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1.
Anesthesiology ; 133(1): 154-164, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33377922

RESUMO

BACKGROUND: Ketamine is often used for the management of refractory chronic pain. There is, however, a paucity of trials exploring its analgesic effect several weeks after intravenous administration or in association with magnesium. The authors hypothesized that ketamine in neuropathic pain may provide pain relief and cognitive-emotional benefit versus placebo and that a combination with magnesium may have an additive effect for 5 weeks. METHODS: A randomized, double-blind, crossover, placebo-controlled study (NCT02467517) included 20 patients with neuropathic pain. Each ketamine-naïve patient received one infusion every 35 days in a random order: ketamine (0.5 mg/kg)/placebo or ketamine (0.5 mg/kg)/magnesium sulfate (3g) or placebo/placebo.The primary endpoint was the area under the curve of daily pain intensity for a period of 35 days after infusion. Secondary endpoints included pain (at 7, 15, 21 and 28 days) and health-related, emotional, sleep, and quality of life questionnaires. RESULTS: Daily pain intensity was not significantly different between the three groups (n = 20) over 35 days (mean area under the curve = 185 ± 100, 196 ± 92, and 187 ± 90 pain score-days for ketamine, ketamine/magnesium, and placebo, respectively, P = 0.296). The effect size of the main endpoint was -0.2 (95% CI [-0.6 to 0.3]; P = 0.425) for ketamine versus placebo, 0.2 (95% CI [-0.3 to 0.6]; P = 0.445) for placebo versus ketamine/magnesium and -0.4 (95% CI [-0.8 to 0.1]; P = 0.119) for ketamine versus ketamine/magnesium. There were no significant differences in emotional, sleep, and quality of life measures. During placebo, ketamine, and ketamine/magnesium infusions, 10%, 20%, and 35% of patients respectively reported at least one adverse event. CONCLUSIONS: The results of this trial in neuropathic pain refuted the hypothesis that ketamine provided pain relief at 5 weeks and cognitive-emotional benefit versus placebo and that a combination with magnesium had any additional analgesic effect.


Assuntos
Ketamina/uso terapêutico , Sulfato de Magnésio/uso terapêutico , Neuralgia/tratamento farmacológico , Adulto , Idoso , Estudos Cross-Over , Método Duplo-Cego , Resistência a Medicamentos , Emoções , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultados Negativos , Neuralgia/psicologia , Medição da Dor/efeitos dos fármacos , Qualidade de Vida , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sono , Resultado do Tratamento
2.
Medicine (Baltimore) ; 99(40): e22588, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019476

RESUMO

BACKGROUND: The objective of this meta-analysis was to summarize and identify the available evidence from studies to estimate the clinical value of traditional Chinese medicine (TCM) in the treatment of recurrent aphthous stomatitis (RAS) and provides clinicians with evidence on which to base their clinical decision making. METHODS: This review will include all studies comparing clinical efficacy of TCM in the treatment of RAS. The search strategy will be performed in 9 databases. We will not establish any limitations to language and publication status, published from inception to the August 2020. Two reviewers will screen, select studies, extract data, and assess quality independently. Outcome is clinical efficacy, pain relief, duration of wound healing, effect on wound healing, rate of recurrence, adverse events, and safety. The methodological quality including the risk of bias of the included studies will be evaluated. We will carry out statistical analysis using RevMan 5.3 software. RESULTS: This study will summarize current evidence to assess the efficacy and safety of TCM in the treatment of RAS. CONCLUSION: The findings of this study will provide helpful evidence for the clinician, and will promote further studies, as well as studying the value of TCM. REGISTRATION NUMBER: INPLASY202080126 (DOI number: 10.37766/inplasy2020.8.0126).


Assuntos
Medicina Tradicional Chinesa/métodos , Medição da Dor/estatística & dados numéricos , Estomatite Aftosa/terapia , China/epidemiologia , Tomada de Decisão Clínica , Feminino , Humanos , Incidência , Masculino , Medicina Tradicional Chinesa/efeitos adversos , Estudos Observacionais como Assunto , Medição da Dor/efeitos dos fármacos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Segurança , Estomatite Aftosa/epidemiologia , Resultado do Tratamento , Cicatrização/efeitos dos fármacos
3.
Anesthesiology ; 133(5): 1021-1028, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32898213

RESUMO

BACKGROUND: Ketamine is a dissociative anesthetic with analgesic properties. Ketamine's analgesic properties have been suggested to result from its dissociative properties. To the authors' knowledge, this postulate is unsubstantiated. The authors hypothesize that the dissociative and analgesic properties of ketamine are independent. METHODS: The authors conducted a single-site, open-label study of ketamine anesthesia (2 mg/kg) in 15 healthy subjects. Midazolam was administered at a prespecified time point to attenuate dissociation. The authors longitudinally assessed precalibrated cuff pain intensity and quality using Patient-Reported Outcomes Measurement Information System questionnaires, and dissociation, using the Clinician Administered Dissociative States Scale. Mixed effects models were used to assess whether dissociation accounted for the effect of ketamine on pain intensity and quality. RESULTS: The dissociation model demonstrated an inverted U-shaped quadratic relationship between time and dissociation scores. Additive to this effect, midazolam reduced the dissociation adjusted means by 10.3 points (95% CI, 3.4 to 17.1; P = 0.005). The pain intensity model also demonstrated a U-shaped quadratic relationship between time and pain intensity. When the pain intensity model was reanalyzed with dissociation scores as an additional covariate, the dissociation term was not retained in the model, and the other effects were preserved in direction and strength. This result was conserved for nociceptive and neuropathic pain quality. CONCLUSIONS: Ketamine's analgesic properties are not exclusively caused by dissociation. Thus, ketamine may be used as a probe to advance our knowledge of dissociation independent neural circuits that encode pain.


Assuntos
Analgésicos/administração & dosagem , Anestésicos Dissociativos/administração & dosagem , Eletroencefalografia/efeitos dos fármacos , Ketamina/administração & dosagem , Medição da Dor/efeitos dos fármacos , Administração Intravenosa , Adulto , Eletroencefalografia/métodos , Feminino , Humanos , Masculino , Medição da Dor/métodos , Adulto Jovem
4.
Lancet Neurol ; 19(9): 784-796, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32822636

RESUMO

Trigeminal neuralgia is a very painful neurological condition with severe, stimulus-evoked, short-lasting stabbing pain attacks in the face. The past decade has offered new insights into trigeminal neuralgia symptomatology, pathophysiology, and treatment, leading to a change in the classification of the condition. An accurate diagnosis is crucial because neuroimaging interpretation and clinical management differ among the various forms of facial pain. MRI using specific sequences should be a part of the diagnostic workup to detect a possible neurovascular contact and exclude secondary causes. Demonstration of a neurovascular contact should not be used to confirm a diagnosis but rather to facilitate surgical decision making. Carbamazepine and oxcarbazepine are drugs of first choice for long-term treatment, whereas microvascular decompression is the first-line surgery in medically refractory patients. Advances in neuroimaging techniques and animal models will provide further insight into the causes of trigeminal neuralgia and its pathophysiology. Development of more efficacious treatment options is highly warranted.


Assuntos
Gerenciamento Clínico , Neuralgia do Trigêmeo/diagnóstico por imagem , Neuralgia do Trigêmeo/fisiopatologia , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Carbamazepina/farmacologia , Carbamazepina/uso terapêutico , Descompressão Cirúrgica/métodos , Humanos , Neuroimagem/métodos , Oxcarbazepina/farmacologia , Oxcarbazepina/uso terapêutico , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Neuralgia do Trigêmeo/classificação , Neuralgia do Trigêmeo/terapia
5.
Pain Physician ; 23(4): 375-382, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32709172

RESUMO

BACKGROUND: Transversus abdominis plane (TAP) blocks provide postoperative pain relief after various abdominal surgeries. Recently, erector spinae plane (ESP) block has obtained vast attention due to its simplicity and usage in truncal procedures. OBJECTIVES: This study aims to compare the ultrasound-guided bilateral ESP block versus bilateral TAP block on postoperative analgesia after open total abdominal hysterectomy. STUDY DESIGN: A prospective, double-blinded, randomized, controlled, clinical trial. SETTING: Zagazig University Hospitals. METHODS: After ending of surgical procedure and before reversing of the muscle relaxant, 48 women were randomly allocated into 2 equal groups: erector spinae (ES) group received bilateral ultrasound-guided ESP block with 20 mL of bupivacaine 0.375% plus 5 ug/mL adrenaline (1:200000) in each side at the level of T9, and transversus abdominis (TA) group received bilateral ultrasound-guided TAP block with the same volume of bupivacaine plus adrenaline. RESULTS: Visual Analog Scale scores at 30 minutes, 2, 4, 6, 8, 12, 16, 20, and 24 hours were statistically significantly lower in the ES group compared with the TA group. The time for requirement of first morphine was highly statistically significantly prolonged in the ES group (14.81 ± 3.52 hours) compared with the TA group (10.58 ± 2.35 hours). The total amount of morphine consumption in 24 hours postoperatively was statistically significantly decreased in the ES group; P = 0.01. Incidence of postoperative nausea and vomiting was higher but statistically insignificant in the TA group than the ES group. There were statistically significant numbers of unsatisfied patients (4) in the TA group compared with the ES group (no patient). LIMITATIONS: Sensorial evaluation of patients was not performed because both blocks had been done under general anesthesia but did not affect outcome. Therefore we recommend further studies comparing between both blocks. CONCLUSIONS: Bilateral ultrasound-guided ESP block provides more potent and longer postoperative analgesia with less morphine consumption than TAP block after open total abdominal hysterectomy. KEY WORDS: Abdominal hysterectomy, transversus abdominis plane block, erector spinae plane block, postoperative analgesia.


Assuntos
Músculos Abdominais/diagnóstico por imagem , Histerectomia/efeitos adversos , Bloqueio Nervoso/métodos , Dor Pós-Operatória/prevenção & controle , Músculos Paraespinais/diagnóstico por imagem , Ultrassonografia de Intervenção/métodos , Músculos Abdominais/efeitos dos fármacos , Músculos Abdominais/inervação , Adulto , Analgesia/métodos , Analgésicos Opioides/administração & dosagem , Anestésicos Locais/administração & dosagem , Bupivacaína/administração & dosagem , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Histerectomia/tendências , Pessoa de Meia-Idade , Morfina/administração & dosagem , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Dor Pós-Operatória/etiologia , Músculos Paraespinais/efeitos dos fármacos , Músculos Paraespinais/inervação , Estudos Prospectivos
6.
Drug Discov Ther ; 14(3): 129-134, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32669521

RESUMO

The aim of this randomized, single-blind, active-controlled pilot study was to investigate the clinical efficacy of oral supplementation with Verbascox®, a proprietary herbal extract capable of inhibiting human cyclooxygenase-2 (COX-2), in patients with mild-to-moderate osteoarthritis (OA) of the knee. Patients in the control group (n = 50) did not undergo any treatment (watchful waiting). Patients in the Verbascox® group (n = 50) received oral supplementation (800 mg/day) with the herbal extract for 2 weeks. The final study group consisted of patients (n = 50) who received celecoxib, a known pharmacological inhibitor of COX-2, 200 mg/day for 2 weeks. Examining physicians and laboratory personnel were blinded to group assignment, whereas patients were unblinded. All participants were evaluated using standard measures of pain relief and improvement in functional capacity at baseline, after 1 week, and at the end of the 2-week treatment course. Moreover, serum levels of substance P (SP), a member of the tachykinin family of neuropeptides involved in pain perception, were measured at the three time points. Both Verbascox® and celecoxib reduced pain, improved functional capacity, and lowered serum SP levels at 2 weeks compared with baseline, without significant inter-arm differences. Both Verbascox® and celecoxib showed a limited number of treatment-emergent adverse events. In summary, oral supplementation with Verbascox® (800 mg/day) in patients with mild-to-moderate OA of the knee is as effective and safe as a standard therapeutic dose of celecoxib in terms of pain relief and improvement in functional capacity after a 2-week treatment course.


Assuntos
Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Preparações de Plantas/uso terapêutico , Adulto , Idoso , Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Preparações de Plantas/farmacologia , Método Simples-Cego , Resultado do Tratamento
7.
Niger J Clin Pract ; 23(6): 835-841, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32525120

RESUMO

Aims: This study aims to investigate the effectiveness of transforaminal epidural steroid injection (TFESI) in patients with lumbar radicular pain or radiculopathy caused by different spinal pathologies. Methods: One hundred and seventy seven patients who underwent single transforaminal epidural steroid injection were included in the study group and divided into 3 subgroups (central spinal stenosis + lateral recess stenosis, foraminal stenosis, lumbar disc herniation) according to existing spinal pathology. Patients' visuel analogue scale (VAS) measures and Oswestry Disability Index (ODI) scores were recorded and the patients who give favourable response to treatment were called respondents and who were not called as non-respondents. Subgroups were compared statistically at the end of 12 months. Results: Sixty patients (33.9%) were considered as respondents and 117 patients (66.1%) were non-respondents in the entire study group. Patients with foraminal stenosis included the vast majority of the respondents and showed better results of pain relief as opposed to patients of other groups at the end of 12 months (P < 0.001). Conclusion: TFESI was an effective treatment modality for pain relief and functional improvement in patients with foraminal stenosis. However, it could not produce the same results in patients with central spinal stenosis and lumbar disc herniations.


Assuntos
Dor nas Costas/tratamento farmacológico , Injeções Epidurais/efeitos adversos , Deslocamento do Disco Intervertebral/diagnóstico , Vértebras Lombares/fisiopatologia , Medição da Dor/métodos , Radiculopatia/tratamento farmacológico , Estenose Espinal/tratamento farmacológico , Esteroides/administração & dosagem , Adulto , Idoso , Dor nas Costas/etiologia , Feminino , Humanos , Vértebras Lombares/efeitos dos fármacos , Região Lombossacral/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Manejo da Dor/métodos , Medição da Dor/efeitos dos fármacos , Estudos Retrospectivos , Estenose Espinal/complicações , Estenose Espinal/diagnóstico , Esteroides/efeitos adversos , Resultado do Tratamento , Escala Visual Analógica
8.
J Headache Pain ; 21(1): 69, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517693

RESUMO

BACKGROUND: erenumab was safe and effective in clinical trials for the prevention of migraine. However, real-life data are still lacking. Here we report the clinical experience from an Italian real-world setting using erenumab in patients with chronic migraine experiencing previous unsuccessful preventive treatments. METHODS: Seventy patients with chronic migraine and failure to ≥4 migraine preventive medication classes initially received monthly erenumab 70 mg s.c. Patients without a clinically meaningful improvement, considered as a > 30% reduction in headache days per month, after ≥3 months of therapy switched to monthly erenumab 140 mg. At the first administration and after 3 and 6 months, patients underwent extensive interviews to assess clinical parameters of disease severity and migraine-related disability and impact, and validated questionnaires to explore depression/anxiety, sleep, and quality of life (QoL). Finally, the Pain Catastrophizing Scale, Allodynia Symptom Checklist-12 and MIGraine attacks-Subjective COGnitive impairments scale (MIG-SCOG) were administered. RESULTS: 70% of patients were "responders" after the third administration of erenumab 70 mg, whereas 30% switched to erenumab 140 mg; 29% (6 pts) responded after the sixth administration. The headache-day frequency was reduced from 21.1 ± 0.7 to 11.4 ± 0.9 days after the third administration (p < 0.001) and to 8.9 ± 0.7 days after the sixth administration (p < 0.001). 53% and 70% of patients, respectively, showed a reduction of ≥50% of headache days/month after the third and the sixth administrations. Also improved were headache pain severity, migraine-related disability, and impact on daily living, QoL, pain catastrophizing and allodynia (all p < 0.001), quality of sleep, symptoms of depression or anxiety (p < 0.05) but not MIG-SCOG. There were no new adverse event signals. CONCLUSION: These real-world data support monthly erenumab 70 or 140 mg s.c. as a safe and effective preventive treatment to reduce headache frequency and severity in chronic migraine patients experiencing previous unsuccessful preventive treatments.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/psicologia , Medição da Dor/métodos , Estudos Prospectivos , Qualidade de Vida/psicologia , Inquéritos e Questionários , Resultado do Tratamento
9.
J Headache Pain ; 21(1): 54, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32429883

RESUMO

BACKGROUND: Pregabalin is approved for the treatment of neuropathic pain, fibromyalgia, and seizure disorders, although the pivotal trials were mostly carried out in Europe or North America. The prescribing patterns among different indications in Asia have rarely been explored. METHODS: This was a population-based retrospective cohort study based on the National Health Insurance Research Database in Taiwan. Prescriptions of pregabalin were identified, and data regarding demographics, indications, co-existing diagnoses, and concomitant medications were extracted. Pregabalin users were followed for at least one year, and factors associated with persistence at one year were determined by using multivariate logistic regression analysis. RESULTS: Between June 2012 and December 2016, 114,437 pregabalin users (mean age 60.7 ± 15.4 years, 57.8% female) were identified. The indications included post-herpetic neuralgia (PHN) (30.5%), musculoskeletal diseases other than fibromyalgia (21.2%), fibromyalgia (18.4%), diabetic peripheral neuropathic pain (DPNP) (11.7%) and epilepsy (2.9%). Overall, 62.5% and 6.4% of patients achieved a maximum dose of ≥150 and ≥ 300 mg/day, respectively. The median duration of persistent pregabalin use was 28 days (interquartile range 14-118 days). The one-year persistence rate was 12.1%, and the indications associated with the highest and lowest persistence rates were epilepsy (42.4%) and PHN (6.1%), respectively. Male gender (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.09-1.18), older age (OR 1.01 per year, 95% CI 1.01-1.01), indications other than PHN, especially epilepsy (OR 8.04, 95% CI 7.33-8.81, PHN as reference), and a higher initial dose (OR 1.12 per 75 mg, 95% CI = 1.10-1.15) were associated with persistence at one year, whereas the initial concomitant use of antiviral agents decreased the likelihood (OR 0.41, 95% CI 0.35-0.47). CONCLUSIONS: Pregabalin prescriptions for pain disorders were limited to short-term use, which is consistent around the world. However, the average prescribed dose in Taiwan was lower than those in Western countries, and was frequently below the recommended ranges. Potential causes included the duration of natural history of PHN, and off-label prescriptions for pain in acute herpes zoster, rather than PHN, as well as intolerance to the side effects.


Assuntos
Analgésicos/administração & dosagem , Medição da Dor/efeitos dos fármacos , Vigilância da População , Pregabalina/administração & dosagem , Adulto , Idoso , Estudos de Coortes , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/epidemiologia , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Feminino , Fibromialgia/tratamento farmacológico , Fibromialgia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/tratamento farmacológico , Neuralgia/epidemiologia , Neuralgia Pós-Herpética/tratamento farmacológico , Neuralgia Pós-Herpética/epidemiologia , Medição da Dor/métodos , Vigilância da População/métodos , Estudos Retrospectivos , Taiwan/epidemiologia , Resultado do Tratamento
10.
Anesthesiology ; 133(1): 154-164, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32384291

RESUMO

BACKGROUND: Ketamine is often used for the management of refractory chronic pain. There is, however, a paucity of trials exploring its analgesic effect several weeks after intravenous administration or in association with magnesium. The authors hypothesized that ketamine in neuropathic pain may provide pain relief and cognitive-emotional benefit versus placebo and that a combination with magnesium may have an additive effect for 5 weeks. METHODS: A randomized, double-blind, crossover, placebo-controlled study (NCT02467517) included 20 patients with neuropathic pain. Each ketamine-naïve patient received one infusion every 35 days in a random order: ketamine (0.5 mg/kg)/placebo or ketamine (0.5 mg/kg)/magnesium sulfate (3g) or placebo/placebo.The primary endpoint was the area under the curve of daily pain intensity for a period of 35 days after infusion. Secondary endpoints included pain (at 7, 15, 21 and 28 days) and health-related, emotional, sleep, and quality of life questionnaires. RESULTS: Daily pain intensity was not significantly different between the three groups (n = 20) over 35 days (mean area under the curve = 185 ± 100, 196 ± 92, and 187 ± 90 pain score-days for ketamine, ketamine/magnesium, and placebo, respectively, P = 0.296). The effect size of the main endpoint was -0.2 (95% CI [-0.6 to 0.3]; P = 0.425) for ketamine versus placebo, 0.2 (95% CI [-0.3 to 0.6]; P = 0.445) for placebo versus ketamine/magnesium and -0.4 (95% CI [-0.8 to 0.1]; P = 0.119) for ketamine versus ketamine/magnesium. There were no significant differences in emotional, sleep, and quality of life measures. During placebo, ketamine, and ketamine/magnesium infusions, 10%, 20%, and 35% of patients respectively reported at least one adverse event. CONCLUSIONS: The results of this trial in neuropathic pain refuted the hypothesis that ketamine provided pain relief at 5 weeks and cognitive-emotional benefit versus placebo and that a combination with magnesium had any additional analgesic effect.


Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ketamina/uso terapêutico , Sulfato de Magnésio/uso terapêutico , Neuralgia/tratamento farmacológico , Adulto , Idoso , Cognição/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Quimioterapia Combinada , Emoções , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Feminino , Humanos , Infusões Intravenosas , Ketamina/efeitos adversos , Sulfato de Magnésio/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neuralgia/psicologia , Medição da Dor/efeitos dos fármacos , Resultado do Tratamento
11.
Psychopharmacology (Berl) ; 237(7): 2139-2149, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32388618

RESUMO

BACKGROUND: HDAC6 is a class IIB histone deacetylase expressed at many levels of the nociceptive pathway. This study tested the ability of novel and selective HDAC6 inhibitors to alleviate sensory hypersensitivity behaviors in mouse models of peripheral nerve injury and peripheral inflammation. METHODS: We utilized the murine spared nerve injury (SNI) model for peripheral nerve injury and the Complete Freund's Adjuvant (CFA) model of peripheral inflammation. We applied the Von Frey assay to monitor mechanical allodynia. RESULTS: Using the SNI model, we demonstrate that daily administration of the brain-penetrant HDAC6 inhibitor, ACY-738, abolishes mechanical allodynia in male and in female mice. Importantly, there is no tolerance to the antiallodynic actions of these compounds as they produce a consistent increase in Von Frey thresholds for several weeks. We observed a similar antiallodynic effect when utilizing the HDAC6 inhibitor, ACY-257, which shows limited brain expression when administered systemically. We also demonstrate that ACY-738 and ACY-257 attenuate mechanical allodynia in the CFA model of peripheral inflammation. CONCLUSIONS: Overall, our findings suggest that inhibition of HDAC6 provides a promising therapeutic avenue for the alleviation of mechanical allodynia associated with peripheral nerve injury and peripheral inflammation.


Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Medição da Dor/efeitos dos fármacos , Animais , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor/métodos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley
12.
An. sist. sanit. Navar ; 43(1): 51-56, ene.-abr. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-193677

RESUMO

FUNDAMENTO: Los pacientes sometidos a cirugía bariátrica presentan mayor riesgo de complicaciones debido al uso de opioides. El objetivo es valorar la seguridad e idoneidad del protocolo Anestesia libre de opioides (OFA) implantado en el Hospital Universitario Virgen de la Victoria en 2018. MATERIAL Y MÉTODOS: Estudio prospectivo llevado a cabo en 38 pacientes sometidos a cirugía bariátrica laparoscópica bajo protocolo OFA durante el año 2018 en el H.U. Virgen de la Victoria (Málaga). Se recogieron variables para establecer el control hemodinámico y del dolor perioperatorio que se analizaron mediante Stata V.16. RESULTADOS: La edad media fue 43 años, el índice de masa corporal medio 48,14 y la estancia media en quirófano 178 minutos. El control de la respuesta hipertensiva tras la laringoscopia sucedió en el 88,1% de los casos. Al ingreso en la Unidad de Recuperación Post Anestésica (URPA), la SpO2 sin aporte suplementario en el traslado presentó una mediana de 97% con p75 ≥ 95%, mientras que el p75 de la evaluación del dolor mediante escala visual analógica (EVA) fue 3, con un 68% de pacientes sin dolor. Al alta de URPA, todos presentaron EVA menor de 4 y solo fue necesario administrar una dosis baja de petidina en siete pacientes. CONCLUSIÓN: La OFA ha resultado ser segura y conseguir un control del dolor óptimo. En los casos reconvertidos, el buen control de los parámetros abre la posibilidad de su utilización en cirugías más dolorosas


BACKGROUND: Patients subjected to bariatric surgery present a greater risk of complications due to the use of opioids. The goal is to evaluate the security and suitability of the Opioid Free Anaesthesia (OFA) protocol implemented in the Hospital Universitario Virgen de la Victoria in 2018. METHOD: Prospective study carried out on 38 patients subjected to laparoscopic bariatric surgery under the OFA protocol in the year 2018 at the H.U. Virgen de la Victoria (Málaga, Spain). Variables were gathered to establish haemodynamic control and perioperative pain, which were analysed using Stata V.16. RESULTS: The average age was 43 years, the average body mass index was 48.14 and the average stay in the operating theatre was 178 minutes. Control of hypertensive response following laryngoscopy occurred in 88.1% of the cases. On entering the Post Anaesthesia Care Unit (PACU), SpO2 without a supplementary contribution in the transfer showed a median of 97% with p75 ≥ 95%, while the p75 of pain evaluation by means of Visual Analogue Scale (VAS) was 3, with 68% of patients without pain. On discharge from the PACU, all presented VAS below 4 and it was only necessary to administer a low dose of Pethidine in seven patients. CONCLUSION: The OFA has proved to be secure and achieves optimum pain control. In the reconverted cases, good control of the parameters opens up the possibility of its use in more painful surgeries


Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Analgésicos não Entorpecentes/administração & dosagem , Cirurgia Bariátrica/métodos , Hospitais Universitários , Laparoscopia , Estudos Prospectivos , Período Perioperatório , Índice de Massa Corporal , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Dor Pós-Operatória
13.
Lancet Gastroenterol Hepatol ; 5(7): 658-666, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32277872

RESUMO

BACKGROUND: Bifidobacterium bifidum MIMBb75 is one of a few probiotic strains that have been shown to be effective in the treatment of irritable bowel syndrome (IBS) and its symptoms. Non-viable strains might have advantages over viable bacteria for product stability and standardisation, as well as for tolerability because safety concerns have been raised for specific patient groups who are susceptible to infection. We aimed to assess the efficacy of non-viable, heat-inactivated (HI) B bifidum MIMBb75 (SYN-HI-001) in the treatment of IBS and its symptoms. METHODS: We did a double-blind, placebo-controlled trial in which patients with IBS were recruited from 20 study sites in Germany and randomly assigned to receive either two placebo capsules or two capsules with a combined total of 1 × 109 non-viable B bifidum HI-MIMBb75 cells to be taken orally once a day for 8 weeks. Eligible patients were diagnosed with IBS according to Rome III criteria and had abdominal pain (≥4 on an 11-point numerical rating scale) on at least 2 days during a 2-week run-in phase. Patients with chronic inflammatory bowel diseases, systemic diseases, cancer, autoimmune diseases, with an intake of antipsychotic medications 3 months before study start, or with an intake of systemic corticosteroids within 1 month before study start were excluded. Randomisation was in a 1:1 ratio according to a computer-generated blocked list. Patients, investigators, clinical monitors, project managers, and statisticians were masked to the randomisation. The primary composite endpoint was the combination of at least 30% improvement of abdominal pain and adequate relief of overall IBS symptoms being fulfilled in at least 4 of 8 weeks during treatment. Analysis of the primary endpoint included all randomly assigned patients receiving at least one dose of study medication and who had no severe protocol violation. Safety analysis included all patients who had taken at least one dose of the study medication and was based on frequency and severity of adverse events, laboratory evaluation, and global assessment of tolerability. This trial is registered with the ISRCTN registry, ISRCTN14066467, and is completed: the results shown here represent the final analysis. FINDINGS: Patients were screened between April 15, 2016, and Feb 3, 2017, and 443 patients were allocated to the placebo group (n=222) or the B bifidum HI-MIMBb75 group (n=221). The composite primary endpoint was reached by 74 (34%) of 221 patients in the B bifidum HI-MIMBb75 group compared with 43 (19%) of 222 in the placebo group (risk ratio 1·7, 95% CI 1·3-2·4; p=0·0007). No serious adverse events occurred in the B bifidum HI-MIMBb75 group; seven adverse events suspected to be related to the study product were reported in the B bifidum HI-MIMBb75 group as were eight in the placebo group. No deaths were reported in this study. The most common reported adverse event with a suspected relationship to the study product was abdominal pain, which was reported in two (<1%) patients in the B bifidum HI-MIMBb75 group and one (<1%) in the placebo group. Tolerability was rated as very good or good by 200 (91%) patients in the B bifidum HI-MIMBb75 group compared with 191 (86%) in the placebo group. INTERPRETATION: This study shows that B bifidum HI-MIMBb75 substantially alleviates IBS and its symptoms in a real-life setting. These results indicate that specific beneficial bacterial effects are mediated independently of cell viability. FUNDING: Synformulas.


Assuntos
Bifidobacterium bifidum/fisiologia , Síndrome do Intestino Irritável/terapia , Probióticos/uso terapêutico , Dor Abdominal/induzido quimicamente , Dor Abdominal/etiologia , Adulto , Estudos de Casos e Controles , Método Duplo-Cego , Feminino , Alemanha/epidemiologia , Humanos , Intestinos/microbiologia , Síndrome do Intestino Irritável/microbiologia , Masculino , Pessoa de Meia-Idade , Medição da Dor/efeitos dos fármacos , Placebos/administração & dosagem , Segurança , Resultado do Tratamento
14.
Best Pract Res Clin Obstet Gynaecol ; 67: 100-112, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32265134

RESUMO

Neuraxial analgesia provides excellent pain relief in labor. Optimizing initiation and maintenance of neuraxial labor analgesia requires different strategies. Combined spinal-epidurals or dural puncture epidurals may offer advantages over traditional epidurals. Ultrasound is useful in certain patients. Maintenance of analgesia is best achieved with a background regimen (either programmed intermittent boluses or a continuous epidural infusion) supplemented with patient-controlled epidural analgesia and using dilute local anesthetics combined with opioids such as fentanyl. Nitrous oxide and systemic opioids are also used for pain relief. Nitrous oxide may improve satisfaction despite variable effects on pain. Systemic opioids can be administered by healthcare providers or using patient-controlled analgesia. Appropriate choice of drug should take into account the stage and progression of labor, local safety protocols, and maternal and fetal/neonatal side effects. Pain in labor is complex, and women should fully participate in the decision-making process before any one modality is selected.


Assuntos
Analgesia Obstétrica/métodos , Anestesia Obstétrica/métodos , Anestésicos Locais/administração & dosagem , Dor do Parto/terapia , Trabalho de Parto/efeitos dos fármacos , Manejo da Dor/métodos , Analgesia Epidural/métodos , Feminino , Humanos , Injeções Espinhais , Óxido Nitroso , Medição da Dor/efeitos dos fármacos , Satisfação do Paciente , Gravidez , Resultado do Tratamento
15.
Behav Pharmacol ; 31(2&3): 136-158, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32168025

RESUMO

The management of pain, particularly chronic pain, is still an area of medical need. In this context, opioids remain a gold standard for the treatment of pain. However, significant side effects, mainly of central origin, limit their clinical use. Here, we review recent progress to improve the therapeutic and safety profiles of opioids for pain management. Characterization of peripheral opioid-mediated pain mechanisms have been a key component of this process. Several studies identified peripheral µ, δ, and κ opioid receptors (MOR, DOR, and KOR, respectively) and nociceptin/orphanin FQ (NOP) receptors as significant players of opioid-mediated antinociception, able to achieve clinically significant effects independently of any central action. Following this, particularly from a medicinal chemistry point of view, main efforts have been directed towards the peripheralization of opioid receptor agonists with the objective of optimizing receptor activity and minimizing central exposure and the associated undesired effects. These activities have allowed the characterization of a great variety of compounds and investigational drugs that show low central nervous system (CNS) penetration (and therefore a reduced side effect profile) yet maintaining the desired opioid-related peripheral antinociceptive activity. These include highly hydrophilic/amphiphilic and massive molecules unable to easily cross lipid membranes, substrates of glycoprotein P (a extrusion pump that avoids CNS penetration), nanocarriers that release the analgesic agent at the site of inflammation and pain, and pH-sensitive opioid agonists that selectively activate at those sites (and represent a new pharmacodynamic paradigm). Hopefully, patients with pain will benefit soon from the incorporation of these new entities.


Assuntos
Analgesia/psicologia , Analgésicos Opioides/farmacologia , Manejo da Dor/métodos , Analgésicos/metabolismo , Analgésicos/farmacologia , Analgésicos Opioides/metabolismo , Animais , Humanos , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Receptores Opioides/agonistas , Receptores Opioides/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas
16.
Behav Pharmacol ; 31(2&3): 174-178, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32168026

RESUMO

Pain management is a challenging and unmet medical need. Despite their demonstrated efficacy, currently used opioid drugs and nonsteroidal anti-inflammatory drugs are frequently associated with several adverse events. The identification of new and safe analgesics is therefore needed. MP1104, an analogue of 3'-iodobenzoyl naltrexamine, is a potent nonselective full agonist at mu (MOR), kappa (KOR), and delta (DOR) opioid receptors, respectively. It was shown to possess potent antinociceptive effects in acute thermal pain assays without aversion in mice. In this study, we investigated MP1104 in the formalin test, a model of tonic pain. MP1104 (0.05, 0.1, and 1.0 mg/kg) reduced pain-like behaviors in phases I and II of the formalin test in male and female ICR mice. Pretreatment with KOR antagonist (norbinaltorphimine 10 mg/kg) and DOR antagonist (naltrindole 10 mg/kg) abolished the antinociceptive effects of MP1104 in the formalin test. These findings support the development of MP1104 for further testing in other pain models.


Assuntos
Morfinanos/farmacologia , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Analgésicos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfinanos/metabolismo , Antagonistas de Entorpecentes/farmacologia , Dor/tratamento farmacológico , Manejo da Dor/métodos , Medição da Dor/efeitos dos fármacos , Receptores Opioides/agonistas , Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistas
17.
Pain Physician ; 23(2): E151-E161, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214292

RESUMO

BACKGROUND: Ginger has been proposed as a complementary treatment for musculoskeletal pain. However, efficacy, type, and safety remains unclear. OBJECTIVES: To determine the effectiveness of consumption or topical application of ginger for pain relief and knee function improvement in patients with knee osteoarthritis. STUDY DESIGN: Systematic review with meta-analysis of randomized clinical trials. METHODS: An electronic search was performed on Medline, Central, CINAHL, PEDro, SPORTDiscus, and LILACS databases. The eligibility criteria for selecting studies included clinical trials that compared consumption and/or topical ginger with placebo or other interventions for the pain relief and knee function in patients with medical diagnosis of knee osteoarthritis. RESULTS: Seven clinical trials met the eligibility criteria, and for the quantitative synthesis, 4 studies were included. For the comparison capsules versus placebo, mean difference for pain was -7.88 mm; 95% confidence interval (CI), 11.92 to 3.85 (P = 0.00), and standard mean difference for knee function was -1.61 points; 95% CI, -4.30 to -1.09 (P = 0.24). For the comparison of topical ginger versus standard treatment, standard mean difference for pain was 0.79 mm; 95% CI, -1.97 to 0.39 (P = 0.19), and standard mean difference for knee function was -0.51 points; 95% CI, -1.15 to 0.13 (P = 0.12). LIMITATIONS: The current evidence is heterogeneous and has a poor methodologic quality. CONCLUSIONS: There is insufficient evidence to support the use of oral ginger compared with placebo in the pain relief and function improvement in patients with knee osteoarthritis. For other comparisons, no statistically significant differences were found. KEY WORDS: Osteoarthritis, knee osteoarthritis, ginger, pain, randomized clinical trial, systematic review.


Assuntos
Gengibre , Osteoartrite do Joelho/tratamento farmacológico , Manejo da Dor/métodos , Extratos Vegetais/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Humanos , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/fisiologia , Dor Musculoesquelética/diagnóstico , Dor Musculoesquelética/tratamento farmacológico , Dor Musculoesquelética/epidemiologia , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/epidemiologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Extratos Vegetais/isolamento & purificação , Recuperação de Função Fisiológica/fisiologia
18.
Pain Physician ; 23(2): E195-E202, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214298

RESUMO

BACKGROUND: Premedication in children with ketamine is useful to produce mild sedation, decrease anxiety, help the child separation from parents, and provide postoperative pain relief with no or little adverse effects. OBJECTIVES: The aims of this study were to compare the level of sedation, parental separation, successful venous cannulation, and postoperative analgesia of oral or nebulized ketamine in preschoolers undergoing elective surgery. STUDY DESIGN: A prospective, comparative, double-blind, randomized study. SETTING: Zagazig University Hospitals. METHODS: In the preparation room, 30 minutes before induction of anesthesia, 62 children were randomly divided into 2 groups: group O (n = 31) received oral ketamine 10 mg/kg in 2 mL apple juice, and group N (n = 31) received nebulized ketamine 3 mg/kg plus 2 mL isotonic saline solution by a standard hospital jet nebulizer via a mouth mask with a continuous 6 L/min flow of 100% oxygen. RESULTS: At 10 minutes after premedication, sedation score was 3 in group O (34.4%) compared with group N (0%), and at 20 minutes in group O (93.5%) compared with group N (9.6%) (P < 0.001 ). However, at 30 minutes, 51.6% of group O showed a sedation score of 1 versus 0% of group N (P < 0.001 ). There were 70.9% of group O versus 6.4% of group N who showed an Emotional State Score of 1 (P < 0.0001), and 29.03% of group O versus 19.3% of group N who showed an Emotional State Score of 2 (P = 0.37), with statistically nonsignificant adverse effects in both groups. Low mean modified Children's Hospital of Eastern Ontario Pain Scale score in group O compared with group N at 30, 60, 90 minutes (P < 0.0001). LIMITATIONS: In this study, although the dose of nebulized ketamine was 3 mg/kg, which was more than the optimum dose investigated in previous studies, it was not adequate, so we recommend conducting more studies investigating higher doses. CONCLUSIONS: Oral ketamine 10 mg/kg as premedication 30 minutes before induction of anesthesia is more effective than 3 mg/kg nebulized ketamine in producing more sedation, satisfactory separation from parents, successful venous cannulation, and effective postoperative analgesia, as it is more tolerable and accepted by preschoolers undergoing elective surgery. KEY WORDS: Nebulized ketamine, oral ketamine, preschooler, elective surgery.


Assuntos
Analgésicos/administração & dosagem , Procedimentos Cirúrgicos Eletivos/métodos , Hipnóticos e Sedativos/administração & dosagem , Ketamina/administração & dosagem , Medição da Dor/efeitos dos fármacos , Administração Oral , Período de Recuperação da Anestesia , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Criança , Pré-Escolar , Método Duplo-Cego , Procedimentos Cirúrgicos Eletivos/psicologia , Feminino , Humanos , Ketamina/efeitos adversos , Masculino , Nebulizadores e Vaporizadores , Medição da Dor/métodos , Medição da Dor/psicologia , Estudos Prospectivos
19.
Pain Physician ; 23(2): 203-208, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214302

RESUMO

BACKGROUND: The superior hypogastric plexus block has been indicated for visceral pelvic pain treatment associated with malignancy. The first international report of this technique was published by Plancarte et al, in which a posterior percutaneous approach guided by fluoroscopy was described by applying neurolytic agents. The considerable variability in the data reported gave rise to 2 clinical approaches to those who performed the blockade early and those who executed it at a later stage of cancer. OBJECTIVES: The present study aims to provide more evidence regarding the effectiveness of this procedure. STUDY DESIGN: This is a retrospective, longitudinal, descriptive study. SETTING: The study was held at the pain unit service of the National Cancer Institute, Mexico City. METHODS: A nonprobabilistic sample was selected; the data collection took place from January 2006 to December 2016 with patients diagnosed with pelvic pain, confirmed by imaging and biopsy studies. Patients who received any other type of intervention of the sympathetic axis, patients with a different approach than the classic or paravertebral technique, and patients with low survival rate were excluded. The Student t test was used to measure the significant difference between Visual Analog Scale (VAS) and morphine equivalent daily dose. The Cochran-Mantel-Haenszel test and the Gamma test were used to measure the association between the initial Karnofsky and blockade success. RESULTS: The study included a total of 180 patients. The success rate was 59.4% at 1 month, 55.5% at 3 months, and 48.8% at 6 months. There was a sustained and significant VAS reduction that was 49.55% at 3 months. A significant reduction in opioid consumption of 12.55% was found at 3 months. There was no significant statistical evidence related to either opioid consumption or the functionality of the patient before the blockade as an influential variable in the success of the procedure. LIMITATIONS: Retrospective study, developed in a single center. CONCLUSIONS: Although opioids remain the cornerstone of cancer pain treatment, they produce many deleterious side effects. The superior hypogastric plexus neurolysis represents a reproducible and effective alternative in the management of pain in this group of patients. KEY WORDS: Pelvic pain, neoplasms, chemical neurolysis, pain management, cancer pain, palliative care, analgesia, nerve block.


Assuntos
Dor do Câncer/terapia , Plexo Hipogástrico/fisiologia , Bloqueio Nervoso/métodos , Manejo da Dor/métodos , Medição da Dor/métodos , Dor Pélvica/terapia , Adulto , Idoso , Analgésicos Opioides/uso terapêutico , Dor do Câncer/diagnóstico , Feminino , Humanos , Plexo Hipogástrico/efeitos dos fármacos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Morfina/uso terapêutico , Medição da Dor/efeitos dos fármacos , Dor Pélvica/diagnóstico , Estudos Retrospectivos
20.
Anesthesiology ; 132(4): 839-853, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32044802

RESUMO

BACKGROUND: Interscalene brachial plexus block, the pain relief standard for shoulder surgery, is an invasive technique associated with important complications. The subomohyoid anterior suprascapular block is a potential alternative, but evidence of its comparative analgesic effect is sparse. The authors tested the hypothesis that anterior suprascapular block is noninferior to interscalene block for improving pain control after shoulder surgery. As a secondary objective, the authors evaluated the success of superior trunk (C5-C6 dermatomes) block with suprascapular block. METHODS: In this multicenter double-blind noninferiority randomized trial, 140 patients undergoing shoulder surgery were randomized to either interscalene or anterior suprascapular block with 15 ml of ropivacaine 0.5% and epinephrine. The primary outcome was area under the curve of postoperative visual analog scale pain scores during the first 24 h postoperatively. The 90% CI for the difference (interscalene-suprascapular) was compared against a -4.4-U noninferiority margin. Secondary outcomes included presence of superior trunk blockade, pain scores at individual time points, opioid consumption, time to first analgesic request, opioid-related side-effects, and quality of recovery. RESULTS: A total of 136 patients were included in the analysis. The mean difference (90% CI) in area under the curve of pain scores for the (interscalene-suprascapular) comparison was -0.3 U (-0.8 to 0.12), exceeding the noninferiority margin of -4.4 U and demonstrating noninferiority of suprascapular block. The risk ratio (95% CI) of combined superior trunk (C5-C6 dermatomes) blockade was 0.98 (0.92 to 1.01), excluding any meaningful difference in superior trunk block success rates between the two groups. When differences in other analgesic outcomes existed, they were not clinically important. CONCLUSIONS: The suprascapular block was noninferior to interscalene block with respect to improvement of postoperative pain control, and also for blockade of the superior trunk. These findings suggest that the suprascapular block consistently blocks the superior trunk and qualify it as an effective interscalene block alternative.


Assuntos
Artroscopia/métodos , Bloqueio do Plexo Braquial/métodos , Osso Hioide/diagnóstico por imagem , Medição da Dor/métodos , Ombro/diagnóstico por imagem , Ombro/cirurgia , Adulto , Artroscopia/efeitos adversos , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/efeitos dos fármacos
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