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.

Management of neuropathic pain induced by surgery: Review of the literature by a group of experts specialized in pain management, anesthesia and surgery.

Chronic postsurgical neuropathic pain (CPSNP) is frequent. While prevalence varies considerably according to type of operation and means of evaluation, it can reach 37% following breast surgery. Identification of risk factors related to the procedure and to the patient and taking into account the development of new, minimally invasive surgical techniques is increasingly nerve-sparing and reduces the likelihood of injury. CPSNP diagnosis in daily practice is facilitated by simple and quickly usable tools such as the NP4 4-question test. Management is based on pharmacological (analgesics, antiepileptics, antidepressants, local anesthetics) and non-pharmacological (kinesitherapy, neurostimulation, psychotherapy) approaches. In light of the present review of the literature, the authors, who constitute an expert group specialized in pain management, anesthesia and surgery, express their support for topical treatments (lidocaine, capsaicin) in treatment of localized postsurgical neuropathic pain in adults.

Dextromethorphan Analgesia in a Human Experimental Model of Hyperalgesia.

BACKGROUND: Central pain sensitization is often refractory to drug treatment. Dextromethorphan, an N-methyl-D-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models. The hypothesis is that dextromethorphan is also antihyperalgesic in humans. METHODS: This randomized, double-blind, placebo-controlled, crossover study explores the antihyperalgesic effect of single and repeated 30-mg dose of oral dextromethorphan in 20 volunteers, using the freeze-injury pain model. This model leads to development of primary and secondary hyperalgesia, which develops away from the site of injury and is associated with central sensitization and activation of N-methyl-D-aspartate receptor in the spinal cord. The primary outcome was antihyperalgesia calculated with the area under the curve of the percentage change in mechanical pain threshold (electronic von Frey) on the area of secondary hyperalgesia. The secondary outcomes were mechanical pain threshold on the area of primary hyperalgesia and cognitive (reaction time) effect. RESULTS: Single 30-mg results are reported. Antihyperalgesia (% · min) is significantly higher on the area of secondary hyperalgesia with dextromethorphan than placebo (median [interquartile range]: 3,029 [746; 6,195] vs. 710 [-3,248; 4,439], P = 0.009, Hedge's g = 0.8, 95% CI [0.1; 1.4]). On primary hyperalgesia area, mechanical pain threshold 2 h after drug intake is significantly higher with dextromethorphan (P = 0.011, Hedge's g = 0.63, 95% CI [0.01; 1.25]). No difference in antinociception is observed after thermal painful stimuli on healthy skin between groups. Reaction time (ms) is shorter with placebo than with dextromethorphan (median [interquartile range]: 21.6 [-37.4; 0.1] vs. -1.2 [-24.3; 15.4], P = 0.015, Hedge's g = 0.75, 95% CI [0.12; 1.39]). Nonserious adverse events occurrence (15%, 3 of 20 volunteers) was similar in both groups. CONCLUSIONS: This study shows that low-dose (30-mg) dextromethorphan is antihyperalgesic in humans on the areas of primary and secondary hyperalgesia and reverses peripheral and central neuronal sensitization. Because dextromethorphan had no intrinsic antinociceptive effect in acute pain on healthy skin, N-methyl-D-aspartate receptor may need to be sensitized by pain for dextromethorphan to be effective.

In-vivo three-dimensional measurement of distal radioulnar joint translation in normal and clinically unstable populations.

UNLABELLED: Assessment of distal radioulnar joint instability is clinically difficult and subjective. The distal radioulnar joint is postulated to 'tighten' in ulnar/radial deviation and pronation/supination. Using a rig, we measured mean distal radioulnar joint translation in neutral forearm rotation and neutral wrist radial and ulnar deviation, as well as extremes of wrist radial and ulnar deviation and forearm rotation. We tested the rig on ten cadaver forearms to validate the measurements we made. We tested 50 normal adults and 50 patients with clinical distal radioulnar joint instability. Distal radioulnar joint stability in men and women and on contralateral sides were comparable. Distal radioulnar joint translation decreased significantly with wrist radial and ulnar deviation and forearm pronation and supination, matching clinical practice and further validating the rig. The data in normal patients is comparable with previous computed tomography-based studies. Translation in all positions was statistically increased within the clinical instability group and did not cross-over with the normal ranges. Distal radioulnar joint translation is a physically measurable phenomenon. Our device appears to be a valid test of distal radioulnar joint translation, establishing normal data in vivo. LEVEL OF EVIDENCE: III.

Functional dysbiosis within the gut microbiota of patients with constipated-irritable bowel syndrome.

BACKGROUND: The role of the gut microbiota in patho-physiology of irritable bowel syndrome (IBS) is suggested by several studies. However, standard cultural and molecular methods used to date have not revealed specific and consistent IBS-related groups of microbes. AIM: To explore the constipated-IBS (C-IBS) gut microbiota using a function-based approach. METHODS: The faecal microbiota from 14 C-IBS women and 12 sex-match healthy subjects were examined through a combined strictly anaerobic cultural evaluation of functional groups of microbes and fluorescent in situ hybridisation (16S rDNA gene targeting probes) to quantify main groups of bacteria. Starch fermentation by C-IBS and healthy faecal samples was evaluated in vitro. RESULTS: In C-IBS, the numbers of lactate-producing and lactate-utilising bacteria and the number of H(2) -consuming populations, methanogens and reductive acetogens, were at least 10-fold lower (P < 0.05) compared with control subjects. Concomitantly, the number of lactate- and H(2) -utilising sulphate-reducing population was 10 to 100 fold increased in C-IBS compared with healthy subjects. The butyrate-producing Roseburia - E. rectale group was in lower number (0.01 < P < 0.05) in C-IBS than in control. C-IBS faecal microbiota produced more sulphides and H(2) and less butyrate from starch fermentation than healthy ones. CONCLUSIONS: A major functional dysbiosis was observed in constipated-irritable bowel syndrome gut microbiota, reflecting altered intestinal fermentation. Sulphate-reducing population increased in the gut of C-IBS and were accompanied by alterations in other microbial groups. This could be responsible for changes in the metabolic output and enhancement in toxic sulphide production which could in turn influence gut physiology and contribute to IBS pathogenesis.

Acetaminophen metabolism after major surgery: a greater challenge with increasing age.

Patients undergoing major surgery represent a good model for the study of the hepatic metabolism of acetaminophen (APAP) after surgery and for the evaluation of how the detoxification process is influenced by aging. Thirty patients received intravenous APAP (1 g/6 h) for 4 days (D1-D4). Daily 24-h urinary metabolites-cysteine-APAP, mercapturate-APAP, APAP, and glucuronide and sulfate conjugates-as well as blood glutathione levels were compared with repeated-measures analysis of variance (significance, P<0.05). Between D1 and D4, cysteine-APAP increased (308±308 mg vs. 570±512 mg, P=0.005), and sulfate and glucuronide conjugates decreased (1,365±1,084 mg vs. 694±600 mg, P<0.0001 and 2,418±817 mg vs. 1,513±1,076 mg, P=0.011, respectively). Blood glutathione decreased (790±125 vs. 623±132 µmol/l, P<0.0001. These changes increased with aging. APAP disposition after major surgery shifts toward the oxidative pathways of metabolism, and this is enhanced with aging. Supplementation with sulfur-containing amino acids should be investigated further as it might minimize the effect on antioxidant defenses, especially in older persons undergoing more extensive surgical procedures.

Reliability study in five languages of the translation of the pain behavioural scale Doloplus.

Non-verbal pain assessment scales are useful tools for pain evaluation in persons with communication disorders and moderate-severe dementia. The Doloplus was one of the first scales to be developed and validated as a pain assessment tool in older adults with dementia. This study aims at evaluating the translation of the Doloplus scale in five languages, as regards test-retest and inter-rater reliability. Results show that both tests are good or excellent for the English, Italian, Portuguese and Spanish versions and moderate for the Dutch version. These results bring a unique opportunity to include the translated Doloplus scale in daily assessment of elderly persons with communication disorders, and future studies should focus on enriching the validation of the scale in each language.

Optimizing the sensory characteristics and acceptance of canned cat food: use of a human taste panel.

A methodology based on descriptive analysis techniques used in the evaluation of human food has been successfully refined to allow for a human taste panel to profile the flavour and texture of a range of cat food products (CFP) and their component parts. Included in this method is the development of evaluation protocols for homogeneous products and for binary samples containing both meat chunk (MC) and gravy/gel (GG) constituents. Using these techniques, 18 flavour attributes (sweet, sour/acid, tuna, herbal, spicy, soy, salty, cereal, caramel, chicken, methionine, vegetable, offaly, meaty, burnt flavour, prawn, rancid and bitter) and four texture dimensions (hardness, chewiness, grittiness and viscosity) were generated to describe the sensations elicited by 13 commercial pet food samples. These samples differed in intensity for 16 of the 18 flavour attributes, which allows for individual CFP flavour profiles to be developed. Principal components analysis (PCA) could successfully discriminate between samples within the PCA space and also reveal some groupings amongst them. While many flavour attributes were weakly correlated, a large number (describing both taste and retro-nasal aroma qualities) were required to adequately differentiate between samples, suggesting considerable complexity in the products assessed. For both MC and GG, differences between samples for each of the texture dimensions were also found. For MC, grittiness appears to be the most discriminating textural attribute, while for GG viscosity discriminates well between samples. Meat chunks and gravy/gels differed significantly from each other in both flavour and texture. Cat food products differed in their liking ratings, although no differences were found between homogeneous, MC and GG samples, and eight flavour attributes were correlated with overall liking scores. It is now necessary to determine the usefulness and limits of sensory data gathered from human panels in describing and predicting food acceptance and preference behaviours in cats. For instance, while the sense of taste in cats appears generally similar to that of other mammals, they lack a sweet taste receptor (Li et al., 2006), which may limit the applicability of sweetness ratings obtained from humans. Modification of existing techniques used with human food research, such as external preference mapping (Naes and Risvik, 1996) may be useful. Ultimately, this may facilitate more economical and efficient methods for optimizing cat food flavour and texture and predicting the effects of composition and processing changes on cat feeding behaviour. This will require collaboration between pet food manufacturers and nutritionists, animal behaviourists and human sensory scientists. The results of this preliminary study should assist in this process.

Quantitative analysis of 3-alkyl-2-methoxypyrazines in juice and wine using stable isotope labelled internal standard assay.

A solid phase microextraction (HS-SPME)-GC-MS methodology was established for the analysis of 3-alkyl-2-methoxypyrazines (MPs) in wine using a stable isotope dilution assay. The compounds analysed were 3-isobutyl-2-methoxypyrazine (IBMP), 3-sec-butyl-2-methoxypyrazine (SBMP), and 3-isopropyl-2-methoxypyrazine (IPMP) using their respective deuterated analogues ([2H3]-IBMP, [2H3]-SBMP, [2H3]-IPMP) as internal standards, synthesised during this work. A divinylbenzene/carboxene/polydimethylsiloxane (DVB/CAR/PDMS) fibre was selected for isolation of MPs and the effects of matrix parameters such as pH and ethanol concentration were examined in the development of the method. Best results were obtained at a pH of approximately 6 and with a wine dilution factor of 1:2.5, resulting in an ethanol concentration of approximately 5% (v/v). Relative standard deviations (RSDs) of replicate samples were 5.6-7% for all MPs at 5 ng L(-1) and <5% for 15 and 30 ng L(-1) samples. The limit of detection was <0.5 ng L(-1) in juice and 1-2 ng L(-1) in wine. The recovery efficiencies for spiked wine samples were between 99 and 102% for all three MPs. Using this method, we investigated the impact of the Multicoloured Asian Lady Beetle (MALB) on MPs in wine. In red wine fermented with live MALB, IPMP is the most prevalent MP detected, although SBMP concentrations are also increased and IBMP is unchanged from background levels. MALB that have been dead for 1 day before addition to juice can still contribute to elevated SBMP concentrations in wine, but not if they have been dead for 3 days or longer. Clarifying juice prior to fermentation leads to substantially lower IPMP concentration in the subsequent wine when compared with unclarified juice.

Detection thresholds for 2-isopropyl-3-methoxypyrazine in Concord and Niagara grape juice.

2-isopropyl-3-methoxypyrazine (IPMP) is the compound responsible for the off-flavor known as ladybug taint, which occurs when Harmnonia axyridis beetles become incorporated with the grapes during juice processing. It is also an important grape-derived component of juice flavor in some varieties. The main objective of this study was to determine the orthonasal (ON) and retronasal (RN) detection thresholds for IPMP in juice. The ASTM E679 ascending forced choice method of limits was used to determine detection thresholds for 26 individuals in Concord and Niagara juices. Group best estimate thresholds (BETs) averaged 0.93 ng/L and were 50% and 21% higher in Concord than in Niagara juices for ON and RN evaluation, respectively. Group BETs for IPMP (ng/L) for Concord were ON: 1.11; RN: 1.02 and for Niagara were ON: 0.74; RN: 0.84. Variation in individual detection thresholds was observed, although familiarity with ladybug taint was not associated with individual threshold values. We conclude that humans are very sensitive to IPMP in juice, and that detection thresholds are more strongly influenced by grape variety than evaluation mode. These results may assist juice producers in establishing tolerance levels for IPMP in juice affected by ladybug taint or derived from grapes of suboptimal ripeness.

Acetaminophen reinforces descending inhibitory pain pathways.

The mechanism of the analgesic action of acetaminophen involves the serotonergic system. This study explores how acetaminophen interferes with serotonergic descending pain pathways. Eighteen rapid metabolizers of tropisetron were included in this double-blind cross-over study. After ethical approval, the healthy volunteers took 1 g oral acetaminophen (A) or placebo (p) combined with either the 5-HT3 antagonist tropisetron (T) (5 mg) or saline, intravenously, at weekly intervals. Mechanical pain thresholds, determined before and after a cold pressor test (CPT), were repeated seven times during the three post-dosing hours, and area under the concentration-time curves (AUCs) of the three treatments were compared. After CPT, AUC (%*min) of Ap (1,561+/-429) was larger than before CPT (393+/-382, P<0.05); these effects were totally inhibited by tropisetron. Acetaminophen reinforces descending inhibitory pain pathways; it suggests a supraspinal target for acetaminophen's antinociceptive action. This study also confirmed that there is a central serotonergic mechanism of action for acetaminophen that is not stimulus-dependent.

Determination of ortho- and retronasal detection thresholds for 2-isopropyl-3-methoxypyrazine in wine.

2-Isopropyl-3-methoxypyrazine (IPMP) is a grape-derived component of wine flavor in some wine varieties as well as the causal compound of the off-flavor known as ladybug taint (LBT), which occurs when Harmonia axyridis beetles are incorporated with the grapes during juice and wine processing. The main objective of this study was to obtain robust estimates of the orthonasal (ON) and retronasal (RN) detection thresholds (DTs) for IPMP in wines of differing styles. The ASTM E679 ascending forced choice method of limits was used to determine DTs for 47 individuals in 3 different wines--Chardonnay, Gewürztraminer, and a red wine blend of Baco Noir and Marechel Foch. The group best estimate thresholds (BETs) obtained for IPMP (ng/L) were Chardonnay, ON: 0.32; Gewürztraminer, ON: 1.56, RN: 1.15, and red wine blend, ON: 1.03, RN: 2.29. A large variation in individual DTs was observed. Familiarity with LBT was inversely correlated with DTs for Gewürztraminer, and no difference in thresholds was observed between winemakers and nonwinemakers. We conclude that the human DT for IPMP is extremely low and influenced significantly by wine style and evaluation mode. We recommend against the reporting of single-threshold values for wine flavor compounds, and encourage the determination of consumer rejection thresholds for IPMP in wine.

Frail elderly, nutritional status and drugs.

This review focuses on the interactions between nutritional status and drugs in frail elderly persons. Impairment of nutritional status, a component of clinical presentation in the frail elderly, has a major impact on the pharmacology of many drugs devolving from the physiological alterations it generates. Food itself plays a central role in nutritional status and in possible interactions with drugs. Conversely, drugs have often, directly and indirectly, a deleterious effect on the nutritional state of the elderly. However, research in this domain is scarce, and future clinical studies will need to include more elderly and frail elderly individuals, to help clinicians to better understand these interactions.

Role of spinal NMDA receptors, protein kinase C and nitric oxide synthase in the hyperalgesia induced by magnesium deficiency in rats.

1. Magnesium (Mg)-deficient rats develop a mechanical hyperalgesia which is reversed by a N-Methyl-D-Aspartate (NMDA) receptor antagonist. Given that functioning of this receptor-channel is modulated by Mg, we wondered whether facilitated activation of NMDA receptors in Mg deficiency state may in turn trigger a cascade of specific intracellular events present in persistent pain. Hence, we tested several antagonists of NMDA and non-NMDA receptors as well as compounds interfering with the functioning of intracellular second messengers for effects on hyperalgesia in Mg-deficient rats. 2. Hyperalgesic Mg-deficient rats were administered intrathecally (10 microl) or intraperitoneally with different antagonists. After drug injection, pain sensitivity was evaluated by assessing the vocalization threshold in response to a mechanical stimulus (paw pressure test) over 2 h. 3. Intrathecal administration of MgSO4 (1.6, 3.2, 4.8, 6.6 micromol) as well as NMDA receptor antagonists such as MK-801 (0.6, 6.0, 60 nmol), AP-5 (10.2, 40.6, 162.3 nmol) and DCKA (0.97, 9.7, 97 nmol) dose-dependently reversed the hyperalgesia. Chelerythrine chloride, a protein kinase C (PKC) inhibitor (1, 10.4, 104.2 nmol) and 7-NI, a specific nitric oxide (NO) synthase inhibitor (37.5, 75, 150 micromol x kg(-1), i.p.) induced an anti-hyperalgesic effect in a dose-dependent manner. SR-140333 (0.15, 1.5, 15 nmol) and SR-48968 (0.17, 1.7, 17 nmol), antagonists of neurokinin receptors, produced a significant, but moderate, increase in vocalization threshold. 4. These results demonstrate that Mg-deficiency induces a sensitization of nociceptive pathways in the spinal cord which involves NMDA and non-NMDA receptors. Furthermore, the data is consistent with an active role of PKC, NO and, to a lesser extent substance P in the intracellular mechanisms leading to hyperalgesia.

Evaluation of the offer of physical activity for the elderly in a region of France.

The aim of this study was an evaluation of the possibilities of physical activity for the elderly in a region of France where 24% of the population is over 65 years old. It stressed the very poor level of physical activity in the community as well as in nursing homes. This situation is linked to a combination of factors: lack of interest, insufficient information and financial constraints. The 5-year plan we are developing in this region aims at the development of the practice of physical activity, to maintain as long as possible the autonomy and the quality of life of this growing elderly population.

[Impact of age on pain perception and analgesic pharmacology]. / Influence de l'âge sur la perception de la douleur et la pharmacologie des antalgiques.

INFLUENCE OF AGING ON PAIN: Although pain affects a large majority of the elderly population living in the community and in institutions, our knowledge of the evolution of pain experience with age is poor. Results of clinical surveys and experimental pain studies are contradictory, showing no change, an increase, or a decrease of pain with age. Many results suggest a decrease of pain perception with age that could be explained by peripheral and central neuroanatomical aging and psychological changes of the aging patient towards pain. INFLUENCE OF AGE ON THE PHARMACOLOGY OF ANALGESICS: Biological aging added to multiple pathologies and polymedication explains the pharmacological changes of analgesics. Among pharmacokinetic changes that are globally well known, vigilance must focus on renal excretion of analgesics and their metabolites and on the increased risk of side-effects and drug interactions. Information on pharmacodynamic changes of analgesics are scarce in aging patients who are susceptible to drugs and which demographical trend increases. PERSPECTIVES: A better fundamental knowledge of the evolution of pain with age could help to improve care in the elderly with pain, especially in very old subjects with cognitive impairment and loss of communication skills, where pain evaluation is particularly difficult. Also, more research is needed on the pharmacodynamics of analgesics in older subjects, with a view of a decreased iatrogenic risk, a better pain treatment and quality of life of the elderly.

Impact of pain on recreational activities of nursing home residents.

The high prevalence of pain in older adults in nursing homes and long-term care institutions is a challenging problem. Nursing home residents were questioned to evaluate whether pain might be an obstacle to their active participation in recreational activities, especially physical activities. This study shows that the intensity and daily experience of pain are both obstacles to participation in physical activities, especially in the oldest patients. The findings also show that participation is linked to the autonomy of the patient; more information about the benefits of physical activity, and coordinating efforts in this area are needed in order to help the elderly preserve their autonomy and quality of life.