Pharmacokinetic–Pharmacodynamic Modelling of Biomarker Response to Sitagliptin in Healthy Volunteers

Pharmacokinetic/pharmacodynamic (PK/PD) models can be useful tools in new drug development and also optimal drug therapy in patients. This study was designed to develop a PK/PD model of sitagliptin based on the physiology of incretin. The PK/PD data included information derived from two different studies. Study 1 was conducted as a one‐sequence, three‐period, repeated‐dose, dose escalation (sitagliptin 25, 50 and 100 mg q.d.) design in twelve healthy volunteers. Study 2 was a first‐in‐man study for the newly developed dipeptidyl peptidase‐4 (DPP‐4) inhibitor in healthy volunteers. In study 1, blood samples were collected to measure sitagliptin concentrations, DPP‐4 activity and active glucagon‐like peptide‐1 (GLP‐1) concentrations. In study 2, only data from the ‘placebo group’ were used, and blood samples were collected to measure DPP‐4 activity, active GLP‐1 concentrations and glucose concentrations. A PK/PD analysis was conducted using a non‐linear mixed effects modelling approach. Sitagliptin pharmacokinetics was modelled using a two‐compartment model with first‐order absorption. Changes in DPP‐4 inhibition were linked to the PK model using a sigmoid E_max model, whereas the active GLP‐1 changes were explained using an indirect response model; this model incorporated the glucose and DPP‐4 inhibition models. The PK/PD model developed adequately described the changes in sitagliptin concentration, DPP‐4 inhibition and active GLP‐1 concentration in healthy volunteers.     

Incorporating Physiological and Biochemical Mechanisms into Pharmacokinetic–Pharmacodynamic Models: A Conceptual Framework*

Abstract: The aim of this conceptual framework paper is to contribute to the further development of the modelling of effects of drugs or toxic agents by an approach which is based on the underlying physiology and pathology of the biological processes. In general, modelling of data has the purpose (1) to describe experimental data, (2a) to reduce the amount of data resulting from an experiment, e.g. a clinical trial and (2b) to obtain the most relevant parameters, (3) to test hypotheses and (4) to make predictions within the boundaries of experimental conditions, e.g. range of doses tested (interpolation) and out of the boundaries of the experimental conditions, e.g. to extrapolate from animal data to the situation in man. Describing the drug/xenobiotic‐target interaction and the chain of biological events following the interaction is the first step to build a biologically based model. This is an approach to represent the underlying biological mechanisms in qualitative and also quantitative terms, thus being inherently connected in many aspects to systems biology. As the systems biology models may contain variables in the order of hundreds connected with differential equations, it is obvious that it is in most cases not possible to assign values to the variables resulting from experimental data. Reduction techniques may be used to create a manageable model which, however, captures the biologically meaningful events in qualitative and quantitative terms. Until now, some success has been obtained by applying empirical pharmacokinetic/pharmacodynamic models which describe direct and indirect relationships between the xenobiotic molecule and the effect, including tolerance. Some of the models may have physiological components built in the structure of the model and use parameter estimates from published data. In recent years, some progress toward semi‐mechanistic models has been made, examples being chemotherapy‐induced myelosuppression and glucose‐endogenous insulin‐antidiabetic drug interactions. We see a way forward by employing approaches to bridge the gap between systems biology and physiologically based kinetic and dynamic models. To be useful for decision making, the ‘bridging’ model should have a well founded mechanistic basis, but being reduced to the extent that its parameters can be deduced from experimental data, however capturing the biological/clinical essential details so that meaningful predictions and extrapolations can be made.     

A Population Pharmacokinetic–Pharmacodynamic Meta‐Analysis of Vortioxetine in Patients with Major Depressive Disorder

Vortioxetine is approved for the treatment of major depressive disorder (MDD). This analysis aimed to develop pharmacokinetic (PK) and PK/Efficacy models to evaluate the exposure–response relationship for vortioxetine in patients with MDD. PK data from 10 MDD and two generalized anxiety disorder studies of vortioxetine (3160 patients), and efficacy data [Montgomery–Åsberg Depression Rating Scale (MADRS)] from seven MDD studies (2537 patients), were used for the development of PK and PK/Efficacy models. One‐ and two‐compartment models were evaluated as structural PK models, and linear and nonlinear (E_max) models were used to describe the relationship between average vortioxetine concentration at steady‐state (C_av) and change in MADRS score from baseline (ΔMADRS). The impact of selected covariates on the PK and efficacy parameters of vortioxetine was also investigated. PK of vortioxetine was best characterized by a two‐compartment model with first‐order absorption and elimination. Mean estimates for oral clearance (CL/F) and volume of distribution for the central compartment of vortioxetine were 42 L/hr and 2920 L. Creatinine clearance, height and geographic region had statistically significant effects on vortioxetine CL/F, but the effect of each of these covariates was not considered clinically relevant, as they lead to ±26% change in area under the curve or C_max of vortioxetine. An E_max model best described the relationship between ΔMADRS and C_av. Half‐maximal effective concentration (EC₅₀) and E_max estimates were 24.9 ng/mL and 7.0. No identified covariates, except region, had clinically meaningful effects on vortioxetine efficacy. These PK/Efficacy models adequately characterized the vortioxetine exposure–response relationship.     

Population Pharmacokinetic–Pharmacogenetic Model of Tacrolimus in the Early Period after Kidney Transplantation

As tacrolimus has a rather narrow therapeutic range and high individual variability in its pharmacokinetics, it is important to determine the cause of the variation in tacrolimus pharmacokinetics. The purpose of this study was to establish a population pharmacokinetic–pharmacogenetic model of tacrolimus and identify covariates that affect pharmacokinetic parameters to prevent fluctuations in the tacrolimus trough concentration during the early period after transplantation. Data from 1501 trough concentrations and 417 densely collected concentrations were compiled from 122 patients who were on post‐operative days 10–20 and analysed with a nonlinear mixed‐effect model. The first‐order conditional estimation (FOCE) with interaction method was used to fit the model using the NONMEM program. Clinical/laboratory data were also collected for the same period, and CYP3A5 and ABCB1 genotypes were analysed for use in modelling from all included patients. An empirical Bayesian approach was used to estimate individual pharmacokinetic profiles. A one‐compartment model with first absorption and elimination and lag time best described the data. The estimated population mean of clearance (CL/F), volume of distribution (V/F) and absorption rate (K_a) were 21.9 L/hr, 205 L, and 3.43/hr, respectively, and the lag time was fixed at 0.25 hr. Clearance increased with days after transplantation and decreased with CYP3A5*3/*3 about 18.4% compared with CYP3A5*1 carriers (p < 0.001). A population pharmacokinetic model was developed for tacrolimus in early post‐kidney transplantation recipients to identify covariates that affect tacrolimus pharmacokinetics. Post‐operative days and CYP3A5 genotype were confirmed as critical factors of tacrolimus pharmacokinetics.     

A型肉毒毒素对神经病理性疼痛大鼠镇痛作用及作用途径的研究

目的：观察A型肉毒毒素（BTX—A）对L5前根切断（L5 VRT）神经病理性疼痛模型大鼠的镇痛作用并探讨其最佳给药途径。方法：雄性SD大鼠108只,随机分为3组（n=36）,皮下注射给药组、坐骨神经表面给药组、坐骨神经注射给药组,制备L5 VRT模型,各组又分为术后4d给药组、术后8d给药组、术后16d给药组且同时各设0．9％氯化钠注射液对照组（n=6）,于术前、术后及术后不同给药时间测定50％撤足阈值（PWT）。结果：①皮下给药组能明显的改善机械痛敏,坐骨神经表面及坐骨神经注射给药组机械痛敏改善不明显。②皮下给药组术后各不同时间给药小组,均能明显的改善机械痛敏,与对照组相比有统计学意义（P〈0．05）;给药后第15天效果最明显;这种镇痛作用持续至少20余天。③坐骨神经表面及坐骨神经注射给药组动物的机械痛敏改善不明显,与对照组相比无统计学意义（P〉0．05）。结论：皮下注射BTX—A,能改善L5VRT模型大鼠的机械痛敏,有镇痛作用,且为最佳给药途径。     

Etodolac Attenuates Mechanical Allodynia in a Mouse Model of Neuropathic Pain

Cyclooxygenase (COX) contributes to neuropathic pain after peripheral nerve injury, yet COX inhibitors are generally ineffective against mechanical allodynia and hyperalgesia in neuropathic pain patients and animal models. In the present study, we investigated the effects of etodolac, a selective COX-2 inhibitor, on mechanical allodynia in mice after partial sciatic nerve ligation (PSNL) compared to indomethacin (a nonselective COX inhibitor) or celecoxib (a selective COX-2 inhibitor). PSNL decreased the paw-withdrawal threshold (PWT) as assessed by the von Frey hair test, and etodolac, but not indomethacin or celecoxib, administered daily for two weeks, partially or wholly reversed the decrease. The efficacy of etodolac gradually increased throughout the administration period, and the higher dosages restored preligation PWT values by day 21. The positive control pregabalin also partially or wholly reversed the decrease in PWT, but in contrast to etodolac, it showed no increase in efficacy throughout the administration period. In normal mice, etodolac did not affect the PWT, whereas pregabalin increased it. These findings suggest that the mechanisms of inhibition of mechanical allodynia by etodolac and pregabalin are different and demonstrate that in contrast to other COX inhibitors, etodolac is effective against mechanical allodynia in a mouse neuropathic pain model.     

Effect of Fluoxetine on an Experimental Model of Diabetes-induced Neuropathic Pain Perception in the Rat

The aim of the present study was to study the effect of chronic treatment (9 weeks) of fluoxetine (20 mg/kg p.o.) a selective serotonin reuptake inhibitor on blood glucose level and in prevention of diabetic neuropathic pain perception. Evaluation of diabetic neuropathy was performed after 9 weeks of single injection of streptozotocin (70 mg/kg i.v.) in rats. Blood glucose level, glycated haemoglobin, grip strength, pain sensitivity and threshold in diabetic rats were measured at the end of 9 weeks. The results of the present study indicate that the 9 weeks treatment of fluoxetine demonstrates hypoglycemic effect; it marked decreases the blood glucose level in diabetic treated animals. There was also decrease in the grip strength in diabetic rat indicates to induction of neuropathy or nerve damage. Fluoxetine increase the grip strength of diabetic rats. There was also found loss of pain perception in diabetes rats which measured using hot plate and tail flick methods. Fluoxetine increases the licking time and withdrawal latency in hot plate and tail flick test respectively indicates the presence of pain perception and prevention of nerve damage demonstrates its protective effect in diabetic neuropathy. Our study concludes the chronic treatment of fluoxetine significantly decreases the glycemic level as well as it protected from the development of diabetic neuropathy.     

Propiverine-Induced Parkinsonism: A Case Report and a Pharmacokinetic/Pharmacodynamic Study in Mice

Purpose. We present a case report of propiverine-inducedParkinsonism. We previously reported the induction of catalepsy by amiodarone,aprindine and procaine, which possess a diethylaminomethyl moietyand demonstrated selective blockade of dopamine D2 receptors bythese drugs in mice. We hypothesized that drugs possessing adiethylaminomethyl structure may generally induce Parkinsonism and/orcatalepsy. Methods. Thus, we performed a study to examine whether oxybutynin,pentoxyverine and etafenone, as well as propiverine, induce catalepsyin mice. Results. The intensity of drug-induced catalepsy was in the order:haloperidol > etafenone > pentoxyverine > propiverine > oxybutynin.In vivo occupancy of dopamine D₁, D₂ and mACh receptors in thestriatum was also examined. The in vitro binding affinities to the D₁,D₂ and mACh receptors in the striatum synaptic membrane were withinthe ranges of 2.4–140 M, 380–4,200 nM, and 1.2–2,800 nM, respectively. Conclusions. These results support the idea that any drug possessinga diethylaminomethyl moiety may contribute to the induction ofcatalepsy, possibly by occupying dopamine receptors.     

Preventive Effects of Bee Venom Derived Phospholipase A2 on Oxaliplatin-Induced Neuropathic Pain in Mice

Oxaliplatin, a chemotherapy drug used to treat colorectal cancer, induces specific sensory neurotoxicity signs that are aggravated by cold and mechanical stimuli. Here we examined the preventive effects of Bee Venom (BV) derived phospholipase A₂ (bvPLA₂) on oxaliplatin-induced neuropathic pain in mice and its immunological mechanism. The cold and mechanical allodynia signs were evaluated by acetone and von Frey hair test on the hind paw, respectively. The most significant allodynia signs were observed at three days after an injection of oxaliplatin (6 mg/kg, i.p.) and then decreased gradually to a normal level on days 7–9. The oxaliplatin injection also induced infiltration of macrophages and upregulated levels of the pro-inflammatory cytokine interleukin (IL)-1β in the lumbar dorsal root ganglia (DRG). Daily treatment with bvPLA₂ (0.2 mg/kg, i.p.) for five consecutive days prior to the oxaliplatin injection markedly inhibited the development of cold and mechanical allodynia, and suppressed infiltration of macrophages and the increase of IL-1β level in the DRG. Such preventive effects of bvPLA₂ were completely blocked by depleting regulatory T cells (Tregs) with CD25 antibody pre-treatments. These results suggest that bvPLA₂ may prevent oxaliplatin-induced neuropathic pain by suppressing immune responses in the DRG by Tregs.     

Analgesic Effects of Bee Venom Derived Phospholipase A2 in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain

A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various pain symptoms. Our recent study demonstrated that BV alleviates oxaliplatin-induced cold allodynia in rats, via noradrenergic and serotonergic analgesic pathways. In this study, we have further investigated whether BV derived phospholipase A₂ (bvPLA₂) attenuates oxaliplatin-induced cold and mechanical allodynia in mice and its mechanism. The behavioral signs of cold and mechanical allodynia were evaluated by acetone and a von Frey hair test on the hind paw, respectively. The significant allodynia signs were observed from one day after an oxaliplatin injection (6 mg/kg, i.p.). Daily administration of bvPLA₂ (0.2 mg/kg, i.p.) for five consecutive days markedly attenuated cold and mechanical allodynia, which was more potent than the effect of BV (1 mg/kg, i.p.). The depletion of noradrenaline by an injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 50 mg/kg, i.p.) blocked the analgesic effect of bvPLA₂, whereas the depletion of serotonin by injecting DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for three successive days did not. Furthermore, idazoxan (α2-adrenegic receptor antagonist, 1 mg/kg, i.p.) completely blocked bvPLA₂-induced anti-allodynic action, whereas prazosin (α1-adrenegic antagonist, 10 mg/kg, i.p.) did not. These results suggest that bvPLA₂ treatment strongly alleviates oxaliplatin-induced acute cold and mechanical allodynia in mice through the activation of the noradrenergic system, via α2-adrenegic receptors, but not via the serotonergic system.     

Botulinum Toxin for Neuropathic Pain: A Review of the Literature

Botulinum neurotoxin (BoNT), derived from Clostridium botulinum, has been used therapeutically for focal dystonia, spasticity, and chronic migraine. Its spectrum as a potential treatment for neuropathic pain has grown. Recent opinions on the mechanism behind the antinociceptive effects of BoNT suggest that it inhibits the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves. There is some evidence showing the axonal transport of BoNT, but it remains controversial. The aim of this review is to summarize the experimental and clinical evidence of the antinociceptive effects, mechanisms, and therapeutic applications of BoNT for neuropathic pain conditions, including postherpetic neuralgia, complex regional pain syndrome, and trigeminal neuralgia. The PubMed and OvidSP databases were searched from 1966 to May 2015. We assessed levels of evidence according to the American Academy of Neurology guidelines. Recent studies have suggested that BoNT injection is an effective treatment for postherpetic neuralgia and is likely efficient for trigeminal neuralgia and post-traumatic neuralgia. BoNT could also be effective as a treatment for diabetic neuropathy. It has not been proven to be an effective treatment for occipital neuralgia or complex regional pain syndrome.     

地佐辛减轻CCI大鼠神经病理性疼痛的实验研究

目的 通过建立坐骨神经慢性压迫性疼痛(Chronic constriction injury,CCI)模型大鼠,观察腹腔注射地佐辛的镇痛作用及其可能机制.方法 SD大鼠32只,随机分为假手术(Sham)组、模型(Model)组、地佐辛 2.5mg·kg-1(D1)组和地佐辛10mg·kg-1(D2)组等4组,每组8只,各组于手术后即刻至术后7天,每天腹腔注射1次药物,假手术组和模型组给予等体积的生理盐水.造模前和造模后1、3、5、7d观察各组大鼠的机械痛阈变化,于造模后7d免疫荧光组织化学法观测各组脊髓胶质纤维酸性蛋白(Glial Fibrillary Acidic Protein,GFAP)表达.结果 大鼠建模1天后,PWT显示CCI大鼠的机械痛阈均出现明显下降,模型组在3d时降到最低,地佐辛干预的D1组在3d对CCI大鼠的痛阈有所改善(P<0.05),随后改变不大,D2组对大鼠的痛阈有明显改善,在5d时提高最为明显(P<0.01),同时,可见7d时各组脊髓GFAP的表达有所区别,模型组GFAP的表达明显增强,D1组较模型组表达减弱(WTBXP<0.05),D2组较模型组差异有显著的统计学意义(P<0.01).结论 地佐辛对神经病理性疼痛的抑制作用可能与下调脊髓GFAP的表达,影响星形胶质细胞的活化有密切关联.     

Botulinum Toxin Type A for the Treatment of Neuropathic Pain in Neuro-Rehabilitation

Pain is a natural protective mechanism and has a warning function signaling imminent or actual tissue damage. Neuropathic pain (NP) results from a dysfunction and derangement in the transmission and signal processing along the nervous system and it is a recognized disease in itself. The prevalence of NP is estimated to be between 6.9% and 10% in the general population. This condition can complicate the recovery from stroke, multiple sclerosis, spinal cord lesions, and several neuropathies promoting persistent disability and poor quality of life. Subjects suffering from NP describe it as burning, itching, lancing, and numbness, but hyperalgesia and allodynia represent the most bothersome symptoms. The management of NP is a clinical challenge and several non-pharmacological and pharmacological interventions have been proposed with variable benefits. Botulinum toxin (BTX) as an adjunct to other interventions can be a useful therapeutic tool for the treatment of disabled people. Although BTX-A is predominantly used to reduce spasticity in a neuro-rehabilitation setting, it has been used in several painful conditions including disorders characterized by NP. The underlying pharmacological mechanisms that operate in reducing pain are still unclear and include blocking nociceptor transduction, the reduction of neurogenic inflammation by inhibiting neural substances and neurotransmitters, and the prevention of peripheral and central sensitization. Some neurological disorders requiring rehabilitative intervention can show neuropathic pain resistant to common analgesic treatment. This paper addresses the effect of BTX-A in treating NP that complicates frequent disorders of the central and peripheral nervous system such as spinal cord injury, post-stroke shoulder pain, and painful diabetic neuropathy, which are commonly managed in a rehabilitation setting. Furthermore, BTX-A has an effect in relief pain that may characterize less common neurological disorders including post-traumatic neuralgia, phantom limb, and complex regional pain syndrome with focal dystonia. The use of BTX-A could represent a novel therapeutic strategy in caring for neuropathic pain whenever common pharmacological tools have been ineffective. However, large and well-designed clinical trials are needed to recommend BTX-A use in the relief of neuropathic pain.     

神经生长因子对神经源性痛大鼠脊髓保护作用研究

目的 探讨神经生长因子对神经源性痛大鼠脊髓的保护作用及其机制。方法 取成年雄性Wistar大鼠66只，随机分为3组，神经生长因子组30只，结扎坐骨神经后腹腔注射神经生长因子，20 μg·kg^-1;0.9%氯化钠溶液组30只，结扎左侧坐骨神经中段后腹腔注射等量0.9%氯化钠溶液;假手术组6只，手术仅暴露而不结扎坐骨神经。于术前和术后6 h、1，3，7，14 d分别进行行为学测定，记录大鼠缩爪与尾弹时间。应用免疫组织化学方法和图像分析系统检测脊髓中TNF-α和IL-6的表达，采用TUNEL法观察脊髓神经元凋亡，采用HE染色及尼氏染色法观察脊髓的病理形态学变化。结果 与0.9%氯化钠溶液组比较，神经生长因子组大鼠脊髓TNF-α和IL-6表达降低，脊髓神经元凋亡指数降低且疼痛减轻(均P＜0.01)。 病理学检查显示，神经生长因子组脊髓组织损伤程度较0.9%氯化钠溶液组明显减轻。结论 神经生长因子对大鼠脊髓有保护作用。其机制可能与抑制促炎性细胞因子的表达，从而抑制神经元凋亡和疼痛有关。     

Protein–Ligand Interaction Study of CpOGA in Complex with GlcNAcstatin

The GlcNAcstatin is a potent inhibitor of O‐glycoprotein 2‐acetamino‐2‐deoxy‐β‐D‐glucopyranosidase, which has been related with type II diabetes and neurodegenerative disorders. Herein, hybrid quantum mechanics/molecular mechanics, molecular dynamics simulations, and potential of mean force were employed to study the interactions established between GlcNAcstatin and a bacterial O‐GlcNAcase enzyme from Clostridium perfringens. The results reveal that the imidazole nitrogen atom of GlcNAcstatin has shown a better interaction with the active site of Clostridium perfringens in its protonated form, which is compatible with a substrate‐assisted reaction mechanism involving two conserved aspartate residues (297 and 298). Furthermore, the quantum mechanics/molecular mechanics–molecular dynamics simulations appointed a strong interaction between Asp401, Asp298, and Asp297 residues and the GlcNAcstatin inhibitor, which is in accordance with experimental data. Lastly, these results may contribute to understand the molecular mechanism of inhibition of Clostridium perfringens by GlcNAcstatin inhibitor and, consequently, this study might be useful to design new molecules with more interesting inhibitory activity.     

The Effect of a Combination of Diclofenac and Methadone Applied as Gel in a Human Experimental Pain Model – A Randomized,Placebo‐controlled Trial

Pain involves responses in which both peripheral and central mechanisms contribute to the generation of pain. Pre‐clinical laboratory data have supported that a topical formulation of combined diclofenac and methadone (Diclometh) may alleviate local pain, and potentially, the side effect profile should be low. We hypothesized that antiallodynic and antihyperalgesic effects of Diclometh could be demonstrated in a human experimental pain model and that Diclometh would be safe to administer. Thus, the aims were as follows: (i) to compare two doses of Diclometh versus placebo; and (ii) to assess the safety profile of Diclometh. The study was a crossover, randomized, double‐blind, placebo‐controlled comparison of two doses of Diclometh gel (0.1% and 0.2%) administered topically in healthy participants. Nerve growth factor (NGF) and capsaicin intradermal injections were used as human pain models. Pressure stimulation, contact heat stimulation, hyperalgesia (pinprick stimulation) and allodynia (brush stimulation) to mechanical stimulation were performed in the area where capsaicin and NGF were injected. Side effects were recorded on a four‐point Likert scale. Twenty‐one men completed the study (mean age 26.14 ± 5.3). Diclometh 0.2% reduced the capsaicin‐induced dynamic mechanical allodynia compared to placebo (primary end‐point, p = 0.03). No other primary or secondary end‐points were found significantly different (all p > 0.05). All side effects were reported as mild with no differences between treatments (p = 0.15). Indication of antiallodynic effect of Diclometh 0.2% was found. Additionally, it was demonstrated that Diclometh was safe to use.     

芩术颗粒对发热和疼痛模型鼠的解热镇痛作用

目的:研究芩术颗粒的解热镇痛作用。方法:采用干酵母或2,4-二硝基苯酚致大鼠发热模型,观察芩术颗粒对模型大鼠的解热作用;通过热板法及小鼠醋酸致扭体反应,观察芩术颗粒对模型小鼠疼痛的影响。结果:40、20、10 g/kg芩术颗粒对模型大鼠体温有降低作用;40、20 g/kg芩术颗粒可明显延长模型小鼠疼痛潜伏期及减少其扭体反应次数。结论:芩术颗粒具有一定的解热镇痛作用。     

Multidimensional Effectiveness of Botulinum Toxin in Neuropathic Pain: A Systematic Review of Randomized Clinical Trials

Although botulinum toxin (BoNT) has been suggested as a treatment to counter neuropathic pain, no previous systematic reviews investigated the multidimensional effects of BoNT on pain relief and Health-Related Quality of Life (HR-QoL). The aim of this systematic review is to summarize the current evidence on the effectiveness of BoNT treatment for neuropathic pain, and to characterize its multidimensional effectiveness in order to guide physicians in clinical practice. Five databases were systematically searched up to 4 April 2022, to identify randomized controlled trials satisfying the following criteria: adults suffering from neuropathic pain, BoNT administration, any comparator, multidimensional assessment of pain as primary outcome, HR-QoL, physical function, anxiety and depression, and sleep quality as secondary outcomes. Twelve studies were included. The multidimensional pain scales used were short-form McGill Pain Questionnaire, Neuropathic pain scale, Neuropathic Pain Symptom Inventory, International SCI Pain Basic Data Set, West Haven-Yale Multidimensional Pain Inventory, Brief Pain Inventory, and Douleur Neuropathique 4. These scales highlighted the positive effects of BoNT administration. According to the Jadad scale, all the RCTs included were high-quality studies. BoNT administration might be effectively introduced in the comprehensive management of neuropathic pain. Further research should focus on optimal and cost-effective therapeutic protocols.