Reply to Rossettini et al. "Do Not Mix Apples with Oranges" to Avoid Misinterpretation of Placebo Effects in Manual Therapy: The Risk Is Resulting in a Fruit Basket. Comment on "Molina-Álvarez et al. Manual Therapy Effect in Placebo-Controlled Trials: A Systematic Review and Meta-Analysis. Int. J. Environ. Res. Public Health 2022, 19, 14021".

We have thoroughly reviewed and carefully analyzed the points raised in the comment titled: "Do not mix apples with oranges" to avoid misinterpretation of placebo effects in manual therapy: the risk is resulting in a fruit basket [...].

Promising biomedical subcutaneous delivery system in opioid disaccustom process: In vitro/in vivo evaluation of naloxone microparticles on antagonist effect of morphine.

The addiction induced by the misuse of opioids, is not only a public health emergency but also a social and economic welfare. The main therapy is based on opioid antagonists. Oral and injectable naltrexone administration is the most widely used, presenting some inconveniences: poor patient adherence to the oral daily dosing schedule, cases of hepatitis and clinically significant liver dysfunction. This study proposes the in vitro e in vivo evaluation of anti-opioid properties of naloxone loaded-poly(lactic-co-glycolic) acid microparticles (NX-MP). In previous studies, NX-MP showed in vitro sustained naloxone release for one week at least. Our results demonstrate the in vitro efficacy of the NX-MP antagonizing for 7 days the morphine effect in SH-SY5Y cells and myenteric plexus-longitudinal muscle preparations isolated from guinea-pig ileum. The in vivo evaluation of the NX-MP was carried out in mice testing the antagonism of the antinociceptive effect of morphine. Results showed that subcutaneous administration of NX-MP blocked the morphine effect. The results of this work suggest that the subcutaneous administration of NX-MP enhances naloxone therapeutic efficacy as non-addictive medication and could be a promising alternative to naltrexone. Furthermore, the dose of NX-MP can be adapted to the patient necessities. It would be an interesting advantage to treat opioid-addiction.

Manual Therapy Effect in Placebo-Controlled Trials: A Systematic Review and Meta-Analysis.

PURPOSE: Background: Evaluate whether the design of placebo control groups could produce different interpretations of the efficacy of manual therapy techniques. METHODS: Nine databases were searched (EMBASE, CINAHL, PsycINFO, MEDLINE, PubMed, SCOPUS, WEB of SCIENCE, COCHRANE, and PEDro). Randomized placebo-controlled clinical trials that used manual therapy as a sham treatment on subjects suffering from pain were included. Data were summarized qualitatively, and meta-analyses were conducted with R. RESULTS: 53 articles were included in the qualitative analysis and 48 were included in the quantitative analyses. Manipulation techniques did not show higher effectiveness when compared with all types of sham groups that were analyzed (SMD 0.28; 95%CI [-0.24; 0.80]) (SMD 0.28; 95%CI [-0.08; 0.64]) (SMD 0.42; 95%CI [0.16; 0.67]) (SMD 0.82; 95%CI [-0.57; 2.21]), raising doubts on their therapeutic effect. Factors such as expectations of treatment were not consistently evaluated, and analysis could help clarify the effect of different sham groups. As for soft tissue techniques, the results are stronger in favor of these techniques when compared to sham control groups (SMD 0.40; 95%CI [0.19, 0.61]). Regarding mobilization techniques and neural gliding techniques, not enough studies were found for conclusions to be made. CONCLUSIONS: The literature presents a lack of a unified placebo control group design for each technique and an absence of assessment of expectations. These two issues might account for the unclear results obtained in the analysis.

Effect of Physiotherapeutic Interventions on Biomarkers of Neuropathic Pain: A Systematic Review of Preclinical Literature.

The purpose of this systematic review was to evaluate the effects of physiotherapeutic interventions on biomarkers of neuropathic pain in preclinical models of peripheral neuropathic pain (PNP). The search was performed in Pubmed, Web of Science, EMBASE, Cochrane, Cinhal, Psycinfo, Scopus, Medline, and Science Direct. Studies evaluating any type of physiotherapy intervention for PNP (systemic or traumatic) were included. Eighty-one articles were included in this review. The most common PNP model was chronic constriction injury, and the most frequently studied biomarkers were related to neuro-immune processes. Exercise therapy and Electro-acupuncture were the 2 most frequently studied physiotherapy interventions while acupuncture and joint mobilization were less frequently examined. Most physiotherapeutic interventions modulated the expression of biomarkers related to neuropathic pain. Whereas the results seem promising; they have to be considered with caution due to the high risk of bias of included studies and high heterogeneity of the type and anatomical localization of biomarkers reported. The review protocol is registered on PROSPERO (CRD42019142878). PERSPECTIVE: This article presents the current evidence about physiotherapeutic interventions on biomarkers of neuropathic pain in preclinical models of peripheral neuropathic pain. Existing findings are reviewed, and relevant data are provided on the effectiveness of each physiotherapeutic modality, as well as its certainty of evidence and clinical applicability.

Signs Indicative of Central Sensitization Are Present but Not Associated with the Central Sensitization Inventory in Patients with Focal Nerve Injury.

OBJECTIVE: Carpal tunnel syndrome (CTS) is the most common focal nerve injury. People with CTS may show alterations in central processing of nociceptive information. It remains unclear whether the central sensitization inventory (CSI) is capable of detecting such altered central pain processing. METHODS: Thirty healthy volunteers were matched with 30 people with unilateral CTS from the orthopaedic waitlist. Changes to central pain processing were established through psychophysical sensory testing (bilateral pressure pain thresholds (PPT), conditioned pain modulation, temporal summation) and pain distribution on body charts. Patients also completed pain severity and function questionnaires, psychological questionnaires and the CSI. RESULTS: Compared to healthy volunteers, patients with CTS have lower PPTs over the carpal tunnel bilaterally (t = -4.06, p < 0.0001 ipsilateral and t = -4.58, p < 0.0001 contralateral) and reduced conditioned pain modulation efficacy (t = -7.31, p <0.0001) but no differences in temporal summation (t = 0.52, p = 0.60). The CSI was not associated with psychophysical measures or pain distributions indicative of altered central pain processing. However, there was a correlation of the CSI with the Beck Depression Inventory (r = 0.426; p = 0.019). CONCLUSION: Patients with CTS show signs of altered central pain mechanisms. The CSI seems unsuitable to detect changes in central pain processing but is rather associated with psychological factors in people with focal nerve injuries.

Effects of neural mobilizations through movement representation techniques for the improvement of neural mechanosensitivity of the median nerve region: a randomized controlled trial.

PURPOSE: The main objective was to compare the effects of neural mobilization (NM), NM performed through mirror therapy (MT), NM performed through action observation (AO) training and finally classic rehabilitation program (mobility and strength) exercises on neural mechanosensitivity, widespread of proximal and distal pain and pressure pain thresholds (PPT). The second objective was to assess the effects of these interventions on handgrip strength, conditioned pain modulation, motor imagery ability and temporal summation. MATERIALS AND METHODS: Single-blinded randomized controlled trial. Fifty-four healthy subjects were randomly assigned to each group. Neural mechanosensitivity, widespread pain and PPT were the main variables. The secondary variables included handgrip strength, conditioned pain modulation, motor imagery ability and temporal summation. RESULTS: All groups showed significant differences in time*factor for neural mechanosensitivity (p = 0.001), PPT in the dermatome of the median nerve (p = 0.007), PPT at carpal tunnel (p < 0.05) and proximal widespread (p = 0.01). No differences were found for distal widespread, conditioned pain modulation, handgrip strength motor imagery ability or temporal summation (p > 0.05). There is an absence of statistically significant differences between groups. CONCLUSIONS: NM through movement representation techniques can reduce mechanosensitivity and mechanical hyperalgesia in the median nerve dermatome and forearm, although no differences were found between groups.

Evaluación del dolor en consultas de reumatología españolas: Estudio EVADOR / Pain assessment in Spanish rheumatology outpatient clinics: EVADOR Study

Introducción: Las enfermedades reumáticas son la causa más frecuente de dolor crónico no maligno. En los últimos años el dolor y su manejo han cobrado mayor relevancia en reumatología. Objetivos: Establecer la prevalencia y las características del dolor asociado a enfermedad reumática atendido en consultas de reumatología de nuestro país, así como de su tratamiento y la respuesta a este. Métodos: Estudio multicéntrico observacional con 2 fases, una transversal y otra prospectiva. Se recogieron variables del médico, paciente, dolor y su manejo, comorbilidades, respuesta terapéutica y aspectos psicosociales relacionados. Se analizaron las diferencias entre pacientes nuevos y en revisión (PR). Resultados: Se incluyeron 34 centros y 1.084 pacientes, 32% pacientes nuevos y 68% PR. En general, el dolor estaba presente en el 86% de los pacientes, era crónico en el 81% y neuropático en un 12%. El 50% de los pacientes consideraría el dolor aceptable cuando la intensidad en la escala visual numérica fuese≤2. Entre los PR existía mayor percepción de dolor controlado (65,5% vs. 49,4%) y satisfacción con el tratamiento (53,3% vs. 35,6%). El 23,5% estaba en tratamiento con opioides en el mes previo. Conclusiones: En la última década la prevalencia de dolor en el ámbito reumatológico en nuestro país persiste elevada, aunque ha disminuido. El empleo de opioides, por otra parte, ha aumentado.(AU)

Introduction: rheumatic diseases are the most frequent cause of non-malignant chronic pain. In recent years, pain and its management have become more important in rheumatology. Objectives: to estimate the prevalence and characteristics of pain associated with rheumatic pathology treated in rheumatology clinics in Spain, as well as their treatment and response to it. Methods: Multicentre observational study with two phases (cross-sectional and prospective). Variables were collected from the doctor, patient, pain and its management, comorbidities, therapeutic response and related psychosocial aspects. The differences between de novo (NP) vs follow-up (FP) patients were analyzed. Results: 34 centres and 1084 patients were included, 32% NP and 68% FP. Pain was present in 86%, was chronic in 81% and neuropathic in 12% of the surveyed population. Fifty percent of the patients would regard their pain as tolerable if its intensity according to the visual numeric scale (VNS) was≤2. Among the FP it was more frequent to have the perception of controlled pain (65.5% vs 49.4%) and to be satisfied with the treatment (53.3% vs. 35.6%). Of these patients, 23.5% had been treated with opioids in the previous month. Conclusions: In the last decade, the prevalence of pain in rheumatology in Spain remains high, although it has diminished. The use of opioids, on the other hand, has increased.(AU)

Pain assessment in Spanish rheumatology outpatient clinics: EVADOR Study. / Evaluación del dolor en consultas de reumatología españolas: Estudio EVADOR.

INTRODUCTION: rheumatic diseases are the most frequent cause of non-malignant chronic pain. In recent years, pain and its management have become more important in rheumatology. OBJECTIVES: to estimate the prevalence and characteristics of pain associated with rheumatic pathology treated in rheumatology clinics in Spain, as well as their treatment and response to it. METHODS: Multicentre observational study with two phases (cross-sectional and prospective). Variables were collected from the doctor, patient, pain and its management, comorbidities, therapeutic response and related psychosocial aspects. The differences between de novo (NP) vs follow-up (FP) patients were analyzed. RESULTS: 34 centres and 1084 patients were included, 32% NP and 68% FP. Pain was present in 86%, was chronic in 81% and neuropathic in 12% of the surveyed population. Fifty percent of the patients would regard their pain as tolerable if its intensity according to the visual numeric scale (VNS) was≤2. Among the FP it was more frequent to have the perception of controlled pain (65.5% vs 49.4%) and to be satisfied with the treatment (53.3% vs. 35.6%). Of these patients, 23.5% had been treated with opioids in the previous month. CONCLUSIONS: In the last decade, the prevalence of pain in rheumatology in Spain remains high, although it has diminished. The use of opioids, on the other hand, has increased.

Las conexinas en el dolor crónico. ¿Una nueva diana farmacológica? / Connexins in chronic pain. A new target?

No disponible

Dolor orofacial en la clínica odontológica / Orofacial pain in the dental clinic

La mayor parte de las consultas odontológicas están relacionadas con dolores intraorales que afectan a estructuras dentarias, periodontales y mucosas. Aunque generalmente la causa originaria del dolor y la estructura afectada coinciden en la localización, en ocasiones el dolor orofacial y, particularmente, el dolor oral, es referido. Esto es, el dolor puede deberse a procesos de origen extraoral localizados fuera del territorio maxilofacial. De igual manera, determinados trastornos orales, como un desequilibrio oclusivo, pueden afectar también estructuras extraorales, ocasionando tensión y dolor en cuello, cabeza y espalda. La investigación en dolor orofacial es, sin embargo, una disciplina emergente en comparación con otras áreas anatómicas, quizás debido, en parte, a que el dolor tiende a remitir con el tiempo o con la sanación del tejido afectado (si hubiera una lesión). Sin embargo, la mitad de los pacientes con algún tipo de dolor orofacial lo sufre de manera crónica y, a diferencia del dolor agudo, remitente, el dolor crónico no es ya un síntoma, sino una patología de difícil manejo, con escasa o ninguna relación con los mecanismos que lo originaron. Además, la falta de una adecuada anamnesis y exploración clínica, nomenclaturas inapropiadas o la dificultad de diagnóstico, hacen complicado en ocasiones un óptimo abordaje terapéutico. La mayoría de las clasificaciones de dolor oral siguen atendiendo a la estructura anatómica afectada más que al propio mecanismo nociceptivo. Por otra parte, la etiología exacta de muchas algias denominadas atípicas o del síndrome de boca ardiente sigue siendo desconocida. Esta revisión pretende describir los principales motivos de consulta por dolor en la clínica dental, poniendo particular énfasis en el tipo de dolor desde el punto de vista de su mecanismo: nociceptivo, inflamatorio, neuropático, psicogénico o mixto

Most dental consultations are related to intraoral pain disorders affecting dental, periodontal and mucosal structures. Although the originating cause of pain and the anatomical structure frequently co-localise, orofacial pain and particularly oral pain are sometimes referred. That is, pain may be caused by extraoral processes out of the maxillofacial territory. Likely, some intraoral conditions such as an occlusal imbalance may also affect extraoral structures, leading to tension and pain on the neck, head, and back. Orofacial pain research is however an emerging discipline in comparison to other anatomical regions. This may be due, in part, to the fact that oral pain tends to recede over time or after tissue healing -in case there was an injury-. Notwithstanding, half of the patients reporting any sort of orofacial pain suffers chronically. And unlike acute receding pain, chronic pain is no longer a symptom, but a diffi cult-to-manage pathology, with scarce or none relation to the mechanisms that caused it. Moreover, the lack of appropriate anamnesis and clinical examinations, inaccurate pain syndrome nomenclatures or difficulty in diagnosis hamper sometimes an optimal therapeutic approach. Most oral pain classifications are still based on the affected anatomical structure rather than on the nociceptive mechanism itself. On the other hand, the precise aetiology of most of the so-called atypical algiae or the burning mouth syndrome is still unknown. The present review article aims to describe the main reasons for pain consultation at the dental clinic, with particular emphasis on the type of pain from a mechanistically point of view: nociceptive, inflammatory, neuropathic, psychogenic or mixed

Recientes avances en el uso de la luz en la investigación en dolor. Implicaciones en fisiología y farmacología / Recent advances in the use of light in pain research. Implications in physiology and pharmacology

No disponible

Peripheral Nerve Conduction Block by High-Frequency Alternating Currents: A Systematic Review.

Numerous neurological dysfunctions are accompanied by an undesirable increase of nerve activity, such as neuropathic pain or spasticity. There have been several studies over the last years on peripheral nerve block using high-frequency alternating currents, which could become a therapeutic alternative for such nerve hyperactivity. The main aim of this systematic review was to determine the optimal parameters of the electrical currents for producing peripheral nerve conduction block, the underlying neurophysiological mechanisms, and their possible adverse effects. Of the 49 included studies, 30 were animal experiments, 13 were computer simulations, and six were clinical trials. High-frequency alternating currents using frequencies of >4-5 kHz effectively block nerve conduction. However, depending on the type of axon or nerve diameter, the minimum frequency required to produce the nerve block could be >20kHz. Electrodes design, electrode-axon distance, and temperature are variables that affect the block threshold. There is no consensus about the block mechanism, although it has been showed that the frequency is a key factor to produce K+ channels activation or Na+ channels inactivation. The nerve block produced by currents quickly reverts without causing further damage to the nerve. Studies in humans are necessary to further validate what preclinical studies have already shown.

Effect of Unmodulated 5-kHz Alternating Currents Versus Transcutaneous Electrical Nerve Stimulation on Mechanical and Thermal Pain, Tactile Threshold, and Peripheral Nerve Conduction: A Double-Blind, Placebo-Controlled Crossover Trial.

OBJECTIVE: To investigate the effect of unmodulated 5-kHz alternating current on mechanical pain threshold (MPT), heat pain threshold (HPT), tactile threshold (TT), and peripheral nerve conduction (PNC) compared with transcutaneous electrical nerve stimulation (TENS) and sham stimulation. SETTING: National referral center. DESIGN: Randomized, double-blind, placebo-controlled crossover trial. PARTICIPANTS: Healthy volunteers (N=38). No dropouts or adverse events were reported. INTERVENTION: TENS, unmodulated 5-kHz currents, and sham stimulation were applied on the radial nerve for 20 minutes with a 24-hour washout period between them and concealed intervention allocation. MAIN OUTCOME MEASURES: Four measures were taken: before, during, and 2 after the interventions. Algometry was used to assess MPT, a Peltier thermode for HPT using the method of limits, Von Frey filaments for TT, and radial nerve compound action potential. RESULTS: No differences were observed on MPT, HPT, and PNC when 5-kHz current and TENS were compared. However, TT increased 56.2mN (95% confidence interval [CI], 28.8-83.6) in the TENS group compared with the 5-kHz current group during intervention. Compared with sham stimulation during intervention, MPT increased 4.7N (95% CI, 0.3-9.2) using 5-kHz current and 10.4N (95% CI, 3.5-17.3) with TENS. TT increased 17.2mN (95% CI, 4.7-29.7) with 5-kHz current and 73.4mN (95% CI, 47.5-99.2) with TENS. However, HPT increased 1.0°C (95% CI, 0.2-2.0) only with TENS. For the PNC, no differences were found among the 3 groups. CONCLUSIONS: Unmodulated 5-kHz current produced an increase in somatosensory thresholds that was greater than placebo but not when compared with TENS; however, participants perceived 5-kHz currents to be more comfortable and showed more habituation to them.

Farmacología del metotrexato / Pharmacology of methotrexate

A mediados del siglo XX se sintetiza el metotrexato, un fármaco antagonista del ácido fólico, buscando reducir los efectos secundarios de la aminopterina, otro antitumoral inhibidor del ciclo de crecimiento celular. Indicado inicialmente como fármaco antitumoral por sus efectos antiproliferativos e inmunosupresores, en los últimos años el metotrexato se ha convertido en el tratamiento de elección de la artritis reumatoide y otras enfermedades inflamatorias crónicas. Aunque el mecanismo de acción subyacente a este efecto antiinflamatorio no está aún bien caracterizado, su eficacia para frenar la evolución de la enfermedad lo ha convertido en un fármaco de primera línea. En este artículo se resumen sus principales características farmacodinámicas y farmacocinéticas, y se dejan los datos relacionados con la eficacia terapéutica para otros capítulos de esta monografía (AU)

Methotrexate, a folic acid antagonist, was synthesised in the mid-twentieth century, with the aim of reducing the adverse effects of aminopterin, another drug inhibiting the growth rate of cancer cells. Methotrexate was initially indicated as an anti-cancer drug due to its antiproliferative and immunosuppressive effects but in the last few years it has become the treatment of choice in rheumatoid arthritis and other chronic inflammatory diseases. Although the mechanism of action underlying these anti-inflammatory effects has still not been well-characterized, the effectiveness of methotrexate in halting disease progression has made it a first-line drug. This article summarises its main pharmacodynamics and pharmacokinetic characteristics. Data on its therapeutic effectiveness are described elsewhere in this supplement (AU)

Sistemas cannabinoide y opioide en los mecanismos y el control del dolor / Cannabinoid and opioid system in the mechanisms and control of pain

El opio y el hachís han sido utilizados clásicamente para el control del dolor. La justificación farmacológica del uso de estas sustancias radica en el hecho de que son capaces de modular los sistemas endógenos opioide y cannabinoide, respectivamente. Ambos sistemas, depresores del sistema nervioso central (SNC), son capaces de producir efectos analgésicos tanto en animales de experimentación como en humanos al interferir con la transmisión de las señales dolorosas (nociceptivas) desde la periferia hasta los centros superiores del SNC. Se revisarán las principales teorías que explican los efectos periféricos de ambos sistemas y su posible interés desde el punto de vista del tratamiento del dolor músculo-esquelético (AU)

Opium and Hashish have been classically employed for the control of pain. The pharmacologic rationale for the use of these substances lies in the fact that they are able to modulate the endogenous opioid and cannabinoid systems respectively. Both systems, which depress the central nervous system (CNS), are capable of producing analgesia both in experimental animals and in humans by interfering with the transmission of pain signals (nociceptive) from the periphery to the superior centers of the CNS. We will review the main theories that explain the peripheral effects on both systems and its possible interest from the treatment of musculoskeletal pain standpoint (AU)

[Cannabinoid and opioid system in the mechanisms and control of pain]. / Sistemas cannabinoide y opioide en los mecanismos y el control del dolor.

Opium and Hashish have been classically employed for the control of pain. The pharmacologic rationale for the use of these substances lies in the fact that they are able to modulate the endogenous opioid and cannabinoid systems respectively. Both systems, which depress the central nervous system (CNS), are capable of producing analgesia both in experimental animals and in humans by interfering with the transmission of pain signals (nociceptive) from the periphery to the superior centers of the CNS. We will review the main theories that explain the peripheral effects on both systems and its possible interest from the treatment of musculoskeletal pain standpoint.

Role of cannabinoids in the management of neuropathic pain.

The treatment of pain, particularly neuropathic pain, is one of the therapeutic applications of cannabis and cannabinoids that is currently under investigation and that stimulates interest among clinicians and basic researchers. Animal pain models, including models of acute, antinociceptive, inflammatory and neuropathic pain, have demonstrated the antinociceptive efficacy of cannabinoids without causing serious alterations in animal behaviour. These data, together with the historic and current empiric use of cannabinoids, support the interest in the analysis of their effectiveness in treating neuropathic pain. The evaluation of controlled trials that focus on the effect of cannabinoids on neuropathic pain reveals that this class of drugs is able to significantly reduce pain perception. Nevertheless, this effect is generally weak and clinical relevance remains under evaluation. Moreover, there is a lack of controlled trials and, in particular, comparisons with other drugs generally used in the treatment of neuropathic pain. Despite the fact that further research is required to achieve a definitive assessment, current data obtained from basic research and from analysis of the available controlled trials indicate that cannabinoids can be accepted as a useful option in the treatment of neuropathic pain.