; Although studies supporting the use of first- and second-line drugs for various pain conditions vary greatly in terms of quantity and quality&#44; the latest continue to describe the potential for voltage-gated sodium channel blockers in the treatment of pain&#44; an indication which is still underestimated&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">46</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The is little evidence in the literature for the superiority of Nav over gabapentinoids in neuropathic pain&#44; but most studies evaluating these drugs for pain management involve patients with neuropathic pain syndromes&#46; It is interesting to note that many Navs have been associated with the transmission of neuropathic pain&#44;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">10</span></a> and some have also been associated with inflammatory pain&#44; with evidence that prostaglandins increase the activity of Nav1&#46;9 and Nav&#46;1&#46;7&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">10&#44;12</span></a> However&#44; there is no evidence voltage-gated sodium channel blockers can replace non-steroidal anti-inflammatory drugs for inflammatory pain management&#46; However&#44; the pharmacological characteristics indicate that a trial with sodium channel blockers could be effective in patients who cannot tolerate or are contraindicated for NSAIDs due to gastrointestinal or cardiovascular complications&#46; Clinical trials are necessary to fully assess and characterise the targeted use of voltage-dependent sodium channel blockers and their place in the treatment of inflammatory pain&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Treatment targeting specific Nav subtypes could greatly affect the development of drugs to treat chronic pain&#44; and is an area that merits further research&#46; Researchers are currently attempting to design drugs that selectively inhibit specific Nav subtypes&#59; however&#44; this can be complicated because of the structural similarities between the different channels&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Traditionally&#44; the use of CBZ has been limited&#44; due to its pharmacokinetic profile and undesirable side effects&#44; and the use of OXC has decreased by association and due to the assumption that it will have similar effects&#46; Research has validated the improved pharmacokinetic profile and adverse side effects of OXC compared to CBZ&#44; but research into their use in pain management has not been given the priority it merits&#46; The recent launch ESL has generated new and promising evidence on sodium channels blockers as a drug class&#46; More research is needed to identify the different sodium channels subtypes&#44; their role in the underlying causes of pain and their application in clinical practice&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0170" class="elsevierStylePara elsevierViewall">The global effort to minimise and reduce dependence on opioids has been undermined by the limited availability of effective treatment alternatives&#46; The evidence for various first- and second-line drugs for neuropathic pain is conflicting&#44; and must be clarified by further research into specific pain conditions&#46; Targeted sodium channel blocker therapy for musculoskeletal and neuroinflammatory disorders may be a new frontier in research into pain management&#46; Identifying and converting sodium channels subtypes associated with specific pain conditions into pharmacological targets is just one example of the potential of truly individualised treatments and the new approach needed in pain care&#46; Evidence has shown that voltage-gated sodium channels blockers are underutilised&#46; However&#44; emerging research has shown these drugs to be a promising field for clinical trials that can guide future trends in clinical practice&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres1024771"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Voltage-gated sodium channels as therapeutic targets in pain management"
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        6 => array:3 [
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          "titulo" => "Pharmacological profile of voltage-gated sodium channel blockers"
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              "titulo" => "Pharmacokinetic and pharmacodynamic profiles"
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              "titulo" => "Safety"
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          "identificador" => "sec0030"
          "titulo" => "Evidence for voltage-gated sodium channel blockers in analgesia"
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          "titulo" => "Conclusions"
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    "fechaRecibido" => "2017-09-16"
    "fechaAceptado" => "2018-01-22"
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            0 => "Eslicarbazepine acetate"
            1 => "Sodium channel blockers"
            2 => "Carbamazepine"
            3 => "Chronic pain management"
            4 => "Oxcarbazepine"
            5 => "Adjunct therapy"
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          "palabras" => array:6 [
            0 => "Acetato de eslicarbazepina"
            1 => "Bloqueadores de los canales de sodio"
            2 => "Carbamazepina"
            3 => "Manejo del dolor cr&#243;nico"
            4 => "Oxcarbazepina"
            5 => "Tratamiento adyuvante"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Once patients have failed first line therapy&#44; there is an apparent lack of knowledge on how to proceed with choosing subsequent therapy&#46; To choose amongst alternative agents&#44; an understanding of pharmacology&#44; pharmacokinetics&#44; and available evidence in targeting various pain conditions is necessary&#46; This article focuses on the use of the carboxamide class of voltage-gated sodium channel blockers &#40;carbamazepine&#44; oxcarbazepine&#44; eslicarbazepine acetate&#41; for adjunct pain medication management&#59; including research updates in pharmacology&#44; pharmacokinetics&#44; and evidence for pain along on this therapeutic group with promising future areas of research&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Although evidence for voltage-gated sodium channel blockers in chronic pain management is limited&#44; emerging research has identified this area as promising for additional clinical trials to better guide clinical practice&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Una vez que ha fracasado el tratamiento de primera l&#237;nea en los pacientes con dolor cr&#243;nico&#44; parece haber una laguna de conocimiento sobre c&#243;mo proceder en la elecci&#243;n de un tratamiento posterior&#46; Este art&#237;culo se centra en el uso de los bloqueadores de los canales de sodio dependientes de voltaje que pertenecen a la clase de las carboxamidas &#40;carbamazepina&#44; oxcarbazepina&#44; acetato de eslicarbazepina&#41; como tratamiento analg&#233;sico adyuvante&#59; e incluye actualizaciones sobre farmacolog&#237;a&#44; farmacocin&#233;tica y evidencias en dolor de este grupo terap&#233;utico&#44; as&#237; como prometedoras futuras l&#237;neas de investigaci&#243;n&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Aunque la evidencia de los bloqueadores de los canales de sodio dependientes de voltaje en el manejo del dolor cr&#243;nico es limitada&#44; la investigaci&#243;n emergente ha identificado esta &#225;rea como esperanzadora para que ensayos cl&#237;nicos adicionales gu&#237;en mejor nuestra pr&#225;ctica cl&#237;nica&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Alc&#225;ntara Montero A&#44; S&#225;nchez Carnerero CI&#46; Papel de los bloqueadores de los canales de sodio dependientes de voltaje en el tratamiento del dolor cr&#243;nico&#58; usos potenciales en la pr&#225;ctica cl&#237;nica seg&#250;n la evidencia disponible&#46; Rev Esp Anestesiol Reanim&#46; 2018&#59;65&#58;275&#8211;283&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0110">This article is part of the Anaesthesiology and Resuscitation Continuing Medical Education Program&#46; An evaluation of the questions on this article can be made through the Internet by accessing the Education Section of the following web page&#58; <a class="elsevierStyleInterRef" target="_blank" id="intr0110" href="http://www.elsevier.es/redar">www&#46;elsevier&#46;es&#47;redar</a></p>"
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            "apendice" => "<p id="par0185" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0050"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Voltage-dependent sodium channels subtypes and associated pain syndromes&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">CYP450&#58; cytochrome p450 enzyme system&#59; MHD&#58; 10-monohydroxy derivative&#44; active metabolite of oxcarbazepine&#59; OXC&#58; oxcarbazepine&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Sources</span>&#58; Carbamazepine<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">19</span></a>&#59; oxcarbazepine<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">20</span></a>&#59; eslicarbazepine acetate<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">23</span></a>&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Carbamazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Oxcarbazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Eslicarbazepine acetate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bioavailability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">70&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;95&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;90&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Plasma protein binding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">70&#8211;80&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40&#37; &#40;MHD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;40&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metabolism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatic&#58; phase I<br>&#42; CYP3A4 &#40;major&#41;&#44; responsible for the formation of pharmacologically active 10&#44;11-carbamazepine epoxide<br>&#42; CYP2C8 &#40;minor&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Step 1&#58;</span> OXC metabolised by arylketone reductase to MHD<br><span class="elsevierStyleItalic">Step 2&#58;</span> MHD metabolism&#58; hepatic&#58; phase I &#40;CYP450-minor&#41;<span class="elsevierStyleHsp" style=""></span>&#8764;<span class="elsevierStyleHsp" style=""></span>4&#37; inactive metabolite<br>Hepatic&#58; phase II&#58; glucuronidation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatic&#58; phase II<br>Esterases&#44; glucuronidation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Half-life&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">36<span class="elsevierStyleHsp" style=""></span>h &#40;after several administrations&#58; 16&#8211;24<span class="elsevierStyleHsp" style=""></span>h&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;3&#8211;2&#46;3<span class="elsevierStyleHsp" style=""></span>h<br>9&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;8<span class="elsevierStyleHsp" style=""></span>h &#40;MHD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#8211;20<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Excretion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">72&#37; in urine and 28&#37; in stools&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;95&#37; in urine and &#60;4&#37; in stools&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8764;90&#37; in urine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CYP450 interaction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Potent inducer of CYP3A4 and other phase I and phase II hepatic enzyme systems&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">OXC and MHD are weak <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> inducers of CYP3A4 and CYP3A5<br><br><span class="elsevierStyleItalic">In vitro</span>&#44; OXC and MHD are weak inducers of UDP-glucuronyltransferases<br><br>OXC and MHD inhibit CYP2C19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Weak inducer of CYP3A4 at &#8805;800<span class="elsevierStyleHsp" style=""></span>mg&#47;day<br><br>Minor inhibition of CYP2C19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Different side effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Haematological and dermatological adverse effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Hyponatraemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8764; to OXC &#40;less hyponatraemia&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">CBZ&#58; carbamazepine&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Pain syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Carbamazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Oxcarbazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Eslicarbazepine acetate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Level of evidence<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tabetic pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">800<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">30</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Trigeminal neuralgia</td><td class="td" title="table-entry  " align="left" valign="top">400&#8211;1200<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">27&#8211;29</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">600&#8211;2400<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">27&#8211;29</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Multiple sclerosis with refractory trigeminal neuralgia&#58; 400<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">43</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Postimpactomy neuralgia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">600<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">33</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Diabetic neuropathy</td><td class="td" title="table-entry  " align="left" valign="top">200&#8211;600<span class="elsevierStyleHsp" style=""></span>mg&#47;day &#40;often requires &#62;600<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">150&#8211;1200<span class="elsevierStyleHsp" style=""></span>mg&#47;day &#40;often requires<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>600<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#59; average dose<span class="elsevierStyleHsp" style=""></span>&#8764;<span class="elsevierStyleHsp" style=""></span>800<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">35</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Second line treatment&#58; 400&#8211;800<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">44</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glossopharyngeal neuralgia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">400&#8211;800<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">31</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Phantom limb pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">800<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">32</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Central neuropathic pain with allodynia after spinal cord injury&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">900<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Postherpetic neuralgia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Refractory to CBZ and gabapentin&#58; 900<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Paroxysmal symptoms in multiple sclerosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1000<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Complex regional pain syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Refractory to gabapentin&#58; 150&#8211;2000<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">39</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Radiculopathy<br>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Refractory to gabapentin&#58; 150&#8211;900<span class="elsevierStyleHsp" style=""></span>mg&#47;day<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">40</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
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          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:49 [
            0 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Survey of chronic pain in Europe&#58; prevalence&#44; impact on daily life&#44; and treatment"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "H&#46; Breivik"
                            1 => "B&#46; Collett"
                            2 => "V&#46; Ventafridda"
                            3 => "R&#46; Cohen"
                            4 => "D&#46; Gallacher"
                          ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.ejpain.2005.06.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Pain"
                        "fecha" => "2006"
                        "volumen" => "10"
                        "paginaInicial" => "287"
                        "paginaFinal" => "333"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16095934"
                            "web" => "Medline"
                          ]
                        ]
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