Neuromodulación eléctrica en el tratamiento del dolor neuropático refractario. Colocación del primer estimulador medular en Cuba / Electric neuromodulation in the treatment of refractory pain. Placement of the first spinal stimulator in Cuba

El dolor es una causa importante de sufrimiento físico y emocional. El tratamiento médico de los pacientes con dolor crónico refractario es un gran reto. Se presenta el caso de una paciente de 19 años con un cuadro radicular compresivo secundario a Hernia discal L5-S1 derecha, que se le aplicó una discectomía L5-S1 por técnica de Caspar. Al mes de evolución regresa con igual sintomatología. A pesar de múltiples terapias farmacológicas y procederes intervencionistas, el dolor neuropático no mejora, después de múltiples estudios y discusiones en colectivo se determina la posibilidad de la colocación de un neuroestimulador medular, proceder que se lleva a cabo con mejoría considerable de su cuadro doloroso(AU)

Pain is a major cause of physical and emotional suffering. The management of patients with refractory chronic pain is a great challenge. The case is presented of a 19-year-old female patient with compressive radicular symptoms secondary to right L5-S1 disc herniation, who underwent L5-S1 discectomy with Caspar technique. After one month of evolution, she returned with the same symptoms. Despite multiple pharmacological therapies and interventional procedures, the neuropathic pain did not improve. After multiple studies and collective discussions, the possibility of placing a spinal neurostimulator was decided. After the procedure, the patient improved considerably with respect to her painful symptoms(AU)

Regulation of the KATP-JNK gap junction signaling pathway by immunomodulator astragaloside IV attenuates neuropathic pain.

BACKGROUND AND OBJECTIVES: Gap junctions play a pivotal role in contributing to the formation of astroglial networks and in chronic pain. However, the mechanisms underlying the dysfunction of astroglial gap junctions in chronic pain have not been fully elucidated. METHODS: Chronic constriction injury (CCI) of the sciatic nerve was used to establish rat neuropathic pain model. C6 cells were used to perform experiments in vitro. Von Frey hairs and Hargreave's method were used to determine the withdrawal threshold of rats. Protein expression was detected by immunofluorescence and western blotting. RESULTS: Astragaloside IV (AST IV) significantly attenuated neuropathic pain and suppressed the excitation of spinal astrocytes in rats with CCI. The antinociceptive effect of AST IV was reversed by the gap junction decoupler carbenoxolone (CBX). AST IV inhibited the high expression of phosphorylated connexin 43 (p-Cx43) and p-c-Jun N-terminal kinase (p-JNK) in spinal cord of rats with CCI. JNK inhibitor alleviated neuropathic pain, which was reversed by CBX. JNK inhibitor decreased the high expression of p-Cx43 in both rats with CCI and tumor necrosis factor-alpha (TNF-α)-treated C6 cells. Additionally, the analgesic effect of AST IV was reversed by the adenosine triphosphate-sensitive potassium (KATP) channel blocker, glibenclamide (Glib). Glib abolished the inhibitory effects of AST IV on p-JNK and p-Cx43 both in vivo and in vitro. KATP channel opener (KCO) mimicked the inhibitory effects of AST IV on p-JNK and p-Cx43 in TNF-α-treated C6 cells. CONCLUSION: Our results indicate that the sciatic nerve CCI induces the dysfunction of gap junctions in the spinal cord by activating KATP/JNK signaling to contribute to neuropathic pain. AST IV attenuates neuropathic pain via regulating the KATP-JNK gap junction axis.

Chronic pain and psychedelics: a review and proposed mechanism of action.

The development of chronic pain is a complex mechanism that is still not fully understood. Multiple somatic and visceral afferent pain signals, when experienced over time, cause a strengthening of certain neural circuitry through peripheral and central sensitization, resulting in the physical and emotional perceptual chronic pain experience. The mind-altering qualities of psychedelics have been attributed, through serotonin 2A (5-HT2A) receptor agonism, to 'reset' areas of functional connectivity (FC) in the brain that play prominent roles in many central neuropathic states. Psychedelic substances have a generally favorable safety profile, especially when compared with opioid analgesics. Clinical evidence to date for their use for chronic pain is limited; however, several studies and reports over the past 50 years have shown potential analgesic benefit in cancer pain, phantom limb pain and cluster headache. While the mechanisms by which the classic psychedelics may provide analgesia are not clear, several possibilities exist given the similarity between 5-HT2A activation pathways of psychedelics and the nociceptive modulation pathways in humans. Additionally, the alterations in FC seen with psychedelic use suggest a way that these agents could help reverse the changes in neural connections seen in chronic pain states. Given the current state of the opioid epidemic and limited efficacy of non-opioid analgesics, it is time to consider further research on psychedelics as analgesics in order to improve the lives of patients with chronic pain conditions.

Serotonin-norepinephrine reuptake inhibitors for the prevention of migraine and vestibular migraine: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: The role of serotonin-norepinephrine reuptake inhibitors (SNRIs) in migraine prophylaxis has not been completely established. Current treatments for vestibular migraine (VM) are based on scarce evidence. We aimed to perform an updated review focusing on the efficacy and tolerability of SNRIs for migraine and VM prevention. METHODS: We searched the PubMed, Web of Science, and Cochrane Library databases for relevant studies. The primary outcome was migraine frequency. In the case of VM, the Dizziness Handicap Inventory (DHI) scores and Vertigo Severity Scores (VSSs) were extracted. RESULTS: Six randomized controlled trials involving 418 patients were analyzed. Patients receiving SNRIs had fewer migraine days than those receiving a placebo (standardized mean difference -0.38, 95% CI -0.76 to -0.01, p=0.04). The effects of SNRIs and other active drugs were comparable. In patients with VM, venlafaxine had a significant advantage over other active drugs in decreasing the VSS (weighted mean difference (MD) -1.45, 95% CI -2.11 to -0.78, p<0.0001) and the emotional domain score of the DHI (MD -2.64, 95% CI -4.97 to -0.31, p=0.03). We found no significant difference in the rate of withdrawals due to any reason or withdrawals due to side effects between SNRIs and active drugs and between SNRIs and a placebo. CONCLUSIONS: SNRIs were clinically safe and effective for migraine and VM prophylaxis, were better than a placebo, and not inferior to other active drugs. SNRIs may be a preferable choice for patients with VM with psychiatric disorders.

Analysis of quantitative sudomotor axon reflex test patterns in patients with complex regional pain syndrome diagnosed using the Budapest criteria.

BACKGROUND: Although the quantitative sensory axon reflex test (QSART) is used to evaluate sudomotor dysfunction in the diagnosis of complex regional pain syndrome (CRPS), its validity remains controversial. This study investigated the diagnostic performance of the QSART for CRPS and assessed associations between results of the QSART and other clinical variables. METHODS: We examined the electronic medical records of 196 consecutive patients who underwent the QSART with a suspected diagnosis of CRPS, during the period from January 2013 to December 2015. To assess the diagnostic performance of the QSART for CRPS based on the Budapest research criteria, we calculated sensitivity, specificity, positive likelihood ratio and negative likelihood ratio. Furthermore, we performed binary logistic regression analyses to investigate the relationships between QSART results and other clinical variables. RESULTS: The sensitivity and specificity of the QSART for diagnosing CRPS were 67.6% and 40.6%, respectively. The OR for diagnosing CRPS using the QSART was not statistically significant (1.43; 95% CI 0.65 to 3.14; p=0.376), whereas it was for distinguishing CRPS types I and II (4.11; 95% CI 1.34 to 12.57; p=0.013). In multivariable analysis, there were no correlations between the results of the QSART and other variables, except hypertension (OR=0.34; 95% CI 0.13 to 0.91; p=0.032). CONCLUSION: The QSART showed low diagnostic value as a screening or a confirmatory test for CRPS according to the Budapest research criteria. CRPS type II was more likely than CRPS type I to result in abnormal QSART results.

Effect and Mechanism of Dexmedetomidine Hydrochloride on Neuropathic Pain / 医药导报

Objective To establish neuropathic pain models,explore the effects and mechanisms of dexmedetomidine on neuropathic pain.Methods Wistar rats were randomly divided into four groups (n =9):0.9％ sodium chloride solution CCI group (N),dexmedetomidine CCI group (D),ZD7288 CCI group (Z) and sham-operated group (Sham).Sciatic nerve ligation was performed in group N,D and Z.The sciatic nerve in group Sham was exposured without ligation.7 d after surgery,the rats in group D were intraperitoneal injected with dexmedetomidine (40 μg· kg-1),and the rats in group Z were intraperitoneal injected with ZD7288 (10 mg·kg-1)once a day for 3 d.The same volume of 0.9％ sodium chloride solution was given at the same time in group N.The behavioral test was performed before and 7 d after operation,as well as 3 d after injection treatment.Mechanical allodynia was assessed by paw withdrawal mechanical threshold (PWMT) to von Frey filaments.Thermal hyperalgesia was assessed by paw thermal withdrawal latency (TWL) to radiant heat.Dexmedetomidine block of HCN channels in dorsal root ganglion (DRG) neurons were confirmed by whole-cell recording.Results 7 d after surgery,the PWMT and TWL of rats in group N,D and Z were decreased significantly (P ＜ 0.05).The PWMT and TWL in group Sham were no significant difference before and after operation.Dexmedetomidine significantly increased the levers of PWMT and TWL in group D and Z after treatment for 3 d,and group Z was greater than group D (P ＜ 0.05).Dexmedetomidine (0.1,1,10 μmol· L-1) caused a concentration-dependent decrease in the amplitude of Ih in DRG neurons from (-844.43 ± 386.34) to (-215.99 ± 63.90) pA (P ＜ 0.05),and the inhibition rate of Ih was (11.87 ± 1.80) ％,(35.26 ± 3.65) ％ and (52.02 ± 5.56) ％,respectively(P ＜0.05).Dexmedetomidine produced a dose-related shift to the left of the Ih activation,and a negative shift in V1/2 (P ＜ 0.05).V1/2 shifted from (-86.21 ± 1.68) to (-103.54 ± 2.01) mV (P ＜ 0.05).The slope values were not altered by dexmedetomidine.Conclusion Dexmedetomidine produces a dose-dependently analgesic effect on neuropathic pain after peripheral never injury,which is likely due to the inhibition of Ih and reduction of ectopic spontaneous discharge in DRG neurons.

Research Progress in the Mechanism of Neuropathic Pain and the Intervention Effect of Electroacupuncture / 上海针灸杂志

Neuropathic pain is a chronic pain caused by primary nervous system damage and nerve dysfunction. Its pathogenesis is complex and diverse. It is difficult to treat clinically. In recent years, researchers used electroacupuncture to treat neuropathic pain and obtained a desirable effect. This article summarizes recent years’ studies on the main mechanisms of neuropathic pain and the intervention effect of electroacupuncture to provide reference for following studies on electroacupuncture treatment of neuropathic pain.

DHEA administration modulates stress-induced analgesia in rats.

An important aspect of adaptive stress response is the pain response suppression that occurs during or following stress exposure, which is often referred to as acute stress-induced analgesia. Dehydroepiandrosterone (DHEA) participates in the modulation of adaptive stress response, changing the HPA axis activity. The effect of DHEA on the HPA axis activity is dependent on the state and uses the same systems that participate in the regulation of acute stress-induced analgesia. The impact of DHEA on nociception has been studied; however, the effect of DHEA on stress-induced analgesia is not known. Thus, the aim of the present study was to evaluate the effect of DHEA on stress-induced analgesia and determine the best time for hormone administration in relation to exposure to stressor stimulus. The animals were stressed by restraint for 1h in a single exposure and received treatment with DHEA by a single injection before the stress or a single injection after the stress. Nociception was assessed with a tail-flick apparatus. Serum corticosterone levels were measured. DHEA administered before exposure to stress prolonged the acute stress-induced analgesia. This effect was not observed when the DHEA was administered after the stress. DHEA treatment in non-stressed rats did not alter the nociceptive threshold, suggesting that the DHEA effect on nociception is state-dependent. The injection of DHEA had the same effect as exposure to acute stress, with both increasing the levels of corticosterone. In conclusion, acute treatment with DHEA mimics the response to acute stress indexed by an increase in activity of the HPA axis. The treatment with DHEA before stress exposure may facilitate adaptive stress response, prolonging acute stress-induced analgesia, which may be a therapeutic strategy of interest to clinics.

The use of high-intensity focused ultrasound as a novel treatment for painful conditions-a description and narrative review of the literature.

High-intensity focused ultrasound (HIFU) is a non-invasive technique that allows a small, well-circumscribed thermal lesion to be generated within a tissue target. Tissue destruction occurs due to direct heating within the lesion and the mechanical effects of acoustic cavitation. HIFU has been used in a broad range of clinical applications, including the treatment of malignancies, uterine fibroids and cardiac arrhythmias. Interest in the use of the technique to treat pain has recently increased. A number of painful conditions have been successfully treated, including musculoskeletal degeneration, bone metastases and neuropathic pain. The exact mechanism by which HIFU results in analgesia remains poorly understood, but it is thought to be due to localised denervation of tissue targets and/or neuromodulatory effects. The majority of studies conducted investigating the use of HIFU in pain are still at an early stage, although initial results are encouraging. Further research is indicated to improve our understanding of the mechanisms underlying this treatment and to fully establish its efficacy; however, it is likely that HIFU will play a role in pain management in the future. This narrative review provides a synthesis of the recent, salient clinical and basic science research related to this topic and gives a general introduction to the mechanisms by which HIFU exerts its effects.

The natural history of pain and neuropathic pain after knee replacement: a prospective cohort study of the point prevalence of pain and neuropathic pain to a minimum three-year follow-up.

A small proportion of patients have persistent pain after total knee replacement (TKR). The primary aim of this study was to record the prevalence of pain after TKR at specific intervals post-operatively and to ascertain the impact of neuropathic pain. The secondary aim was to establish any predictive factors that could be used to identify patients who were likely to have high levels of pain or neuropathic pain after TKR. A total of 96 patients were included in the study. Their mean age was 71 years (48 to 89); 54 (56%) were female. The mean follow-up was 46 months (39 to 51). Pre-operative demographic details were recorded including a Visual Analogue Score (VAS) for pain, the Hospital Anxiety and Depression score as well as the painDETECT score for neuropathic pain. Functional outcome was assessed using the Oxford Knee score. The mean pre-operative VAS was 5.8 (1 to 10); and it improved significantly at all time periods post-operatively (p < 0.001): (from 4.5 at day three to five (1 to 10), 3.2 at six weeks (0 to 9), 2.4 at three months (0 to 7), 2.0 at six months (0 to 9), 1.7 at nine months (0 to 9), 1.5 at one year (0 to 8) and 2.0 at mean 46 months (0 to 10)). There was a high correlation (r > 0.7; p < 0.001) between the mean VAS scores for pain and the mean painDETECT scores at three months, one year and three years post-operatively. There was no correlation between the pre-operative scores and any post-operative scores at any time point. We report the prevalence of pain and neuropathic pain at various intervals up to three years after TKR. Neuropathic pain is an underestimated problem in patients with pain after TKR. It peaks at between six weeks and three-months post-operatively. However, from these data we were unable to predict which patients are most likely to be affected.

The immune aspect in neuropathic pain: role of chemokines.

Neuropathic pain is a pathological symptom experienced worldwide by patients suffering with nervous system dysfunction caused by various diseases. Treatment of neuropathic pain is always accompanied by a poor response and undesired adverse effects. Therefore, developing a novel "pain-kill" drug design strategy is critical in this field. Recent evidence demonstrates that neuroinflammation and immune response contributes to the development of neuropathic pain. Nerve damage can initiate inflammatory and immune responses, as evidenced by the upregulation of cytokines and chemokines. In this paper, we demonstrated that different chemokines and chemokine receptors (e.g., CX3CL1/CX3CR1, CCL2/CCR2, CCL3/CCR1, CCL4/CCR5 and CCL5/CCR5) serve as mediators for neuron-glia communication subsequently modulate nociceptive signal transmission. By extensively understanding the role of chemokines in neurons and glial cells in nociceptive signal transmission, a novel strategy for a target-specific drug design could be developed.

Thalamus and pain.

The thalamus is a key relay station for the transmission of nociceptive information to the cerebral cortex. We review the input-output connection, functional imaging, direct neuronal recording, stimulation, and lesioning studies on the involvement of thalamus in acute and chronic pain functions. Based on its specific reciprocal connection with the cerebral cortex, strong nociceptive responsiveness, and the severe chronic pain when it is damaged, the thalamus may hold the key to pain consciousness and the key to understanding spontaneous and evoked pain in chronic pain conditions. A work plan is proposed for future study.

Neuroinflammation and the generation of neuropathic pain.

Inflammation is the process by which an organism responds to tissue injury involving both immune cell recruitment and mediator release. Diverse causes of neuropathic pain are associated with excessive inflammation in both the peripheral and central nervous system which may contribute to the initiation and maintenance of persistent pain. Chemical mediators, such as cytokines, chemokines, and lipid mediators, released during an inflammatory response have the undesired effect of sensitizing and stimulating nociceptors, their central synaptic targets or both. These changes can promote long-term maladaptive plasticity resulting in persistent neuropathic pain. This review aims to provide an overview of inflammatory mechanisms at differing levels of the sensory neuroaxis with a focus on neuropathic pain. We will compare and contrast neuropathic pain states such as traumatic nerve injury which is associated with a vigorous inflammatory response and chemotherapy induced pain in which the inflammatory response is much more modest. Targeting excessive inflammation in neuropathic pain provides potential therapeutic opportunities and we will discuss some of the opportunities but also the clinical challenges in such an approach.

MicroRNA-based therapy in pain medicine: Current progress and future prospects.

MicroRNAs (miRNAs) are small noncoding RNA molecules of 18-25 nucleotides in length that regulate gene expression involved in fundamental cell processes. The induction and chronification of pain is associated with many expressional changes in pain-related proteins. miRNA has the potential to regulate gene and protein expression associated with the induction and chronification of pain. Thus, miRNAs might have promise in therapy and as a diagnostic and prognostic biomarker in pain medicine. The application of miRNA has been an emerging field in pain research in recent years. Many studies focusing on the regulation of miRNAs under different tissue and nociceptive stimuli have been performed in recent years. In this review, we intend to introduce the most recent research in the field of miRNA related with pain medicine such as the expression and function of miRNA in different animal pain model, the challenge of application and delivery of miRNA in vivo, the potential toxic effects of miRNA and future problems in clinical application that need to be resolved. This review focuses on the results of miRNA in animal studies and the prospect for future success.

Gabapentin for the Management of Various Neuropathic Pain Syndromes / 대한마취과학회지

BACKGROUND: Anticonvulsant agents have been used and found to be effective for the treatment of neuropathic pain. Even though it is rare, they can have very serious side effects and therefore the search for more selective drugs with fewer side effects is justified. This study was conducted to evaluate the newly introduced anticonvulsants, gabapentin, for various neuropathic pain syndromes in the Korean population. METHODS: According to individual diagnostic group as diabetic neuropathy, postherpetic neuralgia, chronic back pain with radiating pain, there were 20 patients per group. Patients have been stabilized in their analgesic regimen at least four weeks prior to enrollment in the study. An anticonvulsant, if taken, was discontinued for four weeks for wash-out. Pretreatment baseline pain scores (visual analog scale and a pain intensity score) were obtained. Oral administration of gabapentin 300 mg was initiated in all groups and doses were given from 300 mg per day with gradual titration over two weeks 1) to the maximum of 2400 mg per day, 2) to the onset of intolerable side effects, and 3) to the onset of analgesic effect. At two weeks follow-up visit, visual analog scale, pain intensity scores, pain improvement scores judged by family, drug efficacy, tolerability and overall evaluation were assessed. The incidence of side effects, cell blood count and chemistry were also obtained. RESULTS: After two weeks of treatment, the visual analog scale and pain intensity scores improved in all study groups and no patients experienced aggravation. These findings were objectively reflected in pain improvement scores observed by family members. In drug efficacy, tolerability and overall evaluation, the majority of patients scored as good or excellent. There were no reports of serious side effects. Minor side effects were spontaneously subsided even with continuation. CONCLUSIONS: Gabapentin, a newer anticonvulsant, appears to be effective as an adjunctive analgesic for the management of various neuropathic pain syndromes with minimal side effects.