Nefopam Hydrochloride Research Articles

Эффективность применения Контрапаина-10® (нефопама гидрохлорида) при мультимодальной анальгезии собак

Purpose of the research: to estimate the effectiveness of nefopam hydrochloride (Contrapain-10®) as a part of multimodal analgesia in pre- and intraoperative period of dogs, and to find out whether this medicine will reduce the number of anesthetics used during the intraoperative period. Materials and methods: the study included 34 dogs; 2 groups (n = 17) were formed from patients with diagnosed herniated discs of varying severity in different departments. All animals were subject to surgical treatment: group A (control group with nefopam hydrochloride) and B (experimental group without nefopam hydrochloride). For group A dogs in the preoperative period a non-opioid analgesic of central action, nefopam hydrochloride, was introduced into the multimodal analgesia scheme at a dosage of 0.3…0.5 mg/kg of body weight intramuscularly with an assessment of the analgesic effect. For dogs of group B (control) A standard multimodal analgesia protocol was used without the nefopam hydrochloride. During the intraoperative period, patients' pain levels were assessed using numerical hardware parameters (the main components of monitoring are ECG, frequency of respiratory movements, heart rate, noninvasive blood pressure, pulse oximetry, thermometry), as well as visual monitoring. Physiological parameters, pain and degree of sedation were assessed during the whole surgical operation and intermediate results were recorded every 30, 60, 90, 120, 150, 180 minutes. Estimation of clinical effectiveness of the medicine was evaluated based on the results of the pain assessment (from 1 to 5), general condition and values of vital parameters recorded during surgery. Results: Contrapain-10® promotes high-quality and safe anesthesia of patients both during surgery and in the postoperative period. At the same time, the consumption of opioid and non-opioid analgesics is minimal.

Solubility determination and thermodynamic model analysis of nefopam hydrochloride in eight plain solvents and three binary solvents from 273.15 K to 323.15 K

Nefopam hydrochloride (NPH) is a non-narcotic analgesic with antipyretic, analgesic, and muscle relaxant effects. Solubility is an important molecular property that can inform the crystallization and purification of drugs. In the present study, NPH solubility was measured in eight plain solvents and three binary solvents at 273.15 K-323.15 K. Results showed that in the plain solvents, NPH had the greatest solubility in methanol and the least in acetone. The solubility in the solvent system of methanol + acetone and ethanol + acetone becomes greater with the increase of the molar fraction of the positive solvent, while it becomes greatest in the system of water + acetone when the molar fraction of the positive solvent is 0.8 and at molar fractions>0.8 the solubility begins to decrease, which may be owing to the existence of the phenomenon of co-solubility. NPH solubility in plain solvents and binary solvents is positively correlated with temperature. By XRD and TG-DSC, the crystal structure of NPH in solvent did not change and the weight loss and melting temperatures were 500.49 K and 518.34 K respectively, which were much higher than the experimental temperatures. Selection of Hansen solubility parameter to predict the solubility effect of NPH in different solvents. The analysis was carried out using five thermodynamic models, ranging from Modified Apelblat model, Buchowski-Ksiazaczak λh model, CNIBS/R-K model, Jouyban-Acree model and SUN model, to fit the solubility data, out of which Modified Apelblat model and CNIBS/R-K model had more accurate prediction results.

The use of centrally acting analgesics in the postoperative analgesia in patients with the consequences of a severe mine-explosive injury of the lower extremities

In this article, the authors discuss the place of modern analgesics of central action (nefopam hydrochloride) in the analgesia of patients with explosive injuries of the lower extremities. Currently, there is no information in global practice regarding the use of centrally acting analgesics for analgesia in patients with combat trauma. An example was the analgesia of patients in the p/o period with a severe explosive injury of the lower extremities. Attention is drawn to the need for effective analgesia for patients with a combo injury not only in the acute period. A feature of the treatment of such patients is the need for major restorative and reconstructive surgical interventions, which in turn are accompanied by a pronounced pain syndrome. In our experience, the addition of non-narcotic analgesics of central action (nefopam hydrochloride) to the scheme of multimodal analgesia is appropriate to improve analgesia in this category of patients. The addition of nefopam hydrochloride to a multimodal analgesia regimen at 20 mg IV every 6 hours was effective in the treatment of severe acute postoperative pain.

The effects of nefopam hydrochloride and tramadol hydrochloride on postoperative pain in patients undergoing long bone fracture fixations: A randomised triple blinded study

Orthopaedic surgery has one of the most painful post-operative periods. Pain management is an important consideration in Orthopaedic department. The purpose of this study was to assess the effect of Nefopam hydrochloride and Tramadol hydrochloride in postoperative analgesia in patients undergoing long bone fracture fixations.Triple blindedRandomization and allocation to study groups were carried out by odd and even number method. The study was conducted in tertiary care center from May 2019 till March 2020.184 patients who underwent Orthopaedic surgery were included in this randomized study. 92 patients were placed each in group-A and B. Patients in group-A received Tramadol hydrochloride and in group-B received Nefopam hydrochloride. The primary outcome measures were pain intensity assessed by using a Visual Analogue Scale (VAS) Score, Verbal Rating Scale (VRS) score whereas the secondary outcome measures included side effects related to the drugs and number of patients who required rescue analgesia. Unpaired t-test and Chi-square test was used to carry out all the data analysis. The pain intensity assessed on VAS score was significantly better for Tramadol group compared to Nefopam group at all time periods except at 15 minutes and a significant difference was present in verbal rating scale score between the groups only at 24 hours. Side effect profile and requirement of rescue analgesia were more in Nefopam hydrochloride group.Tramadol hydrochloride was more effective in providing post-operative pain relief in patients compared to Nefopam hydrochloride.

A NOVEL METHOD DEVELOPMENT AND VALIDATION FOR THE QUANTIFICATION OF NEFOPAM HYDROCHLORIDE IN PARENTERAL DOSAGE FORM BY RP-HPLC METHOD

Objective: Using RP-HPLC, a simple, accurate, and exact method for estimating the Nefopam Hydrochloride parenteral dose form was devised.
 Methods: The isocratic mode of the RP-HPLC method used an Inertsil C8 column as the stationary phase and a mobile phase of potassium dihydrogen phosphate with pH 3.0: Acetonitrile (70:30) at a flow rate of 1 ml/min. With UV detection at 220 nm, a flow rate of 1 ml/min was established.
 Results: The developed RP-HPLC technique revealed acceptable linearity (R2 = 0.9998) and good assay results in the concentration range of 0.004–0.08 mg/ml (103.3 percent). Further forced degradation investigations using 0.1N Hydrochloric acid (acid degradation), 0.1NNaOH (base degradation), and 3 percent H2O2 (Hydrogen peroxide) were carried out using RP-HPLC, and percent degradation values were determined. In peroxide degradation conditions, the medication was shown to be unstable.
 Conclusion: In compliance with ICH requirements, the developed procedures were validated.

The Effect of Nefopam Hydrochloride on the Liver, Heart, and Brain of Rats: Acute Toxicity and Mechanisms of Nefopam Toxicity

The Effect of Nefopam Hydrochloride on the Liver, Heart, and Brain of Rats: Acute Toxicity and Mechanisms of Nefopam Toxicity

Nefopam hydrochloride as a component of multimodal analgesia in the postoperative period

The modern approach to the multimodal scheme of postoperative analgesia includes the mandatory use of drugs that have a small number of side effects and at the same time have a polymodal effect on the pathogenetic links of pain development. Nefopam hydrochloride is able to prevent the development of: opioid hyperalgesia, stop pain stimuli without respiratory depression, affect platelet aggregation and the condition of the mucous membrane and motility of the gastrointestinal tract, which distinguishes it from classical NSAIDs. Nefopam hydrochloride is characterized by a low risk of addiction with prolonged use, a pronounced anti-sensory effect, especially significant at the stage of awakening and in the early postoperative period.
 Postoperative analgesia based on nefopam hydrochloride as a component of multimodal analgesia is effective and safe in the absence of absolute contraindications. The planned use of nefopam hydrochloride for the correction of pain reduces complications in the postoperative period and improves the quality of life of patients. Nefopam hydrochloride is one of the most effective drugs for the correction of postoperative tremor syndrome. The use of nefopam hydrochloride as a drug, which is a part of premedication before surgical interventions and a component of multimodal analgesia, improves the quality of the postoperative period due to: reduction of pain syndrome, planned correction of postoperative tremor syndrome and correction of complications arising from inadequate treatment of pain syndrome.

Development and Optimization of Nefopam Hydrochloride Push-Pull Osmotic Pumps by Design of Experiments

Nefopam hydrochloride (NFH) is one of the centrally acting NSAIDs drug used for pain management. The main objective of this research is to study the effect of ratio of Cellulose acetate: Polyethylene glycol (PEG) 3350, and %weight gain in extended release (ER) coating of push-pull osmotic pump (PPOP) tablets, optimized by the design of experiment (DoE) using response surface face center (α=1), the central composite design having two independent variables at three levels. PPOP tablets of NFH were administered once a day to reduce dosing frequency and improve patient compliance. PPOP tablets contain drug and push layers, compressed into bilayer tablets, coated with cellulose acetate (CA) as semipermeable membrane polymer, and PEG 3350 as a plasticizer or pore-forming agent. ER coated tablets mechanically drill ~0.50 mm on the drug layer part for the controlled release of the drug up to 24 hrs. Based on the results, the ratio of CA: PEG 3350 and % weight gain in ER coating of PPOP tablets shows a significant impact on % drug release. At lower % of PEG, burst release was observed due to cracking of ER coating layer, while at higher % of PEG, slightly rapid release of drug was observed. %Drug release is decreased with an increase in the %weight gain of tablets. PPOP Tablets with 10% PEG 3350 (Ratio of CA:PEG 3350, 90:10) and 8% weight gain exhibit zero-order kinetic drug release up to 24 hours.

Analgesic Effect of Low Dose Nefopam Hydrochloride after Arthroscopic Rotator Cuff Repair: A Randomized Controlled Trial.

Arthroscopic rotator cuff repair causes acute postoperative hyperalgesia. Multimodal analgesia is preferable to opioid-based intravenous patient-controlled analgesia (IV-PCA) due to postoperative nausea and vomiting (PONV). We evaluated the effect of nefopam as a postoperative non-opioid analgesic after shoulder surgeries. A total of 180 adult patients were enrolled for arthroscopic rotator cuff repair. They were randomly assigned to nefopam (N) or control (C) groups and each group was reclassified according to the interscalene block (B) into NB, CB and NX, CX. Nefopam was applied at a constant dose intravenously during recovery. Pain scores were measured with a Visual Analogue Scale (VAS) before (T0), immediately after (T1), 30 min (T2) and 12 h (T3), 24 h (T4) and 48 h (T5) after surgery. There was no significant difference in demographic data. The overall VAS scores did not differ with regard to nefopam use, except for the NB group at T4 in intention to treat (ITT) analysis (p < 0.05). PONV occurred more frequently in the N group than in the C group (p < 0.05). Neither individual nor all risk factors were associated with PONV occurrence (p > 0.10). In conclusion, nefopam alone did not show a definite decrease in postoperative pain. It instead increased PONV regardless of risk factors.

Intranasal niosomes of nefopam with improved bioavailability: preparation, optimization, and in-vivo evaluation.

ObjectiveOne of the greatest challenges drug formulation is facing is poor bioavailability via oral route. In this regard, nasal drug delivery has been commonly used as an alternative route to improve drug bioavailability. Nefopam hydrochloride (NF) is an analgesic drug that suffers from poor bioavailability due to extensive metabolism in liver. Accordingly, the goal of the present study was to improve NF bioavailability via niosomal-based formulation designed for intranasal delivery.Materials and methodsVesicles were developed by mixing surfactants (Span 20, Span 40, Span 80, and Span 85) at four molar ratios of 1:1, 1:2, 1:3, and 1:4 of cholesterol to surfactant. Entrapment efficiency, particle size, zeta potential, release percentage, ex-vivo permeation parameters, and niosomes’ stability were determined. Also, the pharmacokinetic parameters of the optimized formula in in-situ gel base were measured in rats.ResultsNiosomes showed entrapment efficiency .80%, particle size ,550 nm, and zeta potential ranging from -16.8±0.13 to -29.7±0.15. The produced vesicles showed significantly higher amounts of drug permeated across nasal mucosa (2.5 folds) and prolonged NF release compared with NF solution. Stability studies of optimum formula showed nonsignificant changes in niosomes parameters over a storage period of 6 months. The in-vivo studies showed a 4.77-fold increase in bioavailability of optimized nasal niosomes compared with oral solution of drug.ConclusionThe obtained results revealed the great ability of the produced NF-loaded nio-somes to enhance drug penetration through nasal mucosa and improve its relative bioavailability compared with NF oral solution.

Influence of multimodal anesthesia and analgesia on mechanisms of blood circulation adaptation of oncogynecologic patients in the postoperative period

Objective: to assess the influence and eff ectiveness of multimodal anesthesia and analgesia from the standpoint of personalization of compensatory mechanisms of blood circulation adaptation in oncogynecologic patients in the postoperative period. Materials and methods: a study was conducted in patients who underwent surgical interventions on pelvic organs for oncogynecological diseases. The total number of patients was 39 people. Based on anesthesia with sevoflurane at low concentrations and spinal analgesia, all patients underwent multimodal anesthesia. To determine the nature of the functioning of the circulatory system, the adaptive potential was determined by the index of functional changes. For the relief of pain syndrome in patients in the postoperative period, the administration of ketoprofen and nefopam hydrochloride, used according to the doctor’s prescription or in the patient-controlled analgesia mode, as well as the regional blockade of the nerves innervating the anterior abdominal wall (Transversus Abdominis Plane block) was provided. Results: it was revealed that multimodal anesthesia and analgesia, depending on the level of the adaptation potential, differently affects the adaptation and regulatory mechanisms of the systemic circulation of patients, and its vegetative tone, which can cause the risk of complications in the postoperative period. Conclusions: multimodal anesthesia and analgesia, including a combination of central, regional non-narcotic analgesics and blockades, allows to preserve the reserves of systemic circulation and optimize its vegetative component, is effective and safe in oncogynecologic patients with the stress of regulatory mechanisms of adaptation. The use of multimodal anesthesia and analgesia in oncogynecologic patients with unsatisfactory adaptation is a risk factor for the disruption of the regulatory and compensatory mechanisms of hemodynamics and the vegetative tone of the systemic circulation, contributing to the limitation of its work in the first 24 hours of the postoperative period.

Old is Gold? Nefopam Hydrochloride, a Non-opioid and Non-steroidal Analgesic Drug and Its Practical One-Pot Synthesis in a Single Solvent for Large-Scale Production

Nefopam hydrochloride is extensively used in most of the European countries until today as an analgesic because of its non-opiate (non-narcotic) and non-steroidal action with fewer side effects compared with opioid and other analgesics, which cause more troublesome side effects. A multikilogram synthesis of nefopam hydrochloride has been achieved in one pot using a single solvent (toluene). A ≥99.9% purity of the active pharmaceutical ingredient (API) was achieved in excellent overall yield (≥79%). The one-pot, five-step synthetic process involves formation of an acid chloride (3) from benzoylbenzoic acid (2) followed by amidation (4), reduction (5), cyclization (6), and formation of the hydrochloride salt (1). The major advantages include (i) use of a single solvent, (ii) >90% conversion in each step, (iii) a cost-effective and operationally friendly process, (iv) averting the formation of genotoxic impurities, and (v) improved overall yield (≥79%) provided by the one-pot operation. For the first time, we report the characterization data of API 1, intermediates 3, 4, and 5, and also a possible impurity (5a).

Preformulation studies of nefopam hydrochloride for physicochemical characterization and compatibility analysis with poly-3-hydroxybutyrate and poly-ε-caprolactone

Preformulation studies of nefopam hydrochloride for physicochemical characterization and compatibility analysis with poly-3-hydroxybutyrate and poly-ε-caprolactone

Nefopam hydrochloride loaded microspheres for post-operative pain management: synthesis, physicochemical characterization and in-vivo evaluation

Once-daily oral dosage of nefopam hydrochloride loaded sustained release microspheres (NPH-MS) was investigated as novel therapeutic strategy for post-operative pain management. Microspheres were synthesized using poly-3-hydroxybutyrate and poly-(ɛ-caprolactone) by double emulsion solvent evaporation technique. NPH-MS were characterized through FTIR, PXRD and SEM. In-vitro drug release study revealed sustained behavior till 24 h. Haemolysis was <5% which signified haemocompatibility of formulation. ED50 in rat tail-flick anti-nociceptive test was found ∼18.12 mg/kg. In post-operative pain model, reversal of mechanical allodynia and thermal hyperalgesia by NPH-MS was statistically significant (p < .001) as compared with NPH till 24 h post-dose.

The Antiallodynic Effects of Nefopam Are Mediated by the Adenosine Triphosphate-Sensitive Potassium Channel in a Neuropathic Pain Model.

Nefopam hydrochloride is a centrally acting compound that induces antinociceptive and antihyperalgesic properties in neuropathic pain models. Previous reports have shown that activation of adenosine triphosphate (ATP)-sensitive and calcium-activated potassium (KATP and KCa2+) channels has antiallodynic effects in neuropathic pain. In the present study, we evaluated the relationship between potassium channels and nefopam to determine whether the antiallodynic effects of nefopam are mediated by potassium channels in a neuropathic pain model. Mechanical allodynia was induced by spinal nerve ligation (SNL) in rats, and the paw withdrawal threshold (PWT) was evaluated by the use of von Frey filaments. Nefopam was administered intraperitoneally before or after SNL. We assessed the relationship between nefopam and intrathecal injection of the KCa2+ channel antagonists apamin and charybdotoxin, and the KATP channel blocker glibenclamide to assess their abilities to reverse the antiallodynic effects of nefopam. In addition, we evaluated whether the KATP channel opener pinacidil had antiallodynic effects and promoted the antiallodynic effects of nefopam. Administration of nefopam before and after SNL induced significant antiallodynic effects (P < .01, respectively), which were significantly reduced by glibenclamide (P < .01). Pinacidil improved the antiallodynic effects of nefopam (P < .01); however, apamin and charybdotoxin had little effects on the antiallodynic properties of nefopam. The antiallodynic effects of nefopam are increased by a KATP channel agonist and reversed by a KATP channel antagonist. These data suggest that the KATP channel is involved in the antiallodynic effects of nefopam in a neuropathic pain model.

Development and statistical optimization of nefopam hydrochloride loaded nanospheres for neuropathic pain using Box–Behnken design

Nefopam hydrochloride (NFH) is a non-opioid centrally acting analgesic drug used to treat chronic condition such as neuropathic pain. In current research, sustained release nefopam hydrochloride loaded nanospheres (NFH-NS) were auspiciously synthesized using binary mixture of eudragit RL 100 and RS 100 with sorbitan monooleate as surfactant by quasi solvent diffusion technique and optimized by 35 Box–Behnken designs to evaluate the effects of process and formulation variables. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetric (DSC) and X-ray diffraction (XRD) affirmed absence of drug–polymer incompatibility and confirmed formation of nanospheres. Desirability function scrutinized by design-expert software for optimized formulation was 0.920. Optimized batch of NFH-NS had mean particle size 328.36nm±2.23, % entrapment efficiency (% EE) 84.97±1.23, % process yield 83.60±1.31 and % drug loading (% DL) 21.41±0.89. Dynamic light scattering (DLS), zeta potential analysis and scanning electron microscopy (SEM) validated size, charge and shape of nanospheres, respectively. In-vitro drug release study revealed biphasic release pattern from optimized nanospheres. Korsmeyer Peppas found excellent kinetics model with release exponent less than 0.45. Chronic constricted injury (CCI) model of optimized NFH-NS in Wistar rats produced significant difference in neuropathic pain behavior (p<0.05) as compared to free NFH over 10h indicating sustained action. Long term and accelerated stability testing of optimized NFH-NS revealed degradation rate constant 1.695×10−4 and shelf-life 621days at 25±2°C/60%±5% RH.

Formulation, Optimization and Evaluation of Sustained Release Microspheres using Taguchi Design

The aim of present study is to prepare microspheres of eudragit RL 100 loaded with Nefopam Hydrochloride by single emulsion solvent evaporation technique. Taguchi L9 orthogonal array design has been used to optimize the composition and operating conditions for preparation of formulations. Nine batches (F1-F9) were prepared by taking three independent variables (X 1 - drug: polymer ratio, X 2 - stirring speed and X 3 - stirring time) at three levels (+1, 0, -1). Response variables studied for batches (F1-F9) were mean particle size (µm) (Y 1 ), drug entrapment efficiency (% w/w) (Y 2 ) and drug loading (% w/w) (Y 3 ). Drug- polymer compatibility study was carried out by DSC and FTIR spectroscopy and indicates no physicochemical interaction. Microspheres were analyzed for morphological characteristics, mean particle size, drug entrapment efficiency, drug loading and in-vitro drug release. Percentage cumulative drug release for optimized batch F5 was found to be 85.421 ± 0.054 and followed higuchi model for release of drug.

To enhance the efficiency of nefopam transdermal iontophoresis by using a novel method based on ion-exchange fiber

Background: In the system of the iontophoresis, the external electric field made the ions in the system moving directly, then, the current was generated. Because the current was contributed by all ions in the system, and the small ions with large amount often had higher conductibility than the drug ions, the fraction of the total current contributed by the drug ions was often low. It was the main reason for the generally low efficiency of the transdermal iontophoretic drug delivery.Objectives: The objective of this study was to find a novel method to increase the fraction of the total current contributed by the drug ions so as to enhance the drug's iontophoretic delivery.Method: Iontophoretic transport of nefopam hydrochloride solution and iontophoretic transport of nefopam assisted by ion-exchange materials, including ion-exchange resin, ion-exchange membrane and ion-exchange fiber, across the rat skin were investigated.Results: Both in vitro and in vivo iontophoretic transport experiments showed that the efficiency of the nefopam-fiber iontophoretic system for nefopam permeating across rat skin was the highest among four iontophoretic systems (nefopam solution, nefopam-resin, nefopam-membrane and nefopam-fiber).Conclusion: The results of this study suggested that there was an enhancement of nefopam across rat skin by ion-exchange fibers in ion-exchange fibers assisted iontophoresis. The present study has demonstrated the potential of a new approach of using ion-exchange fibers to improve the efficiency of the transdermal iontophoresis for cationizable drugs.

EVALUATION OF COMBINED NEFOPAM HYDROCHLORIDE AND KETOPROFEN IN THE TREATMENT OF POSTOPERATIVE PAIN IN PATIENTS WITH ENDOMETRIOSIS

Conducted a study to assess the effectiveness of a new centrally acting analgesic nefopam hydrochloride (Acupan). Included 45 patients who underwent laparoscopic surgical treatment of endometriosis of varying severity. Found that pre-emptive analgesia with nefopam and ketoprofen is more effective in patients with endometriosis, I–II severity. In patients with endometriosis stage III application ketoprofen and nefopam significantly improved the quality of postoperative analgesia and reduced the need for narcotic analgesics. In patients with severe endometriosis (IV stage), this scheme was inadequate.

Development and validation of a TLC-densitometry method for quantitative analysis of nefopam hydrochloride beside its degradation products

A quantitative densitometric thin-layer chromatographic method for determination of nefopam hydrochloride in pharmaceutical preparations has been established and validated. Nefopam from the formulations was separated and identified on silica gel 60 F254 TLC plates with chloroform-methanol-glacial acetic acid (9: 2: 0.1, v/v/v) as mobile phase. Densitometric quantification was performed at absorbance maximum 266 nm. The method was validated for linearity, sensitivity, precision and recovery in accordance with ICH guidelines. The presented method is selective and specific with potential application in pharmaceutical analysis. Nefopam hydrochloride was subjected to acidic and alkaline hydrolysis at different temperatures. As the method could effectively separate the drug from its degradation products, it can be employed as a stability indicating one.