Emerging therapies in clinical development and new contributions for neuropathic pain | Revista Española de Anestesiología y Reanimación (English Edition)

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(a) Mirogabalina se une a la subunidad auxiliar α2-δ de los canales de calcio voltaje dependientes, reduciendo la entrada de calcio en las terminaciones nerviosas y, como consecuencia, disminuye la liberación de neurotransmisores excitadores, como el glutamato. (b) BIIB074 es un bloqueador selectivo de los canales de sodio voltaje dependientes Nav1.7, los cuales se expresan principalmente en el sistema nervioso periférico. Fuente: imagen cortesía de Carlos Goicoechea García." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A. Alcántara Montero, C.I. Sánchez Carnerero, C. Goicoechea García" "autores" => array:3 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Alcántara Montero" ] 1 => array:2 [ "nombre" => "C.I." "apellidos" => "Sánchez Carnerero" ] 2 => array:2 [ "nombre" => "C." 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Also note the absence of blood flow through the biological mitral prosthesis, shown on colour Doppler (red arrow). AI: left atrium; lpm: beats per minute; VD: right ventricle; VI: left ventricle." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A. Martínez Salgado, M. Taboada Muñiz, J.M. Martínez Cereijo, P. Otero Castro, J. Álvarez Escudero" "autores" => array:5 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Martínez Salgado" ] 1 => array:2 [ "nombre" => "M." "apellidos" => "Taboada Muñiz" ] 2 => array:2 [ "nombre" => "J.M." "apellidos" => "Martínez Cereijo" ] 3 => array:2 [ "nombre" => "P." "apellidos" => "Otero Castro" ] 4 => array:2 [ "nombre" => "J." 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Alcántara Montero, C.I. Sánchez Carnerero, C. Goicoechea García" "autores" => array:3 [ 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." "apellidos" => "Sánchez Carnerero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "C." "apellidos" => "Goicoechea García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Centro de Salud Manuel Encinas, Consultorio de Malpartida de Cáceres, Cáceres, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Complejo Hospitalario Universitario de Cáceres, Hospital San Pedro de Alcántara, Cáceres, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Terapias emergentes en desarrollo clínico y nuevas aportaciones en dolor neuropático" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2462 "Ancho" => 2917 "Tamanyo" => 492690 ] ] "descripcion" => array:1 [ "en" => "Mechanisms of action of EMA401 fulranumab. ASIC: Acid-sensing ion channel; AT2R: Angiotensin II type 2 receptorNGF: Nerve growth factor; PX/PY: Purinergic receptors; ROS: Reactive oxygen species; TrkA: Tropomyosin receptor kinase A; TRPA1: Transient receptor potential ankyrin 1; TRPV1: Transient receptor potential vanilloid 1. (a) EMA401 is an AT2R antagonist. By blocking this receptor, immune system cells (such as macrophages) release less ROS that act on TRPA1 receptors, which are molecular integrators of many exogenous and endogenous noxious stimuli, including oxygen free radicals and other inflammatory agents released at the site of the injury, promoting the sensitisation of nociceptors. (b) Fulranumab is an anti-NGF antibody; it blocks TrkA, which is the NGF receptor. Under normal conditions, when the NGF bind to its receptor, it facilitates the transmission of the nociceptive signal. In addition, in peripheral sensitisation, stimulation of TrKA stimulates TRPV1, which is the target of multiple inflammatory mediators that trigger nociceptor sensitisation. Therefore, fulranumab can indirectly modulate the response of TRPV1, but has in itself a direct inhibitory effect on the nervous response through its own membrane receptor. Source: Image courtesy of Carlos Goicoechea García." ] ] ] "textoCompleto" => "IntroductionNeuropathic pain is difficult to treat due to the variety of possible causes, symptoms and underlying mechanisms. For this reason, is considered a medical necessity that, to a large extent, has not yet been met, despite the growing number of treatments available. The efficacy and safety profile of most treatments currently used is modest,<a class="elsevierStyleCrossRef" href="#bib0255">1</a> and therefore new options and therapeutic alternatives are welcomed.Currently, more than 100 molecules that act on specific targets of potential interest for neuropathic pain are being developed.<a class="elsevierStyleCrossRefs" href="#bib0260">2–4</a> These include isoform-specific sodium channel blockers, vanilloid receptor antagonists, potassium channel agonists, metabotropic glutamate/NMDA receptor antagonists or new NMDA receptors modulators, new opioid receptor agonists, histamine H3 receptor antagonists, serotonergic modulators, nicotinic agonists, adrenergic agonists, nitric oxide synthase inhibitors, orexin receptor antagonists, angiotensin II receptor antagonists, imidazolid I2 receptor agonists, apoptosis inhibitors, cannabinoid receptor 2 agonists, selective sigma-1 receptor antagonists, fatty acid amide hydrolase inhibitors, nerve growth factor antagonists, gene therapy, etc. Most of these molecules are in the early stages of preclinical development.Several older drugs are available, such as botulinum toxin and oxcarbazepine, most of which are not indicated in pain. However, new data on the use of these drugs in neuropathic pain has recently emerged, so they could be considered emerging treatments.In this review, after a brief summary of the drugs currently recommended for neuropathic pain, we will focus on new pharmacological treatments for this condition for which clinical data are already available, including new evidence for the antineuropathic action of some more familiar drugs. We only discuss those that we consider to have potential clinical relevance, based on evidence from placebo-controlled or active-control randomised clinical trials (RCTs) in peripheral or central neuropathic pain identified in the Medline/PubMed, Google Scholar, PsycInfo and ClinicalTrials.gov databases.Drugs currently recommended for the treatment of neuropathic painMost of the clinical practice guidelines consulted coincide in pointing out that tricyclic (particularly amitriptyline) and dual antidepressants (particularly duloxetine) together with gabapentin/pregabalin antiepileptics are first-line drugs in the treatment of neuropathic pain (Strong recommendation according to the Grading of Recommendations, Assessment, Development and Evaluation system [GRADE]), with tramadol, 5% lidocaine patches and 8% capsaicin patches as second line drugs (Weak Recommendation according to the GRADE system), and powerful opioids as the third line (Weak Recommendation according to the GRADE system) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0275">5–8</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Unfortunately meta-analyses indicate that only a minority of patients with neuropathic pain show adequate response to pharmacological treatment, and that many of these drugs have been limited by negative factors, such as systemic side effects, drug interactions, slow onset of action, need for dose adjustment, administration of multiple daily doses, and possible risk of addiction, dependence, withdrawal symptoms and abuse.<a class="elsevierStyleCrossRef" href="#bib0290">8</a> Other drugs that are expected to be effective, such as cannabinoids, tapentadol and several antiepileptic drugs (lamotrigine, lacosamide, topiramate, eslicarbazepine acetate, etc.), have shown inconsistent results, although some may be effective in some subgroups of patients.<a class="elsevierStyleCrossRefs" href="#bib0295">9,10</a>Drugs in clinical development that act on new therapeutic targets with potential clinical relevance in neuropathic painMirogabalinMirogabalin, like gabapentin and pregabalin, binds to the auxiliary α2-δ subunit of voltage-gated calcium channels, reducing calcium entry into nerve termini, thereby decreasing the release of excitatory neurotransmitters, such as glutamate (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). From the pharmacological point of view, absorption of pregabalin and mirogabalin is linear and not dose-dependent, while the intestinal absorption of gabapentin is saturable, which makes it difficult to titrate. Gabapentin enacarbil has been developed to overcome this drawback of gabapentin, and has demonstrated linear absorption and greater bioavailability than gabapentin. However, gabapentin enacarbil is only available in Japan and the USA. <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarises the main pharmacokinetic parameters of gabapentinoids.<a class="elsevierStyleCrossRef" href="#bib0305">11</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>So far only 1 RCT evaluating mirogabalin in patients with neuropathic pain has been published.<a class="elsevierStyleCrossRef" href="#bib0310">12</a> This double blind, five-week, phase 2 trial compared the efficacy and safety of 5 doses of mirogabalin (5, 10, 15, 20 and 30mg/day) against placebo and pregabalin 300mg/day in patients with diabetic peripheral neuropathic pain (DPNP). Mirogabalina at doses of 5, 10 and 15mg/day was administered once daily, while mirogabalin at doses of 20 and 30mg/day was administered twice daily. The primary outcome measure was the weekly change in the average daily pain score from baseline to week 5. Pain was measured on a 0–10 numerical scale; a difference ≥1.0 point compared with placebo in reducing this score was considered clinically significant. The mean differences in change vs. placebo were −0.22, −0.53, −0.94, −0.88 and −1.01 for the mirogabalin 5, 10, 15, 20, and 30mg/day treatment groups, respectively, and -0.05 for the pregabalin group. Although only mirogabalin 30mg/day met predefined criteria for a clinically significant effect, the 15 and 20mg/day dose of mirogabalin met the criteria of minimally meaningful effect. In fact, the number needed to treat (NNT) to show a reduction ≥30% in the pain score was 4.0, 5.2 and 6.9, respectively, for the 3 highest doses of mirogabalin, and the corresponding NNT for a reduction ≥50% in the pain score was of 6.6, 5.3 and 5.1, respectively.<a class="elsevierStyleCrossRef" href="#bib0310">12</a> With regard to secondary outcomes, it was observed that all doses of mirogabalin were associated with a significant overall improvement rated on the Patient Global Impression of Improvement (PGI-I) questionnaire. These 3 doses (15, 20 and 30mg/day) of mirogabalin were selected by the manufacturer for the evaluation of drug efficacy and safety in 2 Phase 3, placebo-controlled, double-blind, 14-week trials in patients with DPNP<a class="elsevierStyleCrossRef" href="#bib0315">13</a> and in patients with postherpetic neuralgia (PHN)<a class="elsevierStyleCrossRef" href="#bib0320">14</a> performed in Japan, but whose results have not yet been published. In an exposure-response study using data from the phase 2 study, and taking into account the efficacy and safety data, it was estimated that 17.7mg of mirogabalin was equivalent to pregabalin 300mg in reducing pain.<a class="elsevierStyleCrossRef" href="#bib0325">15</a> Using this model, the twice-daily regimen of mirogabalin was predicted to produce a lower incidence of dizziness, the most frequent and dose-dependent adverse effect observed in the phase 2 clinical trial.The results of mirogabalin in patients with DPNP are certainly promising, and show a clinically meaningful effect on pain. The inclusion of an active pregabalin 300mg/day arm in mirogabalin RCTs, both in the phase 2 trial in patients with DPNP<a class="elsevierStyleCrossRef" href="#bib0310">12</a> and in other phase 3 trials in patients with fibromyalgia,<a class="elsevierStyleCrossRef" href="#bib0330">16</a> was a good decision on the part of the manufacturer, and will further defined the effectiveness and tolerability of this medicine. Gabapentin and pregabalin are similar in terms of tolerability, and the limited data available suggest that mirogabalin does not differ from the 2 compounds in this respect. An important task in coming years will be to determine the efficacy and tolerability of mirogabalin in the treatment of chronic pain of different aetiologies. In animal models mirogabalin has been shown to have a superior analgesic effect and a wider margin of safety in the central nervous system than pregabalin.<a class="elsevierStyleCrossRef" href="#bib0335">17</a> Data from ongoing clinical trials in mirogabalin for the treatment of fibromyalgia and PHN are likely to be available in a few years, and it will then be possible to make a clinical comparison of mirogabalin with gabapentin and pregabalin.<a class="elsevierStyleCrossRef" href="#bib0340">18</a>Selective voltage-gated sodium channel blockersNav1.7 is a voltage-dependent sodium channel (NaV) that is preferentially expressed in peripheral neurons, including trigeminal neurons, and the results of genetic and functional studies suggest a link between NaV1.7 and pain symptoms in humans.<a class="elsevierStyleCrossRefs" href="#bib0345">19,20</a> The efficacy of carbamazepine (known to block Nav1.7) and oxcarbazepine support the hypothesis that NaV1.7 could be a therapeutic target in trigeminal neuralgia.<a class="elsevierStyleCrossRef" href="#bib0355">21</a>An increase in NaV1.7 activity also occurs in a common variant of NaV1.7, where an arginine is replaced by a tryptophan at position 1150 (R1150W) in the protein sequence; this variant occurs in 15–30% of the population. According to reports, this variant of NaV1.7 is associated with an increased sensitivity to pain.<a class="elsevierStyleCrossRef" href="#bib0360">22</a> Validation of the NaV1.7 target in many studies of human genetics supports this as a strategy for analgesic development.<a class="elsevierStyleCrossRef" href="#bib0365">23</a>BIIB074 is a selective NaV1.7 sodium channel blocker (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) that is currently under investigation for the treatment of trigeminal neuralgia. Electrophysiological studies have shown that BIIB074 preferentially inhibits high frequencies of firing in neurons, as would be expected in paroxysms of pain in trigeminal neuralgia. The results of phase 1 clinical trials suggest that BIIB074 is well tolerated in healthy individuals, and can be administered at therapeutic doses without prolonged titration. In a phase II, multicentre, placebo-controlled RCT in 67 patients with classic trigeminal neuralgia (29 patients were randomised to double-blind treatment for 28 days), no statistically significant difference (p=0.0974) was found between BIIB074 (150mg 3 time daily) and placebo in the primary endpoint (treatment failure), but the drug was effective in multiple secondary endpoints, including the proportion of responders. Safety was excellent, with side effects in the active group being comparable to placebo. Headache was the most frequent adverse event with BIIB074 in the open-label phase (19%), followed by dizziness (9%). In the double-blind phase, headache, pyrexia, nasopharyngitis, sleep disorder, and tremor were the most frequent adverse events in patients assigned to BIIB074. No serious or severe adverse events were reported in the BIIB074 group during the double-blind phase.<a class="elsevierStyleCrossRef" href="#bib0370">24</a>TV-45070 is a new, potent inhibitor of NaV1.7 and other NaVs expressed in the peripheral nervous system. There is evidence of analgesic activity in the active principle of TV-45070 when administered orally in patients with hereditary erythromelalgia.<a class="elsevierStyleCrossRef" href="#bib0375">25</a> Each of these patients with hereditary erythromelalgia had inherited a Nav1.7 gain-of-function mutation, suggesting that the analgesic effect of TV-45070 was due to its inhibition of NaV1.7.<a class="elsevierStyleCrossRef" href="#bib0375">25</a> A topical form of TV-45070 was developed to maximise local NaV inhibition in the skin and subcutaneous tissue, and thus minimise systemic adverse events and maintain low plasma concentrations. In a randomised, controlled, proof-of-concept, crossover study in 70 patients with PHN (54 completed the study) a topical NaV1.7 antagonist (TV-45070) was applied twice daily for 3 weeks. This study was negative for the primary endpoint (pain intensity), but found a significant effect in the proportion of responders. In addition, 63% of patients with the NaV1.7 R1150W gain-of-function polymorphism responded to treatment compared with 35% of wild-type carriers. No significant side effects were reported.<a class="elsevierStyleCrossRef" href="#bib0380">26</a>In general, these 2 clinical trials, although negative for the primary endpoint, clearly suggest the possible clinical relevance of NaV1.7 antagonists in neuropathic pain, and justify continuing their clinical development. On the basis of these promising results, new clinical trials in BIIB074 are currently under way in both trigeminal neuralgia and in other neuropathic pain models (such as small fibre neuropathy, erythromelalgia and lumbosacral radiculopathy).Angiotensin II type 2 receptor antagonistsClarification of the renin-angiotensin system led to the development of antihypertensive agents (angiotensin-converting enzyme inhibitors, renin inhibitors, and selective angiotensin II type 1 receptor antagonists or blockers [AT1R]).<a class="elsevierStyleCrossRef" href="#bib0385">27</a> During the development of AT1R antagonists, a second angiotensin II binding receptor was identified: the angiotensin II type 2 receptor (AT2R). Findings from initial studies suggested that AT2R antagonists did not control hypertension in animals,<a class="elsevierStyleCrossRef" href="#bib0390">28</a> and no other therapeutic applications for AT2R antagonists in patients have been established.The renin-angiotensin system mediates diverse physiological functions outside the cardiovascular system, even in the central and peripheral nervous systems. Preclinical studies of neuropathic pain in rodent models have shown that highly selective AT2R antagonists, such as EMA401, have analgesic properties. AT2R is expressed in human sensory (nociceptive) neurons, but AT1R is not. Findings from functional studies in sensory neurons from humans and cultured rodents showed that EMA401 inhibits capsaicin-mediated calcium flow, suggesting an antinociceptive effect (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). EMA401, therefore, was added to clinical development as a treatment for chronic pain, including neuropathic pain. Pharmacokinetic and pharmacodynamic studies in animal models, phase 1 pharmacokinetic data in humans, and in vitro functional assays support a potentially effective doses in humans of 10–50mg/day.<a class="elsevierStyleCrossRefs" href="#bib0395">29,30</a> Since EMA401 at doses of up to 400mg met phase 1 safety criteria, a clinical trial with 200mg/day (100mg twice daily) was performed. This was a phase 1, 28-day, multicentre RCT in 183 patients with PHN, which showed that EMA401 was both effective and safe.<a class="elsevierStyleCrossRef" href="#bib0405">31</a> Selective AT2R antagonists may represent a new class of analgesics for neuropathic pain, and are currently being tested in phase III trials.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Nerve growth factor antagonistsInhibition of the effect of nerve growth factor (NGF) has shown the potential to normalise neuronal hyperactivity and produce sustained clinical pain relief. Therefore, there is considerable interest in considering NGF as a possible pharmacological target in neuropathic pain (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), and antibodies targeting human NGF, such as tanezumab, fulranumab and fasinumab, are currently in clinical development for the treatment of chronic, mainly nociceptive, pain.<a class="elsevierStyleCrossRefs" href="#bib0410">32,33</a>Fulranumab, an anti-NGF antibody administered subcutaneously, has been shown to be effective in the treatment of pain related to osteoarthritis of the knee and hip,<a class="elsevierStyleCrossRefs" href="#bib0420">34,35</a> but not in chronic low back pain.<a class="elsevierStyleCrossRef" href="#bib0430">36</a>Fulranumab is the only drug of this class specifically investigated in neuropathic pain.<a class="elsevierStyleCrossRefs" href="#bib0435">37,38</a> It should be noted that all studies performed in anti-NGF antibodies were interrupted prematurely (23 December 2010) by the Food and Drug Administration (FDA) due to reports of rapidly progressive osteoarthritis and osteonecrosis associated with anti-NGF in patients with osteoarthritis. In a phase 2, double-blind, placebo-controlled RCT, patients with DPNP were randomised to fulranumab (1, 3 or 10mg) or placebo administered subcutaneously every 4 weeks. This study included 77 (intention to treat) of the 200 patients planned. The primary endpoint, mean reduction of average daily pain at week 12 compared to baseline, showed a positive dose–response relationship (p=0.014); pairwise comparison between the 10mg group and the placebo group was significant (p=0.040, unadjusted). An analysis revealed that a higher proportion of patients in the 10mg group reported a ≥30% reduction in average pain intensity compared to placebo at week 12 (p=0.006). Although not statistically significant, several secondary endpoints showed results that were directionally similar to the primary dose–response relationship. During the combined efficacy and safety extension phases, the 3 main adverse events arising from treatment in the combined fulranumab group were arthralgia (11%), peripheral oedema (11%) and diarrhoea (9%). Therefore, despite the early termination of the study, treatment with fulranumab was effective, though dose-dependent (10mg fulranumab reduced pain by 1–2 points on an 11-point scale compared to placebo) and, in general, well tolerated.<a class="elsevierStyleCrossRef" href="#bib0435">37</a>In another phase II RCT, patients with PHN were randomised to receive placebo or one of the 3 doses of subcutaneous fulranumab: 1mg, 3mg or 10mg every 4 weeks. The trial also included patients with post-traumatic neuropathy, who were randomised to receive placebo or 10mg fulranumab subcutaneously every 4 weeks. Due to early termination of the study by the FDA, only 49 patients with PHN (of the 150 planned) and 34 with post-traumatic neuropathy (of the 50 planned) completed the effectiveness evaluation in the double-blind phase. There were no significant differences (p>0.05 fulranumab vs. placebo) in mean pain intensity from baseline to the end of the 12-week double-blind efficacy phase (primary endpoint). Nor were significant differences found between fulranumab vs. placebo (p>0.05) in other measures of efficacy in patients in both trial groups. The most common treatment-related adverse events (>10% incidence) in patients with post-traumatic neuropathy were sinusitis, carpal tunnel syndrome, and headache, while in patients with PHN arthralgias were most frequent.<a class="elsevierStyleCrossRef" href="#bib0440">38</a>Drugs with new antineuropathic activity dataOxcarbazepineAlthough the findings of large-scale clinical trials seems to suggest that antiepileptics acting on NaV have limited efficacy in pain, this may be because they do not target the relevant phenotypic profiles.<a class="elsevierStyleCrossRef" href="#bib0355">21</a> Interestingly, a recent multicentre proof-of-concept clinical trial testing the NaV blocker oxcarbazepine in 83 patients (39 patients completed the treatment) with peripheral neuropathic pain stratified into 2 groups according to clinical phenotypes, suggesting underlying mechanisms (“irritable” nociceptors with possible normal nociceptive function vs. deafferentation), reported that only patients with preserved nociceptive function responded significantly to oxcarbazepine, suggesting that this drug mainly targets the remaining hyperexcitable nociceptive fibres.<a class="elsevierStyleCrossRef" href="#bib0445">39</a> This suggests that older drugs acting on NaV can have significant efficacy, at least in subgroups of patients with neuropathic pain, and should be investigated in the future using a phenotype-based approach instead of stratifying patients according to aetiology.<a class="elsevierStyleCrossRef" href="#bib0355">21</a>Botulinum toxin type ABotulinum toxin type A (BTX-A) is widely used to treat muscular hyperactivity, based on its capacity to inhibit synaptic exocytosis and, therefore, to disable neuronal transmission.<a class="elsevierStyleCrossRef" href="#bib0450">40</a> Several experimental studies in animals and clinical models of pain in healthy subjects have shown that BTX-A may have analgesic activity independent of its effect on muscle tone, possibly through a decrease in neurogenic inflammation.<a class="elsevierStyleCrossRef" href="#bib0455">41</a>Four RCTs from a single centre that included between 20 and 60 patients reported the long-term efficacy of BTX-A (single fixed-dose or symptom-adjusted subcutaneous or intradermal injection in the affected dermatome, from 50 to 200 units) in peripheral neuropathic pain (PHN, traumatic nerve injury or DPNP). All reported a high response rate.<a class="elsevierStyleCrossRefs" href="#bib0460">42–45</a> The onset of efficacy (approximately 1 week) and the duration of effect (3 months) in these studies were remarkably similar. However, an unpublished multicentre proof-of-concept RCT was negative in 117 patients with PHN.<a class="elsevierStyleCrossRef" href="#bib0480">46</a> Three other small placebo-controlled RCTs from a single centre also reported the efficacy of BTX-A administered intradermally in the face, mucosa or in common trigeminal neuralgia trigger points.<a class="elsevierStyleCrossRef" href="#bib0485">47</a>A recent double-blind, placebo-controlled RCT performed in 3 centres evaluated the efficacy and prolonged safety of 2 subcutaneous injections of BTX-A (up to 300 units, symptom-adjusted) administered 12 weeks apart in 66 patients with peripheral neuropathic pain (PHN, posttraumatic nerve injury and painful polyneuropathy) with or without allodynia. The results showed that BTX-A improved average intensity of pain over the course of 24 weeks compared to placebo (primary outcome), and that the second injection was of greater therapeutic benefit. BTX-A was particularly effective in some neuropathic symptoms (allodynia and paroxysmal pain), and reduced mechanical allodynia and hyperalgesia, assessed by quantitative sensory tests. The safety profile was excellent, with pain on injection being the only adverse effect. Response to BTX-A at the end of treatment was predicted by the presence or severity of mechanical allodynia and the preservation of intraepidermal nerve fibre density in the skin puncture biopsy (performed at baseline), and a correlation was observed between the preservation of thermal deficits and response to BTX-A.<a class="elsevierStyleCrossRef" href="#bib0490">48</a> These findings suggest that patients with preserved nociceptive input are likely to show the best response to BTX-A. This study also examined whether response to BTX-A was mediated by an effect on neurogenic inflammation. For this purpose, neuropeptide levels (calcitonin gene-related peptide and substance P) were measured from a skin biopsy at the beginning of the study and 1 month later. Contrary to expectations, the level of these neuropeptides was neither modified by the treatment nor linked to its efficacy. These data suggest that BTX-A could act on other mechanisms, preferably central, presumably through axonal retrograde transport.<a class="elsevierStyleCrossRef" href="#bib0495">49</a> In line with this hypothesis, a recent single-centre, double-blind, placebo-controlled RCT in 40 patients with spinal cord injury reported a beneficial effect of BTX-A on pain below the neurological level of injury, which was more marked in patients with preserved motor or sensory function.<a class="elsevierStyleCrossRef" href="#bib0500">50</a> These data have led to the recommendation of BTX-A as a third option in the therapeutic arsenal of peripheral neuropathic pain for refractory patients.<a class="elsevierStyleCrossRef" href="#bib0290">8</a>ConclusionsNew medical treatments for neuropathic pain include drugs that act on new pain targets. Most of these products are in preclinical development or in the early stages of clinical development, but some clinical trials have suggested that mirogabalin, NaV1.7 antagonists, and AT2R antagonists have potential clinical relevance in neuropathic pain. Another option involves drugs such as oxcarbazepine and BTX-A that are mostly used for other indications, but that present an analgesic effect in subgroups of patients with neuropathic pain.<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> summarises the RCTs performed in neuropathic pain with the drugs included in this review.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Conflicts of interestWe have considered the instructions and ethical responsibilities, we fulfil the requirements of authorship, and we declare that we have no conflict of interests." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1196199" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1114597" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1196198" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1114596" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Drugs currently recommended for the treatment of neuropathic pain" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Drugs in clinical development that act on new therapeutic targets with potential clinical relevance in neuropathic pain" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Mirogabalin" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Selective voltage-gated sodium channel blockers" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Angiotensin II type 2 receptor antagonists" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Nerve growth factor antagonists" ] ] ] 7 => array:3 [ "identificador" => "sec0040" "titulo" => "Drugs with new antineuropathic activity data" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Oxcarbazepine" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Botulinum toxin type A" ] ] ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-01-18" "fechaAceptado" => "2019-02-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1114597" "palabras" => array:6 [ 0 => "BIIB074" 1 => "Neuropathic pain" 2 => "EMA401" 3 => "Fulranumab" 4 => "Mirogabalin" 5 => "Botulinum toxin type A" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1114596" "palabras" => array:6 [ 0 => "BIIB074" 1 => "Dolor neuropático" 2 => "EMA401" 3 => "Fulranumab" 4 => "Mirogabalina" 5 => "Toxina botulínica tipo A" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Neuropathic pain is very challenging to manage because of the heterogeneity of aetiologies, symptoms, and underlying mechanisms. Conventional oral therapies have been limited by negative factors such as systemic side effects, drug–drug interactions, slow onset of action, the need for titration, multiple daily dosing, as well as the potential risk of addiction, dependence, withdrawal symptoms, and abuse. Therefore new therapeutic perspectives are justified. New drugs that act on different therapeutic targets are currently in preclinical development or in their first phases of clinical development. In this review, focus will be directed specifically on new pharmacological treatments for neuropathic pain for which clinical data are already available, including older and known drugs with new data on their anti-neuropathic activity." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El dolor neuropático es difícil de tratar debido a la heterogeneidad de causas, síntomas y mecanismos subyacentes. Los tratamientos orales convencionales se han visto limitados por factores negativos, como efectos secundarios sistémicos, interacciones farmacológicas, inicio de acción lento, necesidad de ajuste de la dosis, administración de múltiples dosis diarias, y posible riesgo de adicción, dependencia, síntomas de abstinencia y uso excesivo. Por tanto, se justifican nuevas perspectivas terapéuticas. Actualmente, se encuentran en desarrollo preclínico o en sus primeras fases de desarrollo clínico nuevos fármacos que actúan sobre diferentes dianas terapéuticas. En esta revisión nos centraremos expresamente en nuevos tratamientos farmacológicos para el dolor neuropático para los cuales ya se dispone de datos clínicos, incluyendo fármacos más antiguos y conocidos con nuevos datos sobre su actividad antineuropática." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Alcántara Montero A, Sánchez Carnerero CI, Goicoechea García C. Terapias emergentes en desarrollo clínico y nuevas aportaciones en dolor neuropático. Rev Esp Anestesiol Reanim. 2019;66:324–334." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1914 "Ancho" => 2167 "Tamanyo" => 324940 ] ] "descripcion" => array:1 [ "en" => "Mechanisms of action of mirogabalin and BIIB074. (a) Mirogabalin binds to the auxiliary α2-δ subunit of voltage-gated calcium channels, reducing calcium entry into nerve termini, thereby decreasing the release of excitatory neurotransmitters, such as glutamate. (b) BIIB074 is a selective blocker of Nav1.7 voltage-dependent sodium channels, which are expressed mainly in the peripheral nervous system. Source: Image courtesy of Carlos Goicoechea García." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2462 "Ancho" => 2917 "Tamanyo" => 492690 ] ] "descripcion" => array:1 [ "en" => "Mechanisms of action of EMA401 fulranumab. ASIC: Acid-sensing ion channel; AT2R: Angiotensin II type 2 receptorNGF: Nerve growth factor; PX/PY: Purinergic receptors; ROS: Reactive oxygen species; TrkA: Tropomyosin receptor kinase A; TRPA1: Transient receptor potential ankyrin 1; TRPV1: Transient receptor potential vanilloid 1. (a) EMA401 is an AT2R antagonist. By blocking this receptor, immune system cells (such as macrophages) release less ROS that act on TRPA1 receptors, which are molecular integrators of many exogenous and endogenous noxious stimuli, including oxygen free radicals and other inflammatory agents released at the site of the injury, promoting the sensitisation of nociceptors. (b) Fulranumab is an anti-NGF antibody; it blocks TrkA, which is the NGF receptor. Under normal conditions, when the NGF bind to its receptor, it facilitates the transmission of the nociceptive signal. In addition, in peripheral sensitisation, stimulation of TrKA stimulates TRPV1, which is the target of multiple inflammatory mediators that trigger nociceptor sensitisation. Therefore, fulranumab can indirectly modulate the response of TRPV1, but has in itself a direct inhibitory effect on the nervous response through its own membrane receptor. Source: Image courtesy of Carlos Goicoechea García." ] ] 2 => 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:3 [ "leyenda" => "TAD: tricyclic antidepressants; CPS: Canadian Pain Society; EFNS: European Federation of Neurological Societies; NeuPSIG: Neuropathic Pain Special Interest Group; NICE: National Institute for Health and Care Excellence." "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">EFNS<a class="elsevierStyleCrossRef" href="#bib0275">5</a></th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">NICE<a class="elsevierStyleCrossRef" href="#bib0280">6</a></th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CPS<a class="elsevierStyleCrossRef" href="#bib0285">7</a></th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">NeuPSIG<a class="elsevierStyleCrossRef" href="#bib0290">8</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diabetic neuropathy \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Postherpetic neuralgia \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Trigeminal neuralgia \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Central neuropathic pain \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">All types of neuropathic pain \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Trigeminal neuralgia \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">All types of neuropathic pain \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Trigeminal neuralgia \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">All types of neuropathic pain \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First line treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DuloxetineGabapentinPregabalinTADVenlafaxine<a class="elsevierStyleCrossRef" href="#tblfn0015">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GabapentinPregabalinTADLidocaine patches<a class="elsevierStyleCrossRef" href="#tblfn0020">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CarbamazepineOxcarbazepine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GabapentinPregabalinTAD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AmitriptylineDuloxetineGabapentinPregabalinCapsaicin cream<a class="elsevierStyleCrossRef" href="#tblfn0005">b</a>(localised pain in patients wishing to avoid, or unable to tolerate oral treatment). \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carbamazepine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GabapentinPregabalinTADDuloxetineVenlafaxine<a class="elsevierStyleCrossRef" href="#tblfn0015">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carbamazepine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GabapentinPregabalinTADDuloxetineVenlafaxine<a class="elsevierStyleCrossRef" href="#tblfn0015">d</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Second line treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tramadol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Powerful opioidsCapsaicin cream \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TramadolPowerful opioids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">One of the 3 remaining first line drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TramadolPowerful opioidsTopical lidocaine<a class="elsevierStyleCrossRef" href="#tblfn0010">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lidocaine patches<a class="elsevierStyleCrossRef" href="#tblfn0005">b</a>Capsaicin patches<a class="elsevierStyleCrossRef" href="#tblfn0005">b</a>Tramadol \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Third line treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Powerful opioids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Powerful opioids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">One of the 3 remaining first line drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cannabinoids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Botulinum toxin type APowerful opioids \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fourth line treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lamotrigine(in post-stroke central pain)Cannabinoids(in multiple sclerosis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MethadoneLamotrigineLacosamideTapendatol Botulinum toxinTopical lidocaine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2042203.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "b" "nota" => "Use in the elderly." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "c" "nota" => "Use in localised pain." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "d" "nota" => "Use in postherpetic neuralgia." ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "a" "nota" => "In most European countries, including Spain, venlafaxine is not approved for “neuropathic pain”. Therefore, use of this drug for neuropathic pain should be considered off label." ] ] ] "descripcion" => array:1 [ "en" => "Summary of recommendations for the pharmacological treatment of neuropathic pain (adapted citations 5–8)." ] ] 3 => 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:2 [ "leyenda" => "Clr: renal clearance; N/A: not available; PP: plasma proteins; Tmax: time to reach the maximum concentration in blood after oral administration; T1/2: elimination half-life; Vd: apparent volume of distribution.From Calandre et al.<a class="elsevierStyleCrossRef" href="#bib0305">11</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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gabapentin \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pregabalin \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mirogabalin \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tmáx \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≈3h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤1h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≈1h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bioavailability (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dose-dependent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N/A \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PP bound (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vd \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.8l/kg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5l/kg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N/A \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">125ml/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70ml/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">218ml/min \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T1/2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5–6h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.5–6.7h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N/A \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2042205.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Main pharmacokinetic parameters of gabapentinoids." ] ] 4 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "BID: Twice daily; BTX-A: Botulinum toxin type A; RCT: randomised clinical trial; FDA: Food and Drug Administration; NNT: number needed to treat; PGI-I: Patient Global Impression of Improvement; TID: 3 times a day." "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study design \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diagnosis/patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Primary efficacy outcomes \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Drugs in clinical development that act on new therapeutic targets</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mirogabalin<a class="elsevierStyleCrossRef" href="#bib0310">12</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase 2 RCT: mirogabalin (5, 10, 15, 20 and 30mg/day) vs. placebo and pregabalin (300mg/day) for 5 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peripheral diabetic neuropathy (n=452) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mirogabalin 30mg/day met predefined criteria for a clinically significant effect (weekly change in average daily pain score from baseline to week 5). In secondary outcomes, it was observed that all doses of mirogabalin were associated with a significant overall improvement from the patient's perspective, using the PGI-I questionnaire. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BIIB074<a class="elsevierStyleCrossRef" href="#bib0370">24</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase 2a RCT: BIIB074, 150mg TID for 21 days (open-label phase), then for 28 days (double blind vs. placebo) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Classic trigeminal neuralgia, n=67 (open-label phase), n=29 (double blind phase) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No effect on the primary endpoint (treatment failure), but effects on the proportion of responders \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TV-45070<a class="elsevierStyleCrossRef" href="#bib0380">26</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proof-of-concept placebo-controlled, cross-over trial: TV-45070, ointment, BID for 3 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Postherpetic neuralgia, n=70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No effects on the primary endpoint (mean pain intensity), but significant effect on the proportion of responders (50% pain relief); 63% of patients with the NaV1.7 R1150W gain-of-function polymorphism responded to the drug vs. 35% of carriers of wild-type alleles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EMA401<a class="elsevierStyleCrossRef" href="#bib0405">31</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase 2 RCT: EMA401, 100mg BID vs. placebo for 28 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Postherpetic neuralgia, n=183 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Favourable results for the primary endpoint (intensity of pain) and multiple secondary objectives, including the proportion of respondents and quality of life questionnaires. The NNT for 50% pain relief was 6.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fulranumab<a class="elsevierStyleCrossRef" href="#bib0435">37</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase 2 RCT: fulranumab (1, 3 or 10mg) administered subcutaneously every 4 weeks vs. placebo for 12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peripheral diabetic neuropathy (n=77)(Study terminated prematurely by the FDA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fulranumab showed dose-dependent efficacy, and the 10mg dose gave superior relief compared to placebo at 12 weeks. With the 10mg dose, 60.9% and 30.4% of patients reported ≥30% and ≥50% pain relief, respectively \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fulranumab<a class="elsevierStyleCrossRef" href="#bib0440">38</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase 2 RCT: fulranumab (1, 3 or 10mg) administered subcutaneously every 4 weeks vs. placebo for 12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Postherpetic neuralgia, n=65Posttraumatic neuropathy, n=46(Study terminated prematurely by the FDA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative results for primary and secondary endpoints \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Drugs with new data about their antineuropathic activity</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oxcarbazepine<a class="elsevierStyleCrossRef" href="#bib0445">39</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Double blind, placebo-controlled RCT: oxcarbazepine (1800–2400mg) with 2 treatment periods of 6 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peripheral neuropathic pain (n=83) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Moderate effect on the primary endpoint (intensity of pain). Enhanced effect in the “irritable nociceptive” group (mild sensory deficit); greater effect in patients with paroxysmal pain \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BTX-A<a class="elsevierStyleCrossRef" href="#bib0490">48</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Double blind, placebo-controlled RCT: 2 subcutaneous injections of BTX-A (up to 300 units, symptom-adjusted) administered 12 weeks apart \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peripheral neuropathic pain (n=66) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive effect on the primary endpoint (intensity of pain up to 24 weeks) and some secondary endpoints, including various neuropathic symptoms and allodyniaEnhanced effect in patients with mechanical allodynia and preserved nociceptive function \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2042204.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Summary of RCTs performed in neuropathic pain with the drugs included in this review." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:50 [ 0 => array:3 [ "identificador" => "bib0255" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacotherapy of neuropathic pain: which drugs, which treatment algorithms?" 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Continuing education

Emerging therapies in clinical development and new contributions for neuropathic pain

Terapias emergentes en desarrollo clínico y nuevas aportaciones en dolor neuropático

A. Alcántara Monteroa,

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a.alcantara.montero@hotmail.com

Corresponding author.

, C.I. Sánchez Carnererob, C. Goicoechea Garcíac

a Centro de Salud Manuel Encinas, Consultorio de Malpartida de Cáceres, Cáceres, Spain

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

c Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Madrid, Spain

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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Mechanisms of action of EMA401 fulranumab&#46; <span class="elsevierStyleBold">ASIC</span>&#58; <span class="elsevierStyleItalic">Acid-sensing ion channel</span>&#59; <span class="elsevierStyleBold">AT2R</span>&#58; <span class="elsevierStyleItalic">Angiotensin II type 2 receptor</span><span class="elsevierStyleBold">NGF</span>&#58; <span class="elsevierStyleItalic">Nerve growth factor</span>&#59; <span class="elsevierStyleBold">PX&#47;PY</span>&#58; <span class="elsevierStyleItalic">Purinergic receptors</span>&#59; <span class="elsevierStyleBold">ROS</span>&#58; <span class="elsevierStyleItalic">Reactive oxygen species</span>&#59; <span class="elsevierStyleBold">TrkA</span>&#58; <span class="elsevierStyleItalic">Tropomyosin receptor kinase A</span>&#59; <span class="elsevierStyleBold">TRPA1</span>&#58; <span class="elsevierStyleItalic">Transient receptor potential ankyrin 1</span>&#59; <span class="elsevierStyleBold">TRPV1</span>&#58; <span class="elsevierStyleItalic">Transient receptor potential vanilloid 1&#46;</span> &#40;a&#41; EMA401 is an AT2R antagonist&#46; By blocking this receptor&#44; immune system cells &#40;such as macrophages&#41; release less ROS that act on TRPA1 receptors&#44; which are molecular integrators of many exogenous and endogenous noxious stimuli&#44; including oxygen free radicals and other inflammatory agents released at the site of the injury&#44; promoting the sensitisation of nociceptors&#46; &#40;b&#41; Fulranumab is an anti-NGF antibody&#59; it blocks TrkA&#44; which is the NGF receptor&#46; Under normal conditions&#44; when the NGF bind to its receptor&#44; it facilitates the transmission of the nociceptive signal&#46; In addition&#44; in peripheral sensitisation&#44; stimulation of TrKA stimulates TRPV1&#44; which is the target of multiple inflammatory mediators that trigger nociceptor sensitisation&#46; Therefore&#44; fulranumab can indirectly modulate the response of TRPV1&#44; but has in itself a direct inhibitory effect on the nervous response through its own membrane receptor&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Image courtesy of Carlos Goicoechea Garc&#237;a&#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">Neuropathic pain is difficult to treat due to the variety of possible causes&#44; symptoms and underlying mechanisms&#46; For this reason&#44; is considered a medical necessity that&#44; to a large extent&#44; has not yet been met&#44; despite the growing number of treatments available&#46; The efficacy and safety profile of most treatments currently used is modest&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">1</span></a> and therefore new options and therapeutic alternatives are welcomed&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Currently&#44; more than 100 molecules that act on specific targets of potential interest for neuropathic pain are being developed&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">2&#8211;4</span></a> These include isoform-specific sodium channel blockers&#44; vanilloid receptor antagonists&#44; potassium channel agonists&#44; metabotropic glutamate&#47;NMDA receptor antagonists or new NMDA receptors modulators&#44; new opioid receptor agonists&#44; histamine H3 receptor antagonists&#44; serotonergic modulators&#44; nicotinic agonists&#44; adrenergic agonists&#44; nitric oxide synthase inhibitors&#44; orexin receptor antagonists&#44; angiotensin <span class="elsevierStyleSmallCaps">II</span> receptor antagonists&#44; imidazolid I2 receptor agonists&#44; apoptosis inhibitors&#44; cannabinoid receptor 2 agonists&#44; selective sigma-1 receptor antagonists&#44; fatty acid amide hydrolase inhibitors&#44; nerve growth factor antagonists&#44; gene therapy&#44; etc&#46; Most of these molecules are in the early stages of preclinical development&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Several older drugs are available&#44; such as botulinum toxin and oxcarbazepine&#44; most of which are not indicated in pain&#46; However&#44; new data on the use of these drugs in neuropathic pain has recently emerged&#44; so they could be considered emerging treatments&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In this review&#44; after a brief summary of the drugs currently recommended for neuropathic pain&#44; we will focus on new pharmacological treatments for this condition for which clinical data are already available&#44; including new evidence for the antineuropathic action of some more familiar drugs&#46; We only discuss those that we consider to have potential clinical relevance&#44; based on evidence from placebo-controlled or active-control randomised clinical trials &#40;RCTs&#41; in peripheral or central neuropathic pain identified in the Medline&#47;PubMed&#44; Google Scholar&#44; PsycInfo and ClinicalTrials&#46;gov databases&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Drugs currently recommended for the treatment of neuropathic pain</span><p id="par0025" class="elsevierStylePara elsevierViewall">Most of the clinical practice guidelines consulted coincide in pointing out that tricyclic &#40;particularly amitriptyline&#41; and dual antidepressants &#40;particularly duloxetine&#41; together with gabapentin&#47;pregabalin antiepileptics are first-line drugs in the treatment of neuropathic pain &#40;Strong recommendation according to the Grading of Recommendations&#44; Assessment&#44; Development and Evaluation system &#91;GRADE&#93;&#41;&#44; with tramadol&#44; 5&#37; lidocaine patches and 8&#37; capsaicin patches as second line drugs &#40;Weak Recommendation according to the GRADE system&#41;&#44; and powerful opioids as the third line &#40;Weak Recommendation according to the GRADE system&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">5&#8211;8</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Unfortunately meta-analyses indicate that only a minority of patients with neuropathic pain show adequate response to pharmacological treatment&#44; and that many of these drugs have been limited by negative factors&#44; such as systemic side effects&#44; drug interactions&#44; slow onset of action&#44; need for dose adjustment&#44; administration of multiple daily doses&#44; and possible risk of addiction&#44; dependence&#44; withdrawal symptoms and abuse&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">8</span></a> Other drugs that are expected to be effective&#44; such as cannabinoids&#44; tapentadol and several antiepileptic drugs &#40;lamotrigine&#44; lacosamide&#44; topiramate&#44; eslicarbazepine acetate&#44; etc&#46;&#41;&#44; have shown inconsistent results&#44; although some may be effective in some subgroups of patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">9&#44;10</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Drugs in clinical development that act on new therapeutic targets with potential clinical relevance in neuropathic pain</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Mirogabalin</span><p id="par0035" class="elsevierStylePara elsevierViewall">Mirogabalin&#44; like gabapentin and pregabalin&#44; binds to the auxiliary &#945;2-&#948; subunit of voltage-gated calcium channels&#44; reducing calcium entry into nerve termini&#44; thereby decreasing the release of excitatory neurotransmitters&#44; such as glutamate &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; From the pharmacological point of view&#44; absorption of pregabalin and mirogabalin is linear and not dose-dependent&#44; while the intestinal absorption of gabapentin is saturable&#44; which makes it difficult to titrate&#46; Gabapentin enacarbil has been developed to overcome this drawback of gabapentin&#44; and has demonstrated linear absorption and greater bioavailability than gabapentin&#46; However&#44; gabapentin enacarbil is only available in Japan and the USA&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarises the main pharmacokinetic parameters of gabapentinoids&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">So far only 1 RCT evaluating mirogabalin in patients with neuropathic pain has been published&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">12</span></a> This double blind&#44; five-week&#44; phase 2 trial compared the efficacy and safety of 5 doses of mirogabalin &#40;5&#44; 10&#44; 15&#44; 20 and 30<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; against placebo and pregabalin 300<span class="elsevierStyleHsp" style=""></span>mg&#47;day in patients with diabetic peripheral neuropathic pain &#40;DPNP&#41;&#46; Mirogabalina at doses of 5&#44; 10 and 15<span class="elsevierStyleHsp" style=""></span>mg&#47;day was administered once daily&#44; while mirogabalin at doses of 20 and 30<span class="elsevierStyleHsp" style=""></span>mg&#47;day was administered twice daily&#46; The primary outcome measure was the weekly change in the average daily pain score from baseline to week 5&#46; Pain was measured on a 0&#8211;10 numerical scale&#59; a difference &#8805;1&#46;0 point compared with placebo in reducing this score was considered clinically significant&#46; The mean differences in change vs&#46; placebo were &#8722;0&#46;22&#44; &#8722;0&#46;53&#44; &#8722;0&#46;94&#44; &#8722;0&#46;88 and &#8722;1&#46;01 for the mirogabalin 5&#44; 10&#44; 15&#44; 20&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg&#47;day treatment groups&#44; respectively&#44; and -0&#46;05 for the pregabalin group&#46; Although only mirogabalin 30<span class="elsevierStyleHsp" style=""></span>mg&#47;day met predefined criteria for a clinically significant effect&#44; the 15 and 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day dose of mirogabalin met the criteria of minimally meaningful effect&#46; In fact&#44; the number needed to treat &#40;NNT&#41; to show a reduction &#8805;30&#37; in the pain score was 4&#46;0&#44; 5&#46;2 and 6&#46;9&#44; respectively&#44; for the 3 highest doses of mirogabalin&#44; and the corresponding NNT for a reduction &#8805;50&#37; in the pain score was of 6&#46;6&#44; 5&#46;3 and 5&#46;1&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">12</span></a> With regard to secondary outcomes&#44; it was observed that all doses of mirogabalin were associated with a significant overall improvement rated on the Patient Global Impression of Improvement &#40;PGI-I&#41; questionnaire&#46; These 3 doses &#40;15&#44; 20 and 30<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; of mirogabalin were selected by the manufacturer for the evaluation of drug efficacy and safety in 2 Phase 3&#44; placebo-controlled&#44; double-blind&#44; 14-week trials in patients with DPNP<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">13</span></a> and in patients with postherpetic neuralgia &#40;PHN&#41;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">14</span></a> performed in Japan&#44; but whose results have not yet been published&#46; In an exposure-response study using data from the phase 2 study&#44; and taking into account the efficacy and safety data&#44; it was estimated that 17&#46;7<span class="elsevierStyleHsp" style=""></span>mg of mirogabalin was equivalent to pregabalin 300<span class="elsevierStyleHsp" style=""></span>mg in reducing pain&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">15</span></a> Using this model&#44; the twice-daily regimen of mirogabalin was predicted to produce a lower incidence of dizziness&#44; the most frequent and dose-dependent adverse effect observed in the phase 2 clinical trial&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The results of mirogabalin in patients with DPNP are certainly promising&#44; and show a clinically meaningful effect on pain&#46; The inclusion of an active pregabalin 300<span class="elsevierStyleHsp" style=""></span>mg&#47;day arm in mirogabalin RCTs&#44; both in the phase 2 trial in patients with DPNP<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">12</span></a> and in other phase 3 trials in patients with fibromyalgia&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">16</span></a> was a good decision on the part of the manufacturer&#44; and will further defined the effectiveness and tolerability of this medicine&#46; Gabapentin and pregabalin are similar in terms of tolerability&#44; and the limited data available suggest that mirogabalin does not differ from the 2 compounds in this respect&#46; An important task in coming years will be to determine the efficacy and tolerability of mirogabalin in the treatment of chronic pain of different aetiologies&#46; In animal models mirogabalin has been shown to have a superior analgesic effect and a wider margin of safety in the central nervous system than pregabalin&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">17</span></a> Data from ongoing clinical trials in mirogabalin for the treatment of fibromyalgia and PHN are likely to be available in a few years&#44; and it will then be possible to make a clinical comparison of mirogabalin with gabapentin and pregabalin&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Selective voltage-gated sodium channel blockers</span><p id="par0050" class="elsevierStylePara elsevierViewall">Nav1&#46;7 is a voltage-dependent sodium channel &#40;NaV&#41; that is preferentially expressed in peripheral neurons&#44; including trigeminal neurons&#44; and the results of genetic and functional studies suggest a link between NaV1&#46;7 and pain symptoms in humans&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">19&#44;20</span></a> The efficacy of carbamazepine &#40;known to block Nav1&#46;7&#41; and oxcarbazepine support the hypothesis that NaV1&#46;7 could be a therapeutic target in trigeminal neuralgia&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">21</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">An increase in NaV1&#46;7 activity also occurs in a common variant of NaV1&#46;7&#44; where an arginine is replaced by a tryptophan at position 1150 &#40;R1150W&#41; in the protein sequence&#59; this variant occurs in 15&#8211;30&#37; of the population&#46; According to reports&#44; this variant of NaV1&#46;7 is associated with an increased sensitivity to pain&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">22</span></a> Validation of the NaV1&#46;7 target in many studies of human genetics supports this as a strategy for analgesic development&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">23</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">BIIB074 is a selective NaV1&#46;7 sodium channel blocker &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; that is currently under investigation for the treatment of trigeminal neuralgia&#46; Electrophysiological studies have shown that BIIB074 preferentially inhibits high frequencies of firing in neurons&#44; as would be expected in paroxysms of pain in trigeminal neuralgia&#46; The results of phase 1 clinical trials suggest that BIIB074 is well tolerated in healthy individuals&#44; and can be administered at therapeutic doses without prolonged titration&#46; In a phase <span class="elsevierStyleSmallCaps">II&#44;</span> multicentre&#44; placebo-controlled RCT in 67 patients with classic trigeminal neuralgia &#40;29 patients were randomised to double-blind treatment for 28 days&#41;&#44; no statistically significant difference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0974&#41; was found between BIIB074 &#40;150<span class="elsevierStyleHsp" style=""></span>mg 3 time daily&#41; and placebo in the primary endpoint &#40;treatment failure&#41;&#44; but the drug was effective in multiple secondary endpoints&#44; including the proportion of responders&#46; Safety was excellent&#44; with side effects in the active group being comparable to placebo&#46; Headache was the most frequent adverse event with BIIB074 in the open-label phase &#40;19&#37;&#41;&#44; followed by dizziness &#40;9&#37;&#41;&#46; In the double-blind phase&#44; headache&#44; pyrexia&#44; nasopharyngitis&#44; sleep disorder&#44; and tremor were the most frequent adverse events in patients assigned to BIIB074&#46; No serious or severe adverse events were reported in the BIIB074 group during the double-blind phase&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">24</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">TV-45070 is a new&#44; potent inhibitor of NaV1&#46;7 and other NaVs expressed in the peripheral nervous system&#46; There is evidence of analgesic activity in the active principle of TV-45070 when administered orally in patients with hereditary erythromelalgia&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">25</span></a> Each of these patients with hereditary erythromelalgia had inherited a Nav1&#46;7 gain-of-function mutation&#44; suggesting that the analgesic effect of TV-45070 was due to its inhibition of NaV1&#46;7&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">25</span></a> A topical form of TV-45070 was developed to maximise local NaV inhibition in the skin and subcutaneous tissue&#44; and thus minimise systemic adverse events and maintain low plasma concentrations&#46; In a randomised&#44; controlled&#44; proof-of-concept&#44; crossover study in 70 patients with PHN &#40;54 completed the study&#41; a topical NaV1&#46;7 antagonist &#40;TV-45070&#41; was applied twice daily for 3 weeks&#46; This study was negative for the primary endpoint &#40;pain intensity&#41;&#44; but found a significant effect in the proportion of responders&#46; In addition&#44; 63&#37; of patients with the NaV1&#46;7 R1150W gain-of-function polymorphism responded to treatment compared with 35&#37; of wild-type carriers&#46; No significant side effects were reported&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">26</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In general&#44; these 2 clinical trials&#44; although negative for the primary endpoint&#44; clearly suggest the possible clinical relevance of NaV1&#46;7 antagonists in neuropathic pain&#44; and justify continuing their clinical development&#46; On the basis of these promising results&#44; new clinical trials in BIIB074 are currently under way in both trigeminal neuralgia and in other neuropathic pain models &#40;such as small fibre neuropathy&#44; erythromelalgia and lumbosacral radiculopathy&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Angiotensin <span class="elsevierStyleSmallCaps">II</span> type 2 receptor antagonists</span><p id="par0075" class="elsevierStylePara elsevierViewall">Clarification of the renin-angiotensin system led to the development of antihypertensive agents &#40;angiotensin-converting enzyme inhibitors&#44; renin inhibitors&#44; and selective angiotensin <span class="elsevierStyleSmallCaps">II</span> type 1 receptor antagonists or blockers &#91;AT1R&#93;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">27</span></a> During the development of AT1R antagonists&#44; a second angiotensin <span class="elsevierStyleSmallCaps">II</span> binding receptor was identified&#58; the angiotensin <span class="elsevierStyleSmallCaps">II</span> type 2 receptor &#40;AT2R&#41;&#46; Findings from initial studies suggested that AT2R antagonists did not control hypertension in animals&#44;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">28</span></a> and no other therapeutic applications for AT2R antagonists in patients have been established&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The renin-angiotensin system mediates diverse physiological functions outside the cardiovascular system&#44; even in the central and peripheral nervous systems&#46; Preclinical studies of neuropathic pain in rodent models have shown that highly selective AT2R antagonists&#44; such as EMA401&#44; have analgesic properties&#46; AT2R is expressed in human sensory &#40;nociceptive&#41; neurons&#44; but AT1R is not&#46; Findings from functional studies in sensory neurons from humans and cultured rodents showed that EMA401 inhibits capsaicin-mediated calcium flow&#44; suggesting an antinociceptive effect &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; EMA401&#44; therefore&#44; was added to clinical development as a treatment for chronic pain&#44; including neuropathic pain&#46; Pharmacokinetic and pharmacodynamic studies in animal models&#44; phase 1 pharmacokinetic data in humans&#44; and in vitro functional assays support a potentially effective doses in humans of 10&#8211;50<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">29&#44;30</span></a> Since EMA401 at doses of up to 400<span class="elsevierStyleHsp" style=""></span>mg met phase 1 safety criteria&#44; a clinical trial with 200<span class="elsevierStyleHsp" style=""></span>mg&#47;day &#40;100<span class="elsevierStyleHsp" style=""></span>mg twice daily&#41; was performed&#46; This was a phase 1&#44; 28-day&#44; multicentre RCT in 183 patients with PHN&#44; which showed that EMA401 was both effective and safe&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">31</span></a> Selective AT2R antagonists may represent a new class of analgesics for neuropathic pain&#44; and are currently being tested in phase <span class="elsevierStyleSmallCaps">III</span> trials&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Nerve growth factor antagonists</span><p id="par0085" class="elsevierStylePara elsevierViewall">Inhibition of the effect of nerve growth factor &#40;NGF&#41; has shown the potential to normalise neuronal hyperactivity and produce sustained clinical pain relief&#46; Therefore&#44; there is considerable interest in considering NGF as a possible pharmacological target in neuropathic pain &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; and antibodies targeting human NGF&#44; such as tanezumab&#44; fulranumab and fasinumab&#44; are currently in clinical development for the treatment of chronic&#44; mainly nociceptive&#44; pain&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">32&#44;33</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Fulranumab&#44; an anti-NGF antibody administered subcutaneously&#44; has been shown to be effective in the treatment of pain related to osteoarthritis of the knee and hip&#44;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">34&#44;35</span></a> but not in chronic low back pain&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">36</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Fulranumab is the only drug of this class specifically investigated in neuropathic pain&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">37&#44;38</span></a> It should be noted that all studies performed in anti-NGF antibodies were interrupted prematurely &#40;23 December 2010&#41; by the Food and Drug Administration &#40;FDA&#41; due to reports of rapidly progressive osteoarthritis and osteonecrosis associated with anti-NGF in patients with osteoarthritis&#46; In a phase 2&#44; double-blind&#44; placebo-controlled RCT&#44; patients with DPNP were randomised to fulranumab &#40;1&#44; 3 or 10<span class="elsevierStyleHsp" style=""></span>mg&#41; or placebo administered subcutaneously every 4 weeks&#46; This study included 77 &#40;intention to treat&#41; of the 200 patients planned&#46; The primary endpoint&#44; mean reduction of average daily pain at week 12 compared to baseline&#44; showed a positive dose&#8211;response relationship &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#41;&#59; pairwise comparison between the 10<span class="elsevierStyleHsp" style=""></span>mg group and the placebo group was significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;040&#44; unadjusted&#41;&#46; An analysis revealed that a higher proportion of patients in the 10<span class="elsevierStyleHsp" style=""></span>mg group reported a &#8805;30&#37; reduction in average pain intensity compared to placebo at week 12 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#41;&#46; Although not statistically significant&#44; several secondary endpoints showed results that were directionally similar to the primary dose&#8211;response relationship&#46; During the combined efficacy and safety extension phases&#44; the 3 main adverse events arising from treatment in the combined fulranumab group were arthralgia &#40;11&#37;&#41;&#44; peripheral oedema &#40;11&#37;&#41; and diarrhoea &#40;9&#37;&#41;&#46; Therefore&#44; despite the early termination of the study&#44; treatment with fulranumab was effective&#44; though dose-dependent &#40;10<span class="elsevierStyleHsp" style=""></span>mg fulranumab reduced pain by 1&#8211;2 points on an 11-point scale compared to placebo&#41; and&#44; in general&#44; well tolerated&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">37</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In another phase <span class="elsevierStyleSmallCaps">II</span> RCT&#44; patients with PHN were randomised to receive placebo or one of the 3 doses of subcutaneous fulranumab&#58; 1<span class="elsevierStyleHsp" style=""></span>mg&#44; 3<span class="elsevierStyleHsp" style=""></span>mg or 10<span class="elsevierStyleHsp" style=""></span>mg every 4 weeks&#46; The trial also included patients with post-traumatic neuropathy&#44; who were randomised to receive placebo or 10<span class="elsevierStyleHsp" style=""></span>mg fulranumab subcutaneously every 4 weeks&#46; Due to early termination of the study by the FDA&#44; only 49 patients with PHN &#40;of the 150 planned&#41; and 34 with post-traumatic neuropathy &#40;of the 50 planned&#41; completed the effectiveness evaluation in the double-blind phase&#46; There were no significant differences &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#62;</span><span class="elsevierStyleHsp" style=""></span>0&#46;05 fulranumab vs&#46; placebo&#41; in mean pain intensity from baseline to the end of the 12-week double-blind efficacy phase &#40;primary endpoint&#41;&#46; Nor were significant differences found between fulranumab vs&#46; placebo &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#62;</span><span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; in other measures of efficacy in patients in both trial groups&#46; The most common treatment-related adverse events &#40;&#62;10&#37; incidence&#41; in patients with post-traumatic neuropathy were sinusitis&#44; carpal tunnel syndrome&#44; and headache&#44; while in patients with PHN arthralgias were most frequent&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">38</span></a></p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Drugs with new antineuropathic activity data</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Oxcarbazepine</span><p id="par0105" class="elsevierStylePara elsevierViewall">Although the findings of large-scale clinical trials seems to suggest that antiepileptics acting on NaV have limited efficacy in pain&#44; this may be because they do not target the relevant phenotypic profiles&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">21</span></a> Interestingly&#44; a recent multicentre proof-of-concept clinical trial testing the NaV blocker oxcarbazepine in 83 patients &#40;39 patients completed the treatment&#41; with peripheral neuropathic pain stratified into 2 groups according to clinical phenotypes&#44; suggesting underlying mechanisms &#40;&#8220;irritable&#8221; nociceptors with possible normal nociceptive function vs&#46; deafferentation&#41;&#44; reported that only patients with preserved nociceptive function responded significantly to oxcarbazepine&#44; suggesting that this drug mainly targets the remaining hyperexcitable nociceptive fibres&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">39</span></a> This suggests that older drugs acting on NaV can have significant efficacy&#44; at least in subgroups of patients with neuropathic pain&#44; and should be investigated in the future using a phenotype-based approach instead of stratifying patients according to aetiology&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Botulinum toxin type A</span><p id="par0110" class="elsevierStylePara elsevierViewall">Botulinum toxin type A &#40;BTX-A&#41; is widely used to treat muscular hyperactivity&#44; based on its capacity to inhibit synaptic exocytosis and&#44; therefore&#44; to disable neuronal transmission&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">40</span></a> Several experimental studies in animals and clinical models of pain in healthy subjects have shown that BTX-A may have analgesic activity independent of its effect on muscle tone&#44; possibly through a decrease in neurogenic inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">41</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Four RCTs from a single centre that included between 20 and 60 patients reported the long-term efficacy of BTX-A &#40;single fixed-dose or symptom-adjusted subcutaneous or intradermal injection in the affected dermatome&#44; from 50 to 200 units&#41; in peripheral neuropathic pain &#40;PHN&#44; traumatic nerve injury or DPNP&#41;&#46; All reported a high response rate&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">42&#8211;45</span></a> The onset of efficacy &#40;approximately 1 week&#41; and the duration of effect &#40;3 months&#41; in these studies were remarkably similar&#46; However&#44; an unpublished multicentre proof-of-concept RCT was negative in 117 patients with PHN&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">46</span></a> Three other small placebo-controlled RCTs from a single centre also reported the efficacy of BTX-A administered intradermally in the face&#44; mucosa or in common trigeminal neuralgia trigger points&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">47</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">A recent double-blind&#44; placebo-controlled RCT performed in 3 centres evaluated the efficacy and prolonged safety of 2 subcutaneous injections of BTX-A &#40;up to 300 units&#44; symptom-adjusted&#41; administered 12 weeks apart in 66 patients with peripheral neuropathic pain &#40;PHN&#44; posttraumatic nerve injury and painful polyneuropathy&#41; with or without allodynia&#46; The results showed that BTX-A improved average intensity of pain over the course of 24 weeks compared to placebo &#40;primary outcome&#41;&#44; and that the second injection was of greater therapeutic benefit&#46; BTX-A was particularly effective in some neuropathic symptoms &#40;allodynia and paroxysmal pain&#41;&#44; and reduced mechanical allodynia and hyperalgesia&#44; assessed by quantitative sensory tests&#46; The safety profile was excellent&#44; with pain on injection being the only adverse effect&#46; Response to BTX-A at the end of treatment was predicted by the presence or severity of mechanical allodynia and the preservation of intraepidermal nerve fibre density in the skin puncture biopsy &#40;performed at baseline&#41;&#44; and a correlation was observed between the preservation of thermal deficits and response to BTX-A&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">48</span></a> These findings suggest that patients with preserved nociceptive input are likely to show the best response to BTX-A&#46; This study also examined whether response to BTX-A was mediated by an effect on neurogenic inflammation&#46; For this purpose&#44; neuropeptide levels &#40;calcitonin gene-related peptide and substance P&#41; were measured from a skin biopsy at the beginning of the study and 1 month later&#46; Contrary to expectations&#44; the level of these neuropeptides was neither modified by the treatment nor linked to its efficacy&#46; These data suggest that BTX-A could act on other mechanisms&#44; preferably central&#44; presumably through axonal retrograde transport&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">49</span></a> In line with this hypothesis&#44; a recent single-centre&#44; double-blind&#44; placebo-controlled RCT in 40 patients with spinal cord injury reported a beneficial effect of BTX-A on pain below the neurological level of injury&#44; which was more marked in patients with preserved motor or sensory function&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">50</span></a> These data have led to the recommendation of BTX-A as a third option in the therapeutic arsenal of peripheral neuropathic pain for refractory patients&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">8</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conclusions</span><p id="par0125" class="elsevierStylePara elsevierViewall">New medical treatments for neuropathic pain include drugs that act on new pain targets&#46; Most of these products are in preclinical development or in the early stages of clinical development&#44; but some clinical trials have suggested that mirogabalin&#44; NaV1&#46;7 antagonists&#44; and AT2R antagonists have potential clinical relevance in neuropathic pain&#46; Another option involves drugs such as oxcarbazepine and BTX-A that are mostly used for other indications&#44; but that present an analgesic effect in subgroups of patients with neuropathic pain&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> summarises the RCTs performed in neuropathic pain with the drugs included in this review&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflicts of interest</span><p id="par0135" class="elsevierStylePara elsevierViewall">We have considered the instructions and ethical responsibilities&#44; we fulfil the requirements of authorship&#44; and we declare that we have no conflict of interests&#46;</p></span></span>"
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          "identificador" => "xres1196199"
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Drugs currently recommended for the treatment of neuropathic pain"
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        6 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Drugs in clinical development that act on new therapeutic targets with potential clinical relevance in neuropathic pain"
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              "identificador" => "sec0020"
              "titulo" => "Mirogabalin"
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              "titulo" => "Selective voltage-gated sodium channel blockers"
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              "titulo" => "Angiotensin II type 2 receptor antagonists"
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              "titulo" => "Nerve growth factor antagonists"
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          "titulo" => "Drugs with new antineuropathic activity data"
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              "titulo" => "Oxcarbazepine"
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              "titulo" => "Botulinum toxin type A"
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          "titulo" => "Conclusions"
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          "titulo" => "Conflicts of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2019-01-18"
    "fechaAceptado" => "2019-02-17"
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            0 => "BIIB074"
            1 => "Neuropathic pain"
            2 => "EMA401"
            3 => "Fulranumab"
            4 => "Mirogabalin"
            5 => "Botulinum toxin type A"
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          "titulo" => "Palabras clave"
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            0 => "BIIB074"
            1 => "Dolor neurop&#225;tico"
            2 => "EMA401"
            3 => "Fulranumab"
            4 => "Mirogabalina"
            5 => "Toxina botul&#237;nica tipo A"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Neuropathic pain is very challenging to manage because of the heterogeneity of aetiologies&#44; symptoms&#44; and underlying mechanisms&#46; Conventional oral therapies have been limited by negative factors such as systemic side effects&#44; drug&#8211;drug interactions&#44; slow onset of action&#44; the need for titration&#44; multiple daily dosing&#44; as well as the potential risk of addiction&#44; dependence&#44; withdrawal symptoms&#44; and abuse&#46; Therefore new therapeutic perspectives are justified&#46; New drugs that act on different therapeutic targets are currently in preclinical development or in their first phases of clinical development&#46; In this review&#44; focus will be directed specifically on new pharmacological treatments for neuropathic pain for which clinical data are already available&#44; including older and known drugs with new data on their anti-neuropathic activity&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El dolor neurop&#225;tico es dif&#237;cil de tratar debido a la heterogeneidad de causas&#44; s&#237;ntomas y mecanismos subyacentes&#46; Los tratamientos orales convencionales se han visto limitados por factores negativos&#44; como efectos secundarios sist&#233;micos&#44; interacciones farmacol&#243;gicas&#44; inicio de acci&#243;n lento&#44; necesidad de ajuste de la dosis&#44; administraci&#243;n de m&#250;ltiples dosis diarias&#44; y posible riesgo de adicci&#243;n&#44; dependencia&#44; s&#237;ntomas de abstinencia y uso excesivo&#46; Por tanto&#44; se justifican nuevas perspectivas terap&#233;uticas&#46; Actualmente&#44; se encuentran en desarrollo precl&#237;nico o en sus primeras fases de desarrollo cl&#237;nico nuevos f&#225;rmacos que act&#250;an sobre diferentes dianas terap&#233;uticas&#46; En esta revisi&#243;n nos centraremos expresamente en nuevos tratamientos farmacol&#243;gicos para el dolor neurop&#225;tico para los cuales ya se dispone de datos cl&#237;nicos&#44; incluyendo f&#225;rmacos m&#225;s antiguos y conocidos con nuevos datos sobre su actividad antineurop&#225;tica&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Please cite this article as&#58; Alc&#225;ntara Montero A&#44; S&#225;nchez Carnerero CI&#44; Goicoechea Garc&#237;a C&#46; Terapias emergentes en desarrollo cl&#237;nico y nuevas aportaciones en dolor neurop&#225;tico&#46; Rev Esp Anestesiol Reanim&#46; 2019&#59;66&#58;324&#8211;334&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mechanisms of action of mirogabalin and BIIB074&#46; &#40;a&#41; Mirogabalin binds to the auxiliary &#945;2-&#948; subunit of voltage-gated calcium channels&#44; reducing calcium entry into nerve termini&#44; thereby decreasing the release of excitatory neurotransmitters&#44; such as glutamate&#46; &#40;b&#41; BIIB074 is a selective blocker of Nav1&#46;7 voltage-dependent sodium channels&#44; which are expressed mainly in the peripheral nervous system&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Image courtesy of Carlos Goicoechea Garc&#237;a&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Mechanisms of action of EMA401 fulranumab&#46; <span class="elsevierStyleBold">ASIC</span>&#58; <span class="elsevierStyleItalic">Acid-sensing ion channel</span>&#59; <span class="elsevierStyleBold">AT2R</span>&#58; <span class="elsevierStyleItalic">Angiotensin II type 2 receptor</span><span class="elsevierStyleBold">NGF</span>&#58; <span class="elsevierStyleItalic">Nerve growth factor</span>&#59; <span class="elsevierStyleBold">PX&#47;PY</span>&#58; <span class="elsevierStyleItalic">Purinergic receptors</span>&#59; <span class="elsevierStyleBold">ROS</span>&#58; <span class="elsevierStyleItalic">Reactive oxygen species</span>&#59; <span class="elsevierStyleBold">TrkA</span>&#58; <span class="elsevierStyleItalic">Tropomyosin receptor kinase A</span>&#59; <span class="elsevierStyleBold">TRPA1</span>&#58; <span class="elsevierStyleItalic">Transient receptor potential ankyrin 1</span>&#59; <span class="elsevierStyleBold">TRPV1</span>&#58; <span class="elsevierStyleItalic">Transient receptor potential vanilloid 1&#46;</span> &#40;a&#41; EMA401 is an AT2R antagonist&#46; By blocking this receptor&#44; immune system cells &#40;such as macrophages&#41; release less ROS that act on TRPA1 receptors&#44; which are molecular integrators of many exogenous and endogenous noxious stimuli&#44; including oxygen free radicals and other inflammatory agents released at the site of the injury&#44; promoting the sensitisation of nociceptors&#46; &#40;b&#41; Fulranumab is an anti-NGF antibody&#59; it blocks TrkA&#44; which is the NGF receptor&#46; Under normal conditions&#44; when the NGF bind to its receptor&#44; it facilitates the transmission of the nociceptive signal&#46; In addition&#44; in peripheral sensitisation&#44; stimulation of TrKA stimulates TRPV1&#44; which is the target of multiple inflammatory mediators that trigger nociceptor sensitisation&#46; Therefore&#44; fulranumab can indirectly modulate the response of TRPV1&#44; but has in itself a direct inhibitory effect on the nervous response through its own membrane receptor&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Image courtesy of Carlos Goicoechea Garc&#237;a&#46;</p>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">TAD&#58; tricyclic antidepressants&#59; CPS&#58; Canadian Pain Society&#59; EFNS&#58; European Federation of Neurological Societies&#59; NeuPSIG&#58; Neuropathic Pain Special Interest Group&#59; NICE&#58; National Institute for Health and Care Excellence&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">EFNS<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">5</span></a></th><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">NICE<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">6</span></a></th><th class="td" title="\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CPS<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">NeuPSIG<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">8</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diabetic neuropathy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Postherpetic neuralgia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Trigeminal neuralgia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Central neuropathic pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">All types of neuropathic pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Trigeminal neuralgia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">All types of neuropathic pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Trigeminal neuralgia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">All types of neuropathic pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">First line treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DuloxetineGabapentinPregabalinTADVenlafaxine<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GabapentinPregabalinTADLidocaine patches<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CarbamazepineOxcarbazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GabapentinPregabalinTAD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AmitriptylineDuloxetineGabapentinPregabalinCapsaicin cream<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">b</span></a>&#40;localised pain in patients wishing to avoid&#44; or unable to tolerate oral treatment&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carbamazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GabapentinPregabalinTADDuloxetineVenlafaxine<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carbamazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GabapentinPregabalinTADDuloxetineVenlafaxine<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Second line treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tramadol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Powerful opioidsCapsaicin cream&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TramadolPowerful opioids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">One of the 3 remaining first line drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TramadolPowerful opioidsTopical lidocaine<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lidocaine patches<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">b</span></a>Capsaicin patches<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">b</span></a>Tramadol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Third line treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Powerful opioids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Powerful opioids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">One of the 3 remaining first line drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cannabinoids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Botulinum toxin type APowerful opioids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fourth line treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lamotrigine&#40;in post-stroke central pain&#41;Cannabinoids&#40;in multiple sclerosis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MethadoneLamotrigineLacosamideTapendatol Botulinum toxinTopical lidocaine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Use in the elderly&#46;</p>"
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            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Use in localised pain&#46;</p>"
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            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Use in postherpetic neuralgia&#46;</p>"
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            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">In most European countries&#44; including Spain&#44; venlafaxine is not approved for &#8220;neuropathic pain&#8221;&#46; Therefore&#44; use of this drug for neuropathic pain should be considered off label&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Summary of recommendations for the pharmacological treatment of neuropathic pain &#40;adapted citations 5&#8211;8&#41;&#46;</p>"
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      ]
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        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Clr&#58; renal clearance&#59; N&#47;A&#58; not available&#59; PP&#58; plasma proteins&#59; Tmax&#58; time to reach the maximum concentration in blood after oral administration&#59; T1&#47;2&#58; elimination half-life&#59; Vd&#58; apparent volume of distribution&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">From Calandre et al&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">11</span></a></p>"
          "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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gabapentin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pregabalin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mirogabalin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tm&#225;x&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8776;3<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8804;1<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8776;1<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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bioavailability &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dose-dependent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8805;90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PP bound &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vd&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;8<span class="elsevierStyleHsp" style=""></span>l&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5<span class="elsevierStyleHsp" style=""></span>l&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">125<span class="elsevierStyleHsp" style=""></span>ml&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70<span class="elsevierStyleHsp" style=""></span>ml&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">218<span class="elsevierStyleHsp" style=""></span>ml&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T1&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#8211;6<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;5&#8211;6&#46;7<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">BID&#58; Twice daily&#59; BTX-A&#58; Botulinum toxin type A&#59; RCT&#58; randomised clinical trial&#59; FDA&#58; Food and Drug Administration&#59; NNT&#58; number needed to treat&#59; PGI-I&#58; Patient Global Impression of Improvement&#59; TID&#58; 3 times a day&#46;</p>"
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                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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diagnosis&#47;patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Primary efficacy outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Drugs in clinical development that act on new therapeutic targets</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mirogabalin<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase 2 RCT&#58; mirogabalin &#40;5&#44; 10&#44; 15&#44; 20 and 30<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; vs&#46; placebo and pregabalin &#40;300<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; for 5 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Peripheral diabetic neuropathy &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>452&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mirogabalin 30<span class="elsevierStyleHsp" style=""></span>mg&#47;day met predefined criteria for a clinically significant effect &#40;weekly change in average daily pain score from baseline to week 5&#41;&#46; In secondary outcomes&#44; it was observed that all doses of mirogabalin were associated with a significant overall improvement from the patient&#39;s perspective&#44; using the PGI-I questionnaire&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>BIIB074<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase 2a RCT&#58; BIIB074&#44; 150<span class="elsevierStyleHsp" style=""></span>mg TID for 21 days &#40;open-label phase&#41;&#44; then for 28 days &#40;double blind vs&#46; placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Classic trigeminal neuralgia&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>67 &#40;open-label phase&#41;&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>29 &#40;double blind phase&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No effect on the primary endpoint &#40;treatment failure&#41;&#44; but effects on the proportion of responders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>TV-45070<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Proof-of-concept placebo-controlled&#44; cross-over trial&#58; TV-45070&#44; ointment&#44; BID for 3 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Postherpetic neuralgia&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No effects on the primary endpoint &#40;mean pain intensity&#41;&#44; but significant effect on the proportion of responders &#40;50&#37; pain relief&#41;&#59; 63&#37; of patients with the NaV1&#46;7 R1150W gain-of-function polymorphism responded to the drug vs&#46; 35&#37; of carriers of wild-type alleles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>EMA401<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">31</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase 2 RCT&#58; EMA401&#44; 100<span class="elsevierStyleHsp" style=""></span>mg BID vs&#46; placebo for 28 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Postherpetic neuralgia&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>183&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Favourable results for the primary endpoint &#40;intensity of pain&#41; and multiple secondary objectives&#44; including the proportion of respondents and quality of life questionnaires&#46; The NNT for 50&#37; pain relief was 6&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Fulranumab<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase 2 RCT&#58; fulranumab &#40;1&#44; 3 or 10<span class="elsevierStyleHsp" style=""></span>mg&#41; administered subcutaneously every 4 weeks vs&#46; placebo for 12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Peripheral diabetic neuropathy &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>77&#41;&#40;Study terminated prematurely by the FDA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fulranumab showed dose-dependent efficacy&#44; and the 10<span class="elsevierStyleHsp" style=""></span>mg dose gave superior relief compared to placebo at 12 weeks&#46; With the 10<span class="elsevierStyleHsp" style=""></span>mg dose&#44; 60&#46;9&#37; and 30&#46;4&#37; of patients reported &#8805;30&#37; and &#8805;50&#37; pain relief&#44; respectively&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fulranumab<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase 2 RCT&#58; fulranumab &#40;1&#44; 3 or 10<span class="elsevierStyleHsp" style=""></span>mg&#41; administered subcutaneously every 4 weeks vs&#46; placebo for 12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Postherpetic neuralgia&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>65Posttraumatic neuropathy&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>46&#40;Study terminated prematurely by the FDA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative results for primary and secondary endpoints&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Drugs with new data about their antineuropathic activity</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Oxcarbazepine<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">39</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Double blind&#44; placebo-controlled RCT&#58; oxcarbazepine &#40;1800&#8211;2400<span class="elsevierStyleHsp" style=""></span>mg&#41; with 2 treatment periods of 6 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Peripheral neuropathic pain &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>83&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moderate effect on the primary endpoint &#40;intensity of pain&#41;&#46; Enhanced effect in the &#8220;irritable nociceptive&#8221; group &#40;mild sensory deficit&#41;&#59; greater effect in patients with paroxysmal pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>BTX-A<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">48</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Double blind&#44; placebo-controlled RCT&#58; 2 subcutaneous injections of BTX-A &#40;up to 300 units&#44; symptom-adjusted&#41; administered 12 weeks apart&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Peripheral neuropathic pain &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>66&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Positive effect on the primary endpoint &#40;intensity of pain up to 24 weeks&#41; and some secondary endpoints&#44; including various neuropathic symptoms and allodyniaEnhanced effect in patients with mechanical allodynia and preserved nociceptive function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Summary of RCTs performed in neuropathic pain with the drugs included in this review&#46;</p>"
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