Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations

Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018. The main inclusion criteria were chronic neuropathic pain for at least three months, a randomized controlled methodology, at least three weeks of follow-up, at least 10 patients per group, and a double-blind design for drug therapy. Based on the GRADE system, we provide weak-to-strong recommendations for use and proposal as a first-line treatment for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a second-line treatment for pregabalin, tramadol, combination therapy (antidepressant combined with gabapentinoids), and for high-concentration capsaicin patches and botulinum toxin A specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recommended as a second-line therapy, as an add-on to other therapies. An algorithm encompassing all the recommended treatments is proposed.

Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations.

Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018. The main inclusion criteria were chronic neuropathic pain for at least three months, a randomized controlled methodology, at least three weeks of follow-up, at least 10 patients per group, and a double-blind design for drug therapy. Based on the GRADE system, we provide weak-to-strong recommendations for use and proposal as a first-line treatment for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a second-line treatment for pregabalin, tramadol, combination therapy (antidepressant combined with gabapentinoids), and for high-concentration capsaicin patches and botulinum toxin A specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recommended as a second-line therapy, as an add-on to other therapies. An algorithm encompassing all the recommended treatments is proposed.

Elastin expression in very severe human COPD.

Alveolar elastic fibres are key targets of proteases during the pathogenesis of chronic obstructive pulmonary disease (COPD). In the current study, we hypothesised that a response to injury leads to enhanced alveolar elastin gene expression in very severe COPD. Lung samples obtained from 43 patients, including 11 with very severe COPD (stage 4), 10 donors, 10 with moderate/severe COPD (stage 2-3) and 12 non-COPD subjects, were analysed for elastin mRNA expression by real-time RT-PCR and in situ hybridisation. Alveolar elastic fibres were visualised using Hart's staining of sections of frozen inflated lungs obtained from 11 COPD stage 4 patients and three donor lungs. Compared with donors, non-COPD and stage 2-3 COPD, elastin mRNA expression was significantly increased in very severe COPD lungs (12-fold change), and localised in situ hybridisation induced elastin expression to alveolar walls. Compared with donors, alveolar elastic fibres also comprised a greater volume fraction of total lung tissue in very severe COPD lungs (p<0.01), but elastic fibre content was not increased per lung volume, and desmosine content was not increased. The present study demonstrates enhanced alveolar elastin expression in very severe COPD. The efficiency of this potential repair mechanism and its regulation remain to be demonstrated.

Determination of phenols in lake and ground water samples by stir bar sorptive extraction-thermal desorption-gas chromatography-mass spectrometry.

A simple and inexpensive method for sorptive extraction of phenols from water samples is presented. A polydimethyl siloxane (PDMS) stir bar (Twister) is used as an extraction medium for derivatized phenols, which is thermally desorbed and analyzed by gas chromatography-mass spectrometry (GC-MS). Its performance was illustrated and evaluated for the enrichment of microg l(-1) to ng l(-1) of phenol and selected chlorophenols in water samples. The method showed good linearity, recoveries and blank levels, as well as advantages such as sensitivity, simplicity, low cost and high feasibility, being successfully applied for the analysis of phenolic compounds in natural water samples.

Disturbances in the peripheral T-cell repertoire of patients with motor neuron disease: high levels of activation and indirect evidence of superantigen.

Our data on peripheral blood T cells from Motor neuron disease (MND) patients indicate major immunological disturbances linked to this disease. Both CD4+ and CD8+ T-cell subsets display an increased fraction of cells showing activation markers compared to controls, indicating an unusually high level of activity in both populations. Likewise, an increased number of T-cell expansions were noted in MND patients compared to controls, most dramatically observed in the CD4+ T-cell subset, where 5/144 T-cell V genes analyzed in eight subjects turned out to be expanded in the peripheral blood. In the CD8+ T-cell subset, four out of eight MND patients had peripheral BV gene expansions, 9/144 V genes analyzed. However, the most interesting result was the observation that in three out eight MND patients, expansions concerning the same BV gene were present in both CD4+ and CD8+ subsets (BV8S1 in two and BV12S1 in one patient). Parallel expansions of BV-gene restricted populations in both CD4+ and CD8+ subsets in the same individual, in an major histocompatibility complex (MHC)-unrestricted manner, are normally limited to situations where superantigens are involved. No known superantigen has to date been described with the capacity to simultaneously stimulate both BV8S1 and BV12S1, suggesting that the postulated 'MND-associated' superantigen is a hitherto undefined molecule.

[Treatment of peripheral arterial thromboembolic occlusions using a new percutaneous mechanical thrombectomy system]. / Behandlung peripherer arterieller Thrombembolien durch ein neuartiges perkutanes mechanisches Thrombektomiesystem.

PURPOSE: We report our experience with a new percutaneous thrombectomy device for the treatment of thromboembolic occlusions of peripheral arteries. MATERIAL AND METHODS: Between November 1999 and May 2000 12 patients (10 male) with thromboembolic occlusions of peripheral arteries were treated. 8 occlusions were located in the femoral and popliteal arteries, 3 in the infrapopliteal vessels and 1 in the brachial artery. In all cases a new 6 F-catheter with a rotational screw and a suction vacuum unit was used. RESULTS: The intervention was successful in 11 patients. 1 patient with a failed procedure had a duration of occlusion > 90 days. There were no complications. All patients were discharged on the same or the following day. CONCLUSION: Percutaneous treatment with the thrombectomy device is a feasible option in a small group of patients with thromboembolic occlusions of the peripheral arteries. Often additional treatment is necessary. The major indication seems to be acute thrombosis. The procedure is easy and safe to apply.

Fatal toxic epidermal necrolysis related to lamotrigine administration.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe life-threatening dermatologic conditions. To date, eight cases of TEN and one of SJS related to lamotrigine administration have been reported in the literature. Most patients were also taking concomitant valproic acid. It was hypothesized that valproic acid may interfere with glucuronidation of lamotrigine, leading to increased serum lamotrigine levels, or perhaps alter the drug's metabolism, resulting in accumulation of a toxic intermediate metabolite. Ultimately, this may possibly predispose a patient to increased dermatologic reactions, including TEN. A 54-year-old man developed TEN 4 weeks after beginning lamotrigine for complex partial seizures related to a glioblastoma multiforme brain tumor. The patient had also been taking concomitant allopurinol and captopril for more than 4 years with no complications, and valproic acid 3 months before the cutaneous event. Despite aggressive intensive care management, the patient died 17 days from the onset of symptoms due to multiple organ failure. Administration of lamotrigine, especially in combination with valproic acid, may lead to the development of TEN.

[Improved knowledge resulted in better care of ALS]. / Kunskapslyft har medfört bättre vård vid ALS.

An example of the substantial advances in the management and treatment of patients with amyotrophic lateral sclerosis (ALS) in recent years is the introduction in 1996 of Riluzole, the first drug with verified effect on the disease course. The article consists in a review of recent advances in our knowledge of the pathogenic mechanisms, diagnosis, management and treatment of ALS.

Sudden death due to metronidazole/ethanol interaction.

Metronidazole (Flagyl), a commonly prescribed antimicrobial agent, can produce a reaction similar to that of disulfiram (Antabuse) when administered to patients drinking ethanol. This drug/chemical interaction results in accumulation of acetaldehyde in the blood. Acetaldehyde is hepatotoxic, cardiotoxic, and arrythmogenic; no lethal serum acetaldehyde level has been established. Sudden death has been reported in patients taking disulfiram while using ethanol; no fatalities have been reported due to ethanol/ metronidazole interactions. Described is a case of a 31-year-old woman who died moments after an assault by a male companion, during which he inflicted minor physical trauma to her upper arm. Toxicologic analysis yielded elevated concentrations of serum ethanol (162 mg/d), acetaldehyde (4.6 mg/d), and metronidazole (0.42 mg/L). The cause of death was reported to be cardiac dysrhythmia due to acetaldehyde toxicity due to an ethanol/ metronidazole interaction. Autonomic stress associated with the assault is likely to have contributed to this woman's death. The mechanism of death is examined.

Pitfalls in the evaluation of isometric strength (TQNE) data in ALS.

The phase of rapid reduction of isometric strength in single muscle groups was identified and its slope was calculated in patients studied with the TQNE method. This parameter was studied in the extremities and in respiration in 4 ALS patients and 4 PMA (progressive spinal muscle atrophy) patients. The slopes of the strength reduction in these muscle groups and their mean values exceeded the slopes of the corresponding megascores; this difference was larger in the extremities than in respiration. It is concluded that repeated spirometry gives a good expression of reduction of muscle strength ir ALS, and is well suited for monitoring treatment effects.

Firearm-related hunting fatalities in North Carolina: impact of the 'Hunter Orange' Law.

In the decade spanning 1983 through 1992, 68 people were killed by firearms while hunting in North Carolina (average of 1.66 fatalities/100,000 licenses issued). Of these, 58 deaths involved two parties, a shooter and a victim. In 22% of the incidents the victims were mistaken for game. During the 1987-1988 hunting season a "Hunter Orange" law was initially enforced. This law requires sportsmen to wear an article of bright orange clothing while hunting. After enactment of this law, a reduction in the incidence of hunters being killed because they were "mistaken for game" has proven statistically significant. The present study documents that legally mandating bright orange clothing has resulted in fewer firearms-related fatalities due to the victim's being mistaken for game while hunting. The North Carolina experience implies that governmental intervention can influence the incidence of accidental deaths during recreational hunting.

Dyadic deaths involving Huntington's disease: a case report.

Huntington's disease is a hereditary neurodegenerative disorder characterized by involuntary choreiform movements and progressive dementia. Although controversy exists regarding the exact risk of suicide in patients with Huntington's chorea, the literature supports an increased risk of suicide, especially in the early stages of this disease. We describe a case of homicide-suicide involving a father and son. The 60-year-old father, the homicide victim, suffered from advanced Huntington's disease; his 30-year-old son, the assailant, had a history of depression but had not been diagnosed with Huntington's disease at the time of his suicide. The psychiatric implications of this dementing disease, including the risk of suicide, are discussed. The gross, histologic, and molecular genetic features of this neurodegenerative disease are also described. The recognition of this autosomal dominantly inherited disorder at autopsy can make a profound impact on the lives of surviving family members.

Outcome of Sturge-Weber syndrome in 52 adults.

Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by cutaneous facial angioma, leptomeningeal angioma associated with seizures and other neurologic complications including mental retardation, and glaucoma. Only limited information about long-term outcome, including the societal integration of adult patients, is available in the literature. Data on 52 adults with SWS, ages 18-63 years, ascertained through the Sturge-Weber Foundation, were obtained via written questionnaires, telephone interviews, and reviews of medical records. The distribution of port-wine stains (cranial 98%, extracranial 52%) and the prevalences of glaucoma (60%), seizures (83%), neurologic deficit (65%), and other complications were established. The age of onset of glaucoma (0-41 years), the age of onset of seizures (0-23 years), and the correlation between the distribution of port-wine stains and the prevalence of seizures was identified. The relationship between the age of onset of seizures and seizure control was established. In those with and without seizures, the prevalences of developmental delay (43% vs. 0%), emotional and behavior problems (85% vs. 58%), special education requirements (71% vs. 0%), and employability (46% vs. 78%) were analyzed. Overall, 39% were financially self-sufficient, and 55% were or could be married. Ten participants produced 20 liveborn offspring; 17 were healthy, and tuberous sclerosis, a café-au-lait spot, and a "birthmark" were found in 1 child each. The results of this study can be used for genetic counseling in Sturge-Weber syndrome.

[Videofluoroscopy in the examination of swallowing disorders. A useful method for evaluation of rehabilitation]. / Videofluoroskopi for undersøkelse av svelgevansker. En nyttig undersøkelsesmetode innen rehabilitering.

This article presents a protocol for videofluoroscopy based upon the literature and on four years of practical experience in a rehabilitation hospital from evaluation and treatment of dysphagia in patients with cerebral vascular and/or traumatic head injury. The protocol includes a description of clinical evaluation, necessary equipment and personnel. It also describes the types of food and liquids used, the positioning of the patient, the compensatory and therapeutic techniques which may be tested during the study, and the evaluation and reporting of results. During rehabilitation, patients with swallowing disorders can receive specific and practical advice on food intake, based on the results of videofluoroscopy.

Sturge-Weber syndrome: age of onset of seizures and glaucoma and the prognosis for affected children.

Data were obtained on 171 individuals with Sturge-Weber syndrome via questionnaire and medical records. The age of the study group ranged from 2 months to 59 years; the median was 8 years. In addition to the facial location of port-wine stains in the areas of the trigeminal dermatomes present in 170 patients, 45% also had extracranial port-wine stains over the torso and/or extremities, and 17% had other vascular or pigmentary lesions. Seizures were present in 80% of all patients (87% of those with bilateral and 71% of those with unilateral port-wine stains); in all but one case, seizures were associated with port-wine stains in V1 alone or V1 and V2 trigeminal dermatomes location. The age of onset of seizures ranged from birth to 23 years; 75% had onset of seizures before 1 year of age; these children had an 83% incidence of developmental and academic problems. Fifty-eight percent showed early developmental delay and required special education classes. The rate of retardation showed a decreasing tendency with increasing age of onset of seizures; of the children without seizures, only 6% had developmental delay and 11% required special education classes. Glaucoma was present in 48% of patients (67% unilateral and 33% bilateral). Of all patients with glaucoma, 92% had port-wine stains in both V1 and V2 dermatomes and 8% only in V1. The laterality of glaucoma did not correspond to the trigeminal distribution of the port-wine stains in all instances. Glaucoma was diagnosed during the 1st year of life in 61% and by 5 years in 72%; one patient did not have onset of symptoms until 38 years. The results of our data can serve as a guide for estimating relative risk figures for seizures, glaucoma, and mental retardation in children with Sturge-Weber syndrome.

Suicidal cyanide ingestion as detailed in Final Exit.

Final Exit is an "informational aid" advocating the practice of active euthanasia and describing the proper method for the foolproof commission of suicide. Although it has been directed toward assisting the terminally ill patient who desires to terminate suffering, it has been suggested that the widespread availability of this book may result in its abuse. Specifically, there is growing concern that "do-it-yourself suicide manuals" could bring about the fruition of suicidal ideations that are relatively common among mentally ill patients and impressionable adolescents. Described is the suicidal ingestion of cyanide by a physically healthy 30-year-old man. His diary, found next to the body, contains a recipe for suicide copied verbatim from Derek Humphry's Final Exit. Although the decedent's history, the scene investigation, and the external examination strongly suggest an underlying psychiatric disorder, postmortem examination disclosed minimal underlying physical disease. This case graphically illustrates the abuse potential of this literary genre. To our knowledge, this is the first case of its kind to appear in the literature. We recommend that forensic pathologists and medical investigators familiarize themselves with the methods of suicide described in Final Exit.