dimarts, 15 d’octubre del 2019

FDA approves new treatment for patients with migraine

The U.S. Food and Drug Administration today approved Reyvow (lasmiditan) tablets for the acute (active but short-term) treatment of migraine with or without aura (a sensory phenomenon or visual disturbance) in adults. Reyvow is not indicated for the preventive treatment of migraine.
“Reyvow is a new option for the acute treatment of migraine, a painful condition that affects one in seven Americans,” said Nick Kozauer, M.D., acting deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “We know that the migraine community is keenly interested in additional treatment options, and we remain committed to continuing to work with stakeholders to promote the development of new therapies for the acute and preventive treatment of migraine.” 
Migraine headache pain is often described as an intense throbbing or pulsing pain in one area of the head. Additional symptoms include nausea and/or vomiting and sensitivity to light and sound. Approximately one-third of individuals who suffer from migraine also experience aura shortly before the migraine. An aura can appear as flashing lights, zig-zag lines, or a temporary loss of vision. Migraines can often be triggered by various factors including stress, hormonal changes, bright or flashing lights, lack of food or sleep, and diet. Migraine is three times more common in women than in men and affects more than 10% of people worldwide.
The effectiveness of Reyvow for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials. A total of 3,177 adult patients with a history of migraine with and without aura treated a migraine attack with Reyvow in these studies. In both studies, the percentages of patients whose pain resolved and whose most bothersome migraine symptom (nausea, light sensitivity, or sound sensitivity) resolved two hours after treatment were significantly greater among patients receiving Reyvow at all doses compared to those receiving placebo. Although patients were allowed to take a rescue medication two hours after taking Reyvow, opioids, barbiturates, triptans and ergots were not allowed within 24 hours of the study drug’s administration. Twenty-two percent of patients were taking a preventive medication for migraine.
There is a risk of driving impairment while taking Reyvow. Patients are advised not to drive or operate machinery for at least eight hours after taking Reyvow, even if they feel well enough to do so. Patients who cannot follow this advice are advised not to take Reyvow. The drug causes central nervous system (CNS) depression, including dizziness and sedation. It should be used with caution if taken in combination with alcohol or other CNS depressants.
The most common side effects that patients in the clinical trials reported were dizziness, fatigue, a burning or prickling sensation in the skin (paresthesia), and sedation.
The FDA granted the approval of Reyvow to Eli Lilly and Company.     
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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dissabte, 5 d’octubre del 2019



September 30, 2019

For Community-Acquired Pneumonia, Oral Lefamulin Noninferior to Moxifloxacin

By Kelly Young
Oral lefamulin, a pleuromutilin antibiotic recently approved by the FDA, is noninferior to oral moxifloxacin for community-acquired pneumonia, according to an industry-conducted phase III trial in JAMA.
Over 700 adults with community-acquired pneumonia were randomized to either 5 days of lefamulin or 7 days of moxifloxacin.
Clinical response at 96 hours after starting treatment was 91% in both groups. But the lefamulin group had a higher rate of treatment-emergent adverse events (33% vs. 25%), particularly mild-to-moderate gastrointestinal events.
An editor's note says that the cost of lefamulin (over $200 a day) and adverse events (e.g., diarrhea) are likely to be concerns. However, "lefamulin is an important addition to the current antibiotic armamentarium, especially because bacterial pneumonia remains one of the most common indications for antibiotic use."

LINK(S):

JAMA article (Free)
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dilluns, 23 de setembre del 2019

FDA approves first oral GLP-1 treatment for type 2 diabetes


For Immediate Release:
The U.S. Food and Drug Administration today approved Rybelsus (semaglutide) oral tablets to improve control of blood sugar in adult patients with type 2 diabetes, along with diet and exercise. Rybelsus is the first glucagon-like peptide (GLP-1) receptor protein treatment approved for use in the United States that does not need to be injected. GLP-1 drugs are non-insulin treatments for people with type 2 diabetes.
“Patients want effective treatment options for diabetes that are as minimally intrusive on their lives as possible, and the FDA welcomes the advancement of new therapeutic options that can make it easier for patients to control their condition,” said Lisa Yanoff, M.D, acting director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “Before this approval, patients did not have an oral GLP1 option to treat their type 2 diabetes, and now patients will have a new option for treating type 2 diabetes without injections.”
Type 2 diabetes is the most common form of diabetes, occurring when the pancreas cannot make enough insulin to keep blood sugar at normal levels. GLP-1, which is a normal body hormone, is often found in insufficient levels in type 2 diabetes patients. Like GLP-1, Rybelsus slows digestion, prevents the liver from making too much sugar, and helps the pancreas produce more insulin when needed.
The efficacy and safety of Rybelsus in reducing blood sugar in patients with type 2 diabetes were studied in several clinical trials, two of which were placebo-controlled and several of which were compared to other GLP-1 injection treatments. Rybelsus was studied as a stand-alone therapy and in combination with other diabetes treatments, including metformin, sulfonylureas (insulin secretagogues), sodium-glucose co-transporter-2 (SGLT-2) inhibitors, insulins and thiazolidinediones, all in patients with type 2 diabetes.
In the placebo-controlled studies, Rybelsus as a stand-alone therapy resulted in a significant reduction in blood sugar (hemoglobin A1c) compared with placebo, as determined through HbA1c tests, which measure average levels of blood sugar over time. After 26 weeks, 69% of those taking 7 mg once daily and 77% of those taking 14 mg once daily of Rybelsus decreased their HbA1c to lower than 7%, compared with 31% of patients on placebo.
The prescribing information for Rybelsus includes a boxed warning to advise health care professionals and patients about the potential increased risk of thyroid c-cell tumors, and that Rybelsus is not recommended as the first choice of medicine for treating diabetes. Patients who have ever had medullary thyroid carcinoma (MTC) or who have a family member who has ever had MTC are advised not to use Rybelsus. Additionally, patients who have ever had an endocrine system condition called multiple endocrine neoplasia syndrome type 2 (MEN 2) are advised not to use Rybelsus. Rybelsus is not for use in patients with type 1 diabetes and people with diabetic ketoacidosis.
Rybelsus also has warnings about pancreatitis (inflammation of the pancreas), diabetic retinopathy (damage to the eye’s retina), hypoglycemia (low blood sugar), acute kidney injury and hypersensitivity reactions. It is not known whether Rybelsus can be used by patients who have had pancreatitis. The risk of hypoglycemia increased when Rybelsus was used in combination with sulfonylureas or insulin.
Rybelsus should be taken at least 30 minutes before the first food, beverage or other oral medication of the day, with no more than 4 ounces of plain water. Rybelsus slows digestion, so patients should discuss other medications they are taking with their health care provider before starting Rybelsus. The most common side effects are nausea, diarrhea, vomiting, decreased appetite, indigestion and constipation.
The approval of Rybelsus was granted to Novo Nordisk.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.


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dilluns, 2 de setembre del 2019

Indicaciones del Topiramato

Mecanismo de acción
Topiramato

Bloquea los canales de sodio estado-dependientes en las neuronas y potencia la actividad del GABA.

Indicaciones terapéuticas
Topiramato

- Monoterapia: ads. Y niños > 6 años con crisis epilépticas parciales con o sin crisis generalizadas secundarias, y crisis tónico-clónicas generalizadas primarias. 
- Tto. Concomitante: niños ≥ 2 años y ads. Con crisis epilépticas parciales con o sin generalización secundaria o crisis tónico-clónicas generalizadas primarias; crisis asociadas al s. de Lennox-Gastaut.
- Tto. Profiláctico de la migraña en ads. Después de una cuidadosa evaluación de otras posibles alternativas terapéuticas. 
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dimecres, 21 d’agost del 2019

FDA approves new antibiotic to treat community-acquired bacterial pneumonia

For Immediate Release:
August 19, 2019
The U.S. Food and Drug Administration today approved Xenleta (lefamulin) to treat adults with community-acquired bacterial pneumonia.
“This new drug provides another option for the treatment of patients with community-acquired bacterial pneumonia, a serious disease,” said Ed Cox, M.D., M.P.H., director of FDA’s Office of Antimicrobial Products. “For managing this serious disease, it is important for physicians and patients to have treatment options. This approval reinforces our ongoing commitment to address treatment of infectious diseases by facilitating the development of new antibiotics.”
Community-acquired pneumonia occurs when someone develops pneumonia in the community (not in a hospital). Pneumonia is a type of lung infection that can range in severity from mild to severe illness and can affect people of all ages. According to datafrom the Centers from Disease Control and Prevention, each year in the United States, about one million people are hospitalized with community-acquired pneumonia and 50,000 people die from the disease.
The safety and efficacy of Xenleta, taken either orally or intravenously, was evaluated in two clinical trials with a total of 1,289 patients with CABP. In these trials, treatment with Xenleta was compared to another antibiotic, moxifloxacin with or without linezolid. The trials showed that patients treated with Xenleta had similar rates of clinical success as those treated with moxifloxacin with or without linezolid. 
The most common adverse reactions reported in patients taking Xenleta included diarrhea, nausea, reactions at the injection site, elevated liver enzymes and vomiting. Xenleta has the potential to cause a change on an ECG reading (prolonged QT interval). Patients with prolonged QT interval, patients with certain irregular heart rhythms (arrhythmias), patients receiving treatment for certain irregular heart rhythms (antiarrhythmic agents), and patients receiving other drugs that prolong the QT interval should avoid Xenleta. In addition, Xenleta should not be used in patients with known hypersensitivity to lefamulin or any other members of the pleuromutilin antibiotic class, or any of the components of Xenleta. Based on findings of fetal harm in animal studies, pregnant women and women who could become pregnant should be advised of the potential risks of Xenleta to a fetus. Women who could become pregnant should be advised to use effective contraception during treatment with Xenleta and for two days after the final dose.
Xenleta received FDA’s Qualified Infectious Disease Product (QIDP) designation. The QIDP designation is given to antibacterial and antifungal drug products intended to treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, Xenleta was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.
The FDA granted the approval of Xenleta to Nabriva Therapeutics.
A key global challenge the FDA faces as a public health agency is addressing the threat of antimicrobial-resistant infections. Among the FDA’s other efforts to address antimicrobial resistance, is the focus on facilitating the development of safe and effective new treatments to give patients more options to fight serious infections.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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diumenge, 14 de juliol del 2019

Alexia en Medicina

La noticia se ha conocido recientemente, y está generando alguna polémica. El National Health Service británico utilizará Alexa, el asistente de voz de Amazon, como plataforma de información sanitaria a los ciudadanos. ¿Es una buena idea? ¿Compromete la calidad del servicios? ¿Se hace con la intención de descongestionar la asistencia presencial? ¿Pueden los británicos estar tranquilos en relación con la confidencialidad de la información que proporcionan al sistema?
Habría que comenzar por reconocer que el NHS es probablemente el servicio de salud del mundo que más avances está haciendo en materia de salud digital orientada a los pacientes. Desde hace años ha creado estructuras organizativas dedicadas específicamente a conocer y escrutar las nuevas áreas de innovación que llegan desde cualquier lugar del mundo, y a adoptarlas cuando resulte conveniente para la prestación de sus servicios a través nuevos canales. Lo que ya han demostrado es que es posible, para estos procesos, utilizar metodologías de análisis del valor similares a las que se usan en otros campos de la sanidad, y en particular los reputados modelos del NICE. Mediante el NHS Innovation Accelerator (NIA) no sólo promueven la creación de soluciones nuevas en este campo, sino que incluso proponen la financiación y el reembolso de las que crean que aportan ayuda a los pacientes.
En relación con los canales, desde hace un tiempo vienen usando herramientas como la videoconferencia o los chatbots para que los demandantes de servicios sanitarios dispongan de acceso a consultas o consejos sobre su salud de una manera más directa. Este tipo de soluciones, que en otros países sólo las ponen en marcha aseguradoras privadas, están al alcance de todos los británicos a través de su sistema público de salud. Especialmente notable es, por ejemplo, la aplicación Your.MD, que sirve para que cualquier persona pueda verificar una sintomatología común o para saber dónde encontrar un recurso asistencial. Utiliza sistemas algorítmicos, y es realmente uno de los mejores chatbots sanitarios que se pueden emplear en todo el mundo. El NHS también usa sistemas inteligentes para las citaciones y de videoconferencia sanitaria como Babylon Health, Push Doctor o Now GP.
Parece lógico pensar, entonces, que si el NHS se ha planteado esta apertura a los nuevos canales, acabaría usando un asistente de voz, símplemente porque es ya una tecnología de consumo ampliamente difundida, y que tiene enormes posibilidades. Pero, ¿es Alexa la mejor opción?

  • Realmente el sistema de Amazon es el más versátil y el que más está trabajando para crear aplicaciones de terceros que sean soportadas por su tecnología. De hecho, es la empresa que más promociona la opción de que cualquiera que esté interesado en este campo se plantee la posibilidad de crear un skill (una aplicación para Alexa) y para ello ha puesto a disposición de los desarrolladores herramientas de uso muy sencillo. 

    • Probablemente por esta razón el NHS ha visto que era muy sencillo transferir sus bases de datos a la arquitectura de programación de este asistente de voz. Lo que se pretende en esta primera fase es básicamente dar consejos de salud y permitir que los usuarios hagan preguntas generales, sencillas y adaptadas a las particularidades de un asistente de voz, que es por definición un sistema automatizado.
    La controversia ha llegado sobre todo por el problema de la privacidad. Para usar Alexa hay que disponer de una cuenta de Amazon, y es sabido que el procesamiento de las peticiones se hace a través de sistemas de archivos que gestiona Amazon, de manera que cualquier usuario podría estar ofreciéndoles información identificada sobre síntomas o condiciones médicas de interés más particular.      
    De otra parte, como todo el mundo sabe el negocio de Amazon se basa en la venta de todo tipo de artículos, y que para ello es crucial disponer de información de los perfiles de los usuarios que acceden a sus sistemas (web, app, asistente de voz…). Más aún, en Estados Unidos está entrando de lleno en el negocio sanitario, por ejemplo mediante la compra de una innovadora farmacia on line llamada PillPack o a través de nuevos servicios de asistencia médica en domicilio de los que ya se van conociendo más detalles.
    Ciertamente Alexa es un dispositivo con enormes posibilidades en los campos de la salud y sociosanitario, y no parece lógico cercenar la posibilidad de que se creen servicios avanzados asociados a esa plataforma. Su capacidad de llegar a una parte importante de la población, y las características de su interfaz de relación por voz hacen de esta tecnología una gran oportunidad al alcance especialmente de personas que puedan estar más aisladas o tengan problemas en el manejo de otro tipo de dispositivos, como la tercera edad o los discapacitados. Por añadidura, hace pocos meses Alexa adoptó en Estados Unidos protocolos compatibles con la regulación HIPAA, obligatoria para los datos de tipo médico. 
    Amazon ha dicho que todos los datos que maneje su sistema en Reino Unido se mantendrán confidenciales. Y que se sitúan en un nivel de seguridad y confidencialidad similar al de los otros nuevos canales que emplea a día de hoy el NHS. También, que no venderá productos ni hará recomendaciones basadas en los datos recopilados como parte de su asociación con el NHS. También confirmó que no construiría un perfil de salud de los usuarios que hicieran sus preguntas a Alexa.
    En definitiva, que no sería lógico repudiar el uso de asistentes de voz y no hacerlo igual con el resto de soluciones tecnológicas, lo que nos llevaría a despreciar nuevas posibilidad de generar servicios sanitarios en remoto y mejorar la educación para la salud. Todos los datos están encriptados y serán almacenados en centros de servidores en territorio inglés.
    Como ventaja añadida, y no desdeñable, es la existencia misma de un servicio de este tipo a cargo de la sanidad pública, la que ciertamente atesora el conocimiento más adecuado. Seguramente, si el NHS no hubiera construido esta alternativa, el hueco se podría haber llenado por otros proveedores de menor calidad, fiabilidad o con intereses espurios.
    Amazon Alexa-NHS partnership splits expert opinion
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    divendres, 28 de juny del 2019

    Tractament del dolor


    Nonnarcotic Methods of Pain Management

    • Nanna B. Finnerup, M.D.




    Pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or [is] described in terms of such damage” when there is no physical derangement.1 The function of pain is to protect the body by making the organism aware of damaging events and to promote healing by causing sensitivity to movement or other stimuli that may delay recovery. However, pain is not always related to tissue damage and does not always serve a protective function. This is the case with neuropathic pain, which is caused by a lesion or disease of the somatosensory parts of the nervous system, and with some other chronic pain conditions, such as fibromyalgia and migraine.2 Acute and chronic pain may cause suffering and interfere with daily life, factors that influence the choice of treatment.
    Acute pain is the most common reason for visiting an emergency department,3and surgical procedures are often associated with acute postoperative pain.4,5Chronic pain also causes suffering, as reflected by the finding in the Global Burden of Disease Study 2013 that chronic low back pain was the leading cause of years lived with disability.6 In addition to the contribution of pain to disability, that study showed that the associated problem of opioid use disorders accounted for 5.8 million additional years lived with disability,6 an observation that underpins attempts to treat pain with drugs other than opioids. Long-term opioid administration has minimal effects on chronic pain and can cause tolerance, drowsiness, and dependence, as well as impaired memory, concentration, and judgment.7 For these reasons, the International Association for the Study of Pain recommends caution in prescribing opioids for chronic pain,8 and there has been an increased emphasis on the use of nonopioid pain management.
    Table 1.Factors to Consider in the Management of Pain.
    The choice of treatment for pain depends on many factors, and the heterogeneity and large number of acute and chronic pain conditions preclude a general treatment algorithm. In cooperation with the World Health Organization, the International Association for the Study of Pain has developed a classification of chronic pain for the 11th revision of the International Classification of Diseases2 (Table 1), and a similar classification has been proposed for acute pain,5 providing the bases for facilitating treatment pathways.

    Assessment of Pain

    A common way to assess pain is to ask the patient about the intensity of pain on an 11-point numerical scale (0 to 10), but an overemphasis on the effect of treatment on pain intensity and overdependence on the assessment of pain with the use of these scales can lead to unnecessary opioid use.9 Furthermore, pain intensity does not reflect the entirety of the pain experience and is often not a measure of the suffering induced by pain.10 If the pain is known to be short-lived or to serve a purpose such as healing, it may be accepted and tolerated by the patient. Also, if patients perceive pain as a threat, an explanation of the cause and physiological meaning of the pain may alter their perception.9 Patients with chronic pain may have depression and anxiety, as well as “pain catastrophizing” (i.e., overly negative thoughts about pain in association with a tendency to feel helpless and magnify the threat of pain), which may increase the likelihood that pain will interfere with daily activities, whereas self-efficacy (the belief in one’s ability to meet challenges and achieve goals), coping strategies, and resilience have been linked to decreased interference with daily activities.11 Depression, anxiety, emotional distress, and a perceived lack of social support also contribute negatively to the long-term outcome of chronic pain (Table 1).10 These observations make it clear that the experience of pain is complex and subject to substantial individual variation, but they allow for the assessment and treatment of pain to be individualized on the basis of its severity and its interference in daily life, as well as the degree of suffering that pain induces (Table 1).

    Patient Education and Psychological Treatment

    The recent U.S. National Pain Strategy report emphasizes the need for self-management programs, which incorporate information about the nature of pain and the patient’s ability to prevent, cope with, and reduce pain through interdisciplinary pain treatment programs.12 The American Pain Society recommends involving the patient in the pain management plan and choosing treatment that combines pharmacologic and nonpharmacologic methods for managing acute pain and pain from cancer.13 Guidelines for the management of chronic low back pain, issued by the National Institute for Health and Care Excellence in the United Kingdom and the American College of Physicians, recommend educating patients and advising them to continue normal activities and to use self-management programs as first-line approaches, with supervised exercise therapy and cognitive behavioral or other psychological therapies or physical manipulation as second-line treatment.14,15 Only in refractory cases are pharmacologic, interventional, and surgical treatments considered appropriate. Most guidelines acknowledge that the strength of the recommendations is based on evidence that is of low-to-moderate quality and on only a few randomized, controlled trials, which have the inherent difficulty of masking patients to treatment assignments. Moreover, the effect sizes of psychological and self-care interventions are small, with between-group differences in pain intensity of 0.5 to 1.0 on a rating scale of 0 to 10, and results between trials are often conflicting.14,15
    Psychological treatments include cognitive behavioral therapy, hypnosis, mindfulness training, biofeedback, and stress management.16,17 Cognitive behavioral therapy involves practical techniques to change physical activity, reduce distress and catastrophizing, and improve functioning and social engagement. These techniques include coping strategies, exposure to feared activities, activities that divert attention from pain, and relaxation training. There have been few studies of the benefits of psychological treatments in patients with chronic pain, and the available evidence is of only low-to-moderate quality.16-18 Multidisciplinary management of chronic pain, which addresses psychological, social, and occupational factors, is sometimes beneficial, but no specific components of the combined treatment approach have been identified that influence the success of treatment.19,20 Hypnosis as a treatment for pain has been studied in a few randomized trials, with either uncertain evidence of an effect or small effect sizes on self-reported chronic pain; variable effect sizes on emotional stress resulting from pain during medical interventions have been noted.21
    The lack of high-quality evidence supporting the long-term effects of self-management and psychological treatment,16 in combination with patients or physicians who may not follow the recommended approaches, results in wide variations in practice.12 Barriers to implementation of these approaches include resistance on the part of the patient, lack of resources, limitations of insurance coverage, and uncoordinated health care systems. Further studies are needed to determine when and how these strategies should be implemented.12

    Nonopioid Analgesic Agents

    Figure 1.Sites of Action of Various Methods of Pain Management.Table 2.Nonopioid Analgesic Agents for Acute and Chronic Pain.
    Several analgesic agents, developed primarily for conditions other than pain and with various biologic sites of action, are available (Figure 1 and Table 2). These include nonsteroidal antiinflammatory drugs (NSAIDs), antidepressant agents, and antiepileptic drugs.

    ACETAMINOPHEN, ASPIRIN, AND NSAIDS

    Acetaminophen (also known as paracetamol) has well-known analgesic and antipyretic effects. It is widely used as an over-the-counter and prescription analgesic, but its mechanisms of action are not known. There is a small risk of severe skin reactions and a risk of liver damage if this agent is used in large doses. Acetaminophen has been the leading cause of acute liver failure in the United States since 1998 and requires a warning about the hepatotoxic risks.22Although acetaminophen is still considered the safest analgesic, no high-quality studies have assessed chronic adverse effects, and the Food and Drug Administration (FDA) is monitoring the safety of its use during pregnancy.23
    Aspirin (acetylsalicylic acid) and other NSAIDs, unlike acetaminophen, have antiinflammatory properties and inhibit platelet aggregation. Side effects of NSAIDs include nausea, gastrointestinal bleeding, and hypersensitivity reactions. NSAIDs, with the exception of aspirin, are associated with a risk, albeit low, of heart attack or stroke. The magnitude of the risk is not known with certainty, suggesting that the lowest doses should be used for the shortest time possible.24 NSAIDs are used for slight-to-moderate pain such as muscle and joint pain, toothache, menstrual pain, certain types of visceral pain, and postoperative pain and are first-line treatment for conditions such as migraine and single episodes of tension-type headache.25

    ANTIDEPRESSANT AGENTS

    Several drugs initially developed for the treatment of depression have been used for chronic pain. Tricyclic antidepressants and serotonin–norepinephrine (noradrenaline) reuptake inhibitors (SNRIs) reduce the intensity of pain in patients who have depression and in those who do not.26 One randomized, controlled trial estimated that less than 12% of the effect of duloxetine at a dose of 60 mg or 120 mg was attributable to improvement in mood or anxiety.27 However, antidepressants may be more effective in patients with both pain and depressive symptoms than in those with pain alone.28 The reason for the analgesic effect is not known but may be related in part to presynaptic inhibition of the reuptake of serotonin and norepinephrine in pain inhibitory pathways, as well as peripheral mechanisms involving β2-adrenergic receptors and the opioid system.29,30
    Tricyclic antidepressants and SNRIs have been used as first-line treatments for neuropathic pain, defined as pain due to a lesion or disease of the peripheral or central somatosensory nervous system.31 In a systematic review of trials of these agents as compared with placebo, the number of patients who would need to be treated (number needed to treat) in order to achieve at least a 50% reduction in neuropathic pain in one patient was 3.6 for tricyclic antidepressants and 6.4 for SNRIs.31 Antidepressants have also been recommended for prophylactic treatment of migraine and tension-type headache.32 There is some evidence of an analgesic effect of these drugs on pain from fibromyalgia, although it has been suggested that the benefits are outweighed by side effects in most patients.33 Systematic review of studies involving patients with low back pain suggests no overall effect of antidepressants on pain intensity or function, except for a small effect of duloxetine (a reduction in pain of <1 point on a scale of 0 to 10).34 The question of whether certain antidepressants have advantages over others is not settled. Amitriptyline is the tricyclic antidepressant with the best-documented analgesic effects, but desipramine, nortriptyline, and imipramine are likely to have less pronounced anticholinergic and sedative side effects and are associated with a lower risk of falls.30

    ANTIEPILEPTIC MEDICATIONS

    Several drugs used for the treatment of epilepsy have apparent analgesic properties through their putative effects of lowering neurotransmitter release or reducing neuronal firing. Gabapentin and pregabalin are ligands of the α2δ subunit of neuronal voltage-gated calcium channels. They cause reduced calcium-dependent release of excitatory neurotransmitters, thereby decreasing neuronal excitability. Gabapentin and pregabalin are recommended in guidelines for the treatment of neuropathic pain,31 and pregabalin has also been shown to be effective in trials for pain from fibromyalgia, with modest adverse events.35 In a systematic review of trials evaluating antiepileptic medications as compared with placebo for the treatment of neuropathic pain conditions, the number needed to treat in order to achieve 50% pain reduction in one patient was 7.7 for pregabalin and 7.2 for gabapentin.31 Not all trials show the superiority of antiepileptic agents over placebo, and a recent trial failed to show an effect of pregabalin in patients with sciatica.36 Perioperative use of pregabalin has an opioid-sparing effect on acute postoperative pain but an increased risk of serious adverse events and is therefore not recommended as routine postoperative treatment for pain.37 Side effects such as sedation and dizziness are common with both gabapentin and pregabalin, and there is increasing evidence of misuse and abuse of these drugs.38 Pregabalin is approved by the FDA only for neuropathic pain and pain from fibromyalgia; evidence of an effect on pain from other conditions is lacking, and concern has been expressed about increasing off-label use.38
    Oxcarbazepine, carbamazepine, lamotrigine, and lacosamide reduce neuronal excitability in the central and peripheral nervous systems by acting on voltage-gated sodium channels. Oxcarbazepine and carbamazepine are first-line treatments for trigeminal neuralgia,39 and the rate of success with these agents in treating this disorder has been considered to be good. On the basis of a few small, short-duration studies for conditions such as trigeminal neuralgia, the number needed to treat in order to achieve pain control in one patient is approximately 1.7.39 For other types of neuropathic pain, there is inconclusive evidence for the use of these drugs.31

    LOCAL TREATMENT OF PAIN

    An advantage of topical treatment of pain is the absence of effects on the central nervous system and other systemic side effects. Among the most commonly used agents in this class is the lidocaine patch, at a dose of 1.8% or 5%, which is approved by the FDA for postherpetic neuralgia and is recommended for peripheral neuropathic pain.31 The patches are applied over the sites of pain for up to 12 consecutive hours per day. They have few side effects but may cause skin irritation. Too few trials have been conducted to provide a dependable estimate of effect sizes. Capsaicin, which is the active pungent ingredient in chili peppers, activates the transient receptor potential vanilloid channel of small peripheral sensory nerves. The effect of repeated applications or of a single high-dose application is thought to occur through desensitization and a temporary reduction in the number of pain fibers in the skin. The capsaicin 8% patch is a second-line treatment for peripheral neuropathic pain such as postherpetic neuralgia and painful polyneuropathy, but there is no evidence of effectiveness in other pain conditions.31 On the basis of an analysis of seven trials, the combined number needed to treat is 10.6.31 Local side effects include skin reactions and discomfort on initial application. Because of precautions required to avoid contact with mucous membranes, the capsaicin 8% patch is applied by a health care professional. Up to four patches are applied once for 30 or 60 minutes, and the treatment can be repeated every 3 months. There is no good evidence that the weaker, over-the-counter preparations of menthol, methyl salicylate, or capsaicin have an effect on pain. Botulinum toxin type A given subcutaneously in the region of pain is a third-line treatment for peripheral neuropathic pain.31

    Interventional Pain Management

    Surgery is indicated for the treatment of pain if the underlying cause can be addressed safely and with a net clinical benefit. Examples that fulfill these conditions include removal of a tumor or herniated disk adjacent to neural tissue. Devices designed to modulate abnormal activity in the nervous system by stimulating neuronal pathways are used for symptomatic pain treatment. There is weak evidence for a benefit of spinal cord stimulation in patients with painful diabetic polyneuropathy, postsurgical chronic back and leg pain, or complex regional pain syndrome, and the evidence is similarly weak for a benefit of repetitive transcranial magnetic stimulation in the treatment of neuropathic pain and pain from fibromyalgia; in various other conditions, the effect of these devices is absent or unclear.40 The effect of spinal cord stimulation has been compared with the effect of conventional care or reoperation for low back pain, and most studies have been of short duration, making it difficult to estimate effect sizes over the long term.40
    Interventional treatments are available for pain conditions such as microvascular decompression or percutaneous radiofrequency rhizotomy for trigeminal neuralgia and occipital-nerve stimulation for cluster headache. Epidural analgesia or intrathecal treatment with ziconotide (a selective N-type voltage-gated calcium channel blocker), clonidine (a central α2-adrenergic receptor agonist), bupivacaine, or a combination of these agents may be used for uncontrolled pain associated with cancer.

    Complementary Therapies

    Many patients with chronic pain use complementary therapies, which include meditation, yoga, acupuncture, music therapy, heat therapy, massage, chiropractic, guided imagery, and biofeedback.41,42 Complementary therapies such as acupuncture and massage are recommended by the American College of Physicians for chronic low back pain.15 These therapies may support active self-care, and meditation and yoga are recommended to improve psychological well-being.41 However, the quality of evidence supporting the recommendations for complementary therapies is low, and there is controversy about the clinical relevance of the effects of these therapies, the role of placebo responses, and trial design, particularly in the case of acupuncture.43

    Future Directions

    Pharmacologic and interventional treatments for chronic pain often provide no reduction or only a small reduction in pain and are often judged by the patient to be inadequate.34 Each approach may have side effects that are associated with a decreased quality of life and interference with daily activities.44 Education and training of health care professionals to ensure cost-effective and safe evidence-based treatments are therefore considered essential for pain management.12,25
    Recent advances in our understanding of the mechanisms underlying pain have led to the development of new approaches. Several drugs are under investigation, such as calcitonin gene–related peptide antagonists and serotonin (5-hydroxytryptamine) type 1F (5-HT1F) agonists for migraine and angiotensin II type 2 receptor antagonists, selective sodium-channel blockers (e.g., voltage-gated sodium channel Nav1.7), and vanilloid receptor antagonists for neuropathic pain.45,46 New but not rigorously tested interventional treatments include high-frequency spinal cord stimulation and dorsal-root ganglion stimulation. Well-known drugs such as the anesthetics ketamine (an N-methyl-d-aspartate [NMDA] receptor antagonist) and nitrous oxide are also being considered as alternatives to opioids for acute pain in the emergency department or as part of analgesic regimens for postoperative pain.45,47,48
    Attempts are being made to identify biomarkers that predict the likelihood that a treatment will be effective49 by targeting the pain mechanism in each patient. For example, one study showed that refined testing of somatosensory function in patients with neuropathic pain could identify patients who would have a response to the sodium-channel blocker oxcarbazepine.50 Other possible methods that could individualize the approach to pain treatment include molecular profiling in rare pain conditions caused by gene variants that code for specific sodium channels, brain imaging to assess brain networks involved in pain and its emotional effects, and assessment of psychological functioning that may suggest a benefit from the use of specific psychological treatments.49

    Conclusions

    For the management of acute pain, the use of multiple approaches that do not include opioids and the establishment of acute pain services for postoperative pain management can reduce opioid-related adverse effects and dependence.4,25,48Patient education, psychological treatments, and avoidance of opioids may be useful for the management of chronic pain.12
    Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
    Dr. Finnerup reports receiving fees for serving on a data and safety monitoring board from Mitsubishi Tanabe, lecture fees from Astellas, grant support and advisory board fees from Novartis Pharma, advisory board fees from Teva Pharmaceuticals and Merck Selbstmedikation, consulting fees and travel support from Grünenthal, and grant support from Innovative Medicines Initiative. No other potential conflict of interest relevant to this article was reported.

    Author Affiliations

    From the Department of Clinical Medicine, Danish Pain Research Center, Aarhus University, and the Department of Neurology, Aarhus University Hospital — both in Aarhus, Denmark.
    Address reprint requests to Dr. Finnerup at .

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