Scientific letter
Potential benefits of metformin in the treatment of chronic pain
Beneficios potenciales de la metformina en el tratamiento del dolor crónico
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Axial T-1 postdadolinium brain MRI sequences demonstrate nodular IVT enhancing lesions.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M.S. Cámara Marcos, A. Val-Carreres Castellote, I.M. Arruabarrena Echeverria" "autores" => array:3 [ 0 => array:2 [ "nombre" => "M.S." "apellidos" => "Cámara Marcos" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Val-Carreres Castellote" ] 2 => array:2 [ "nombre" => "I.M." "apellidos" => "Arruabarrena Echeverria" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2667049622000047?idApp=UINPBA00004N" "url" => "/26670496/0000000200000002/v3_202401110439/S2667049622000047/v3_202401110439/en/main.assets" ] "asociados" => array:1 [ 0 => array:16 [ "pii" => "S266704962400022X" "issn" => "26670496" "doi" => "10.1016/j.neurop.2024.100165" "estado" => "S100" "fechaPublicacion" => "2024-07-04" "aid" => "100165" "documento" => "simple-article" "crossmark" => 0 "subdocumento" => "err" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:8 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Erratum</span>" "titulo" => "Erratum to articles published in <span class="elsevierStyleItalic">Neurology Perspectives</span>" "subtitulo" => "Fe de errores sobre artículos publicados en la Revista Neurology Perspectives" "tienePdf" => "en" "tieneTextoCompleto" => "en" "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S266704962400022X?idApp=UINPBA00004N" "url" => "/26670496/unassign/S266704962400022X/v2_202408071214/en/main.assets" ] ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Potential benefits of metformin in the treatment of chronic pain" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "107" "paginaFinal" => "109" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "A. Alcántara Montero, C. Goicoechea García, S.R. Pacheco de Vasconcelos, P.M. Hernández Alvarado" "autores" => array:4 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Alcántara Montero" "email" => array:1 [ 0 => "a.alcantara.montero@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "af0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cr0005" ] ] ] 1 => array:3 [ "nombre" => "C." "apellidos" => "Goicoechea García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "af0015" ] ] ] 2 => array:3 [ "nombre" => "S.R." "apellidos" => "Pacheco de Vasconcelos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "af0010" ] ] ] 3 => array:3 [ "nombre" => "P.M. Hernández" "apellidos" => "Alvarado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "af0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Centro de Salud Manuel Encinas, Consultorio de Malpartida de Cáceres, Cáceres, Spain" "etiqueta" => "a" "identificador" => "af0005" ] 1 => array:3 [ "entidad" => "Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Madrid, Spain" "etiqueta" => "b" "identificador" => "af0015" ] 2 => array:3 [ "entidad" => "Complejo Hospitalario Universitario de Cáceres, Hospital Universitario, Cáceres, Spain" "etiqueta" => "c" "identificador" => "af0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cr0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Beneficios potenciales de la metformina en el tratamiento del dolor crónico" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "f0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1757 "Ancho" => 2431 "Tamanyo" => 371017 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">The action mechanism of metformin as an anti-hyperglycaemic drug (B) and its possible analgesic mechanism (A) (Image courtesy of <span class="elsevierStyleItalic">Carlos Goicoechea García</span>).</p> <p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Metformin indirectly promotes adenosine monophosphate-activated protein kinase (AMPK) activation. Activation of this enzyme promotes the action of the glucose transporter and blocks the action of the mammalian target of rapamycin (mTOR). Inhibition of mTOR decreases gluconeogenesis and protein synthesis. The analgesic mechanism of metformin may be related to an inhibitory effect on nuclear factor kappa B (NF-κB),<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> which would lead to a decrease in the synthesis of proinflammatory and pronociceptive proteins, such as interleukin-6 (IL-6), calcitonin gene-related peptide (CGRP), and tumour necrosis factor (TNF). Another possible action mechanism, which may complement the previously mentioned mechanism, may involve alterations in apoptosis.<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a> Metformin would inhibit processes related to chronic pain, such as mitochondrial degradation, autophagy, and apoptosis.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="p1005" class="elsevierStylePara elsevierViewall">Dear Editor:</p><p id="p1010" class="elsevierStylePara elsevierViewall">Metformin (biguanide) is a widely used drug for treating diabetes mellitus type 2. It has been used for 60 years and is a highly effective anti-hyperglycaemic drug.<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a> Extensive research has been conducted on the drug’s action mechanism in order to explain its effects on gluconeogenesis, protein metabolism, fatty acid oxidation, oxidative stress, glucose uptake, autophagia, and pain, among other processes. Some mechanisms were not identified until the late 1990s and early 2000s. Metformin induces beneficial effects in patients with diabetes by activating adenosine monophosphate-activated protein kinase (AMPK). Two kinases are responsible for AMPK activation: liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase II (CaMKII). Once activated, AMPK inhibits the mechanistic target of rapamycin complex 1 (mTORC1), which includes the mammalian target of rapamycin (mTOR). The TOR protein family has pleiotropic functions and participates in the regulation of mRNA transcription and translation in response to intracellular concentrations of amino acids and other essential nutrients.<a class="elsevierStyleCrossRef" href="#bb0010"><span class="elsevierStyleSup">2</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">AMPK is an enzyme that includes three subunits: a catalytic subunit (α) and two non-catalytic subunits (β and γ). It participates in cellular homeostasis and maintains cell energy levels by regulating the production and consumption of adenosine triphosphate (ATP). When cells are affected by such stressors as hypoxia, hypoglycaemia, or chemical insult, ATP levels decrease, which activates AMPK to restore balance.<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">AMPK activation may be achieved by several mechanisms. Direct allosteric activators protect the kinase from dephosphorylation through the β- or γ-subunits.<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a> Indirect activators increase phosphorylation in several regions, thereby increasing enzymatic activity. Two activators of AMPK are metformin and O304. Metformin acts non-specifically as an indirect AMPK activator in several intracellular areas and can cross the blood–brain barrier. However, O304 cannot cross the blood–brain barrier, and is a specific AMPK activator that decreases phosphorylation at the Thr172 site on the α-subunit kinase through protein phosphatase 2C, without suppressing the activating effects of AMPK.<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">As metformin is a disease-modifying drug for diabetes mellitus type 2 that reduces mTORC1 signalling in order to induce its effects on neuronal plasticity, it has been suggested that these mechanisms may also explain the drug’s antinociceptive effect in several models of chronic pain (<a class="elsevierStyleCrossRef" href="#f0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a> Thus, studies in mouse models have shown that AMPK activation may reduce allodynia and peripheral nerve injury within 7 days after the lesion.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a> AMPK activators have also been shown to achieve complete resolution of extensive nerve injury within 60 days of the lesion. A study analysing metformin and O304 in a mouse model of post-operative pain reported decreased sensitivity to mechanical pain with both drugs compared to vehicle. This study also showed the presence of an even greater synergistic effect when both drugs were jointly administered.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a></p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0025" class="elsevierStylePara elsevierViewall">This is an interesting area of research and advancement. Further studies on metformin may be designed to evaluate treatment for neuropathic and post-operative pain, possibly as part of a preventive perioperative regime, such as a protocol to improve recovery after surgery. Another possibility is the development and exhaustive study of other allosteric activators of AMPK, such as A769662 and OSU-53, for clinical use.<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a> These drugs are 100 times more potent than metformin and activate AMPK by targeting specific γ(2) subunits to achieve strong activation without adverse effects.<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a> As specific allosteric drugs, they also present a lower dispersion effect as compared with other non-specific activators. These types of drugs probably represent a more robust line of treatment than the drugs currently under study.</p><p id="p0030" class="elsevierStylePara elsevierViewall">Metformin has been shown to have neuroprotective effects in mouse models of neurodegenerative diseases,<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a> and decreases neuropathic pain induced by spinal nerve ligation and spared nerve injury in rats and mice.<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a> Similarly, treatment with metformin alleviates hyperalgesia and allodynia in a rat model of diabetic neuropathy.<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a> Furthermore, in a mouse model of cisplatin-induced neuropathy, metformin considerably reduced the loss of tactile sensitivity and the onset of mechanical hypersensitivity.<a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">12</span></a> Another preclinical study, using a rat model of oxaliplatin-induced peripheral neuropathy (OIPN), showed that metformin largely protects against intraepidermal nerve fibre degeneration induced by oxaliplatin.<a class="elsevierStyleCrossRef" href="#bb0065"><span class="elsevierStyleSup">13</span></a> In that study, metformin was able to prevent mechanical and cold hypersensitivity induced by chemotherapy. Overall, these data open new paths for the development of treatments to prevent OIPN in human patients.</p><p id="p0035" class="elsevierStylePara elsevierViewall">In summary, there is evidence indicating that AMPK activation signalling underlies the effects of metformin in several conditions, including insulin resistance, diabetes, and chronic pain. However, well-designed placebo-controlled clinical trials are needed to support the putative effect of metformin in preclinical trials, especially for chronic pain and its comorbidities.</p><span id="s7005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st7005">Conflicts of interest</span><p id="p7055" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "s7005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-12-14" "fechaAceptado" => "2022-01-04" "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="p0040" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="ec0005"></elsevierMultimedia></p>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "s0005" ] ] ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "f0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1757 "Ancho" => 2431 "Tamanyo" => 371017 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">The action mechanism of metformin as an anti-hyperglycaemic drug (B) and its possible analgesic mechanism (A) (Image courtesy of <span class="elsevierStyleItalic">Carlos Goicoechea García</span>).</p> <p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Metformin indirectly promotes adenosine monophosphate-activated protein kinase (AMPK) activation. Activation of this enzyme promotes the action of the glucose transporter and blocks the action of the mammalian target of rapamycin (mTOR). Inhibition of mTOR decreases gluconeogenesis and protein synthesis. The analgesic mechanism of metformin may be related to an inhibitory effect on nuclear factor kappa B (NF-κB),<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> which would lead to a decrease in the synthesis of proinflammatory and pronociceptive proteins, such as interleukin-6 (IL-6), calcitonin gene-related peptide (CGRP), and tumour necrosis factor (TNF). Another possible action mechanism, which may complement the previously mentioned mechanism, may involve alterations in apoptosis.<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a> Metformin would inhibit processes related to chronic pain, such as mitochondrial degradation, autophagy, and apoptosis.</p>" ] ] 1 => array:7 [ "identificador" => "ec0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Image " "rol" => "short" ] ] "Ecomponente" => array:2 [ "fichero" => "mmc1.pdf" "ficheroTamanyo" => 200657 ] "descripcion" => array:1 [ "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Supplementary material</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bb0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "host" => array:2 [ 0 => array:2 [ "doi" => "10.2337/dc21-Srev" "Revista" => array:8 [ "titulo" => "Summary of revisions: standards of medical care in diabetes—2021" "tituloSerie" => "Diabetes Care" "fecha" => "2021" "volumen" => "44" "numero" => "Supplement 1" "paginaInicial" => "S4" "paginaFinal" => "S6" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33298411" "web" => "Medline" ] ] ] ] 1 => array:2 [ "doi" => "10.2337/dc21-Srev" "WWW" => array:1 [ "link" => "https://care.diabetesjournals.org/content/44/Supplement_1/S4" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bb0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin: a prospective alternative for the treatment of chronic pain" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "G.D.C. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 101 | 13 | 114 |
| 2024 September | 133 | 19 | 152 |
| 2024 August | 122 | 15 | 137 |
| 2024 July | 150 | 18 | 168 |
| 2024 June | 127 | 7 | 134 |
| 2024 May | 153 | 14 | 167 |
| 2024 April | 125 | 9 | 134 |
| 2024 March | 166 | 17 | 183 |
| 2024 February | 123 | 7 | 130 |
| 2024 January | 174 | 20 | 194 |
| 2023 December | 145 | 23 | 168 |
| 2023 November | 163 | 32 | 195 |
| 2023 October | 159 | 24 | 183 |
| 2023 September | 110 | 13 | 123 |
| 2023 August | 112 | 15 | 127 |
| 2023 July | 92 | 6 | 98 |
| 2023 June | 95 | 11 | 106 |
| 2023 May | 122 | 8 | 130 |
| 2023 April | 90 | 5 | 95 |
| 2023 March | 53 | 3 | 56 |
| 2023 February | 40 | 7 | 47 |
| 2023 January | 72 | 10 | 82 |
| 2022 December | 74 | 3 | 77 |
| 2022 November | 53 | 8 | 61 |
| 2022 October | 54 | 13 | 67 |
| 2022 September | 68 | 11 | 79 |
| 2022 August | 51 | 11 | 62 |
| 2022 July | 53 | 14 | 67 |
| 2022 June | 65 | 17 | 82 |
| 2022 May | 28 | 15 | 43 |
| 2022 April | 43 | 35 | 78 |
| 2022 March | 0 | 11 | 11 |
| 2022 February | 0 | 15 | 15 |
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