Modulating the Activity of the Human Organic Cation Transporter 2 Emerges as a Potential Strategy to Mitigate Unwanted Toxicities Associated with Cisplatin Chemotherapy.

Cisplatin (CDDP) stands out as an effective chemotherapeutic agent; however, its application is linked to the development of significant adverse effects, notably nephro- and ototoxicity. The human organic cation transporter 2 (hOCT2), found in abundance in the basolateral membrane domain of renal proximal tubules and the Corti organ, plays a crucial role in the initiation of nephro- and ototoxicity associated with CDDP by facilitating its uptake in kidney and ear cells. Given its limited presence in cancer cells, hOCT2 emerges as a potential druggable target for mitigating unwanted toxicities associated with CDDP. Potential strategies for mitigating CDDP toxicities include competing with the uptake of CDDP by hOCT2 or inhibiting hOCT2 activity through rapid regulation mediated by specific signaling pathways. This study investigated the interaction between the already approved cationic drugs disopyramide, imipramine, and orphenadrine with hOCT2 that is stably expressed in human embryonic kidney cells. Regarding disopyramide, its influence on CDDP cellular transport by hOCT2 was further characterized through inductively coupled plasma isotope dilution mass spectrometry. Additionally, its potential protective effects against cellular toxicity induced by CDDP were assessed using a cytotoxicity test. Given that hOCT2 is typically expressed in the basolateral membrane of polarized cells, with specific regulatory mechanisms, this work studied the regulation of hOCT2 that is stably expressed in Madin-Darby Canine Kidney (MDCK) cells. These cells were cultured in a matrix to induce the formation of cysts, exposing hOCT2 in the basolateral plasma membrane domain, which was freely accessible to experimental solutions. The study specifically tested the regulation of ASP+ uptake by hOCT2 in MDCK cysts through the inhibition of casein kinase II (CKII), calmodulin, or p56lck tyrosine kinase. Furthermore, the impact of this manipulation on the cellular toxicity induced by CDDP was examined using a cytotoxicity test. All three drugs-disopyramide, imipramine, and orphenadrine-demonstrated inhibition of ASP+ uptake, with IC50 values in the micromolar (µM) range. Notably, disopyramide produced a significant reduction in the CDDP cellular toxicity and platinum cellular accumulation when co-incubated with CDDP. The activity of hOCT2 in MDCK cysts experienced a significant down-regulation under inhibition of CKII, calmodulin, or p56lck tyrosine kinase. Interestingly, only the inhibition of p56lck tyrosine kinase demonstrated the capability to protect the cells against CDDP toxicity. In conclusion, certain interventions targeting hOCT2 have demonstrated the ability to reduce CDDP cytotoxicity, at least in vitro. Further investigations in in vivo systems are warranted to ascertain their potential applicability as co-treatments for mitigating undesired toxicities associated with CDDP in patients.

Uptake, translocation, and metabolization of amitriptyline, lidocaine, orphenadrine, and tramadol by cress and pea.

The uptake, translocation, and metabolization of four widely used drugs, amitriptyline, orphenadrine, lidocaine, and tramadol, were investigated in a laboratory study. Cress (Lepidium sativum L.) and pea (Pisum sativum L.) were employed as model plants. These plants were grown in tap water containing the selected pharmaceuticals at concentrations ranging from 0.010 to 10 mg L-1, whereby the latter concentration was employed for the (tentative) identification of drug-related metabolites formed within the plant. Thereby, mainly phase I metabolites were detected. Time-resolved uptake studies, with sampling after 1, 2, 4, 8, and 16 days, revealed that all four pharmaceuticals were taken up by the roots and further relocated to plant stem and leaves. Also in these studies, the corresponding phase I metabolites could be detected, and their translocation from root to stem (pea only) and finally leaves could be investigated.

[The use of a fixed combination of diclofenac and orphenadrine for postoperative pain relief in orthopedic patients]. / Primenenie fiksirovannoi kombinatsii diklofenaka i orfenadrina dlya posleoperatsionnogo obezbolivaniya u ortopedicheskikh bol'nykh.

OBJECTIVE: To evaluate the efficacy and safety of using a fixed combination of diclofenac and orphenadrine for early postoperative pain relief in orthopedic patients following hip prosthetics. MATERIAL AND METHODS: A prospective comparative study enrolled 65 patients with primary total hip replacement in the setting of spinal bupivacaine anesthesia. Patients were divided into 2 groups - study (39 patients) and control (26 people). The study group underwent Neodolpasse infusion (orphenadrine 30 mg + diclofenac 75 mg) after the end of surgery and morphine infusion in a patient-controlled analgesia (PKA) regimen. The control group underwent morphine monotherapy in the PKA regimen. The intensity of pain syndrome was compared on a visual-analog scale (VAS) from 0 to 100, the total amount of morphine administered, the number of bolus requests, the change in kidney function and the side effect were assessed. RESULTS: In the control group, the duration of the intervention was shorter and amounted to 70 [59; 82] minutes, in the study group - 83 [65; 94] minutes (p=0.05). No significant difference was found in the number of bolus requests (32 [22; 38] and 23 [15; 36], p=0.085 and pain intensity 2 and 12 hours after the start of therapy (5 [4; 6] and 3 [2; 4] and 5 [4; 6] and 2 [2; 3] points) in the control group and in the study group. When assessing the intensity of pain syndrome 24 hours after the start of therapy, differences were found in the groups - in the control group 30 [2; 3] mm, in the study group 20 [2; 3] mm (p=0.05). There was no nephrotoxic effect on Neodolpasse. Complications of analgesic therapy in the form of nausea, vomiting, pruritus were recorded in both groups in equal amounts, which is explained by the administration of morphine in both groups. CONCLUSION: 1. The use of a fixed combination of orphenadrine 30 mg + diclofenac 75 mg as part of postoperative pain relief after operations of primary hip prosthetics improves the quality of postoperative pain relief according to the subjective assessment of patients. 2. The use of a fixed combination of orphenadrine 30 mg + diclofenac 75 mg did not lead to the development of side effects and complications.

Spectrofluorometric determination of orphenadrine, dimenhydrinate, and cinnarizine using direct and synchronous techniques with greenness assessment.

Orphenadrine (ORP), dimenhydrinate (DMN), and cinnarizine (CNN) were investigated using green-sensitive spectrofluorometric methods. Method, I used for determination of DMN in 0.1 M hydrochloric acid (HCl) and 1.0% sodium dodecyl sulphate (SDS) at 286 nm after λex 222 nm, while for determination of ORP in 1.0% w/v SDS involves measuring the fluorescence at 285 nm after λex 220 nm. For DMN and ORP, the detection and quantitation limits were 2.99 and 4.71 and 9.08 and 14.29 ng/mL, respectively. The ranges of DMN and ORP were 0.10-1.0 and 0.04-0.5 µg/mL, respectively, in micellar aqueous solution. Method II, the derivative intensities of DMN and CNN were measured at a fixed of different wavelength between the excitation and the emission wavelengths (Δλ) = 60 nm at 282 and 322 nm, at the zero crossing of each other, respectively. The detection and quantitation limits for DMN and CNN were 1.77 and 0.88 ng/mL and 5.36 and 2.65 ng/mL, correspondingly, through the entire range of 0.1-1.0 µg/mL for DMN and CNN. The linearity was perfectly determined through the higher values of the correlation coefficient ranging from 0.9997 to 0.9999 for both direct and synchronous methods. The precision of the proposed methods was also confirmed via the lower values of the standard deviation which ranged from 0.39 to 1.11. The technique was expanded to analyze this mixture in combined tablets and laboratory-prepared mixtures. The method validation was done depending on the international conference on harmonization (ICH) recommendations. An analysis of the statistical data revealed a high agreement between the proposed data and the comparison methodology. Three different assessment methods demonstrated the greenness of the technique.

[The use of a fixed combination of diclofenac and orphenadrine in the treatment of acute pain syndrome in patients with discogenic lumbosacral radiculopathy and lumboischialgia]. / Primenenie fiksirovannoi kombinatsii diklofenaka i orfenadrina v terapii ostrogo bolevogo sindroma u patsientov s diskogennoi poyasnichno-kresttsovoi radikulopatiei i lyumboishialgiei.

Acute pain syndromes caused by discogenic lumbosacral radiculopathy and lumboischialgia are not uncommon in clinical practice and characterized by a high risk of becoming chronic. The pathogenetic aspects, features of the clinical picture, existing approaches to conservative treatment of these conditions are analyzed in this paper. Data on the efficacy and safety of a fixed combination of diclofenac and orphenadrine (Neodolpasse) use in the treatment of vertebrogenic pain syndromes based on the NEODOLEX study results are presented, and the authors' own clinical observations are given. Possible reasons for the high efficacy of Neodolpasse in patients with discogenic radiculopathies and nonspecific back and neck pain are discussed.

Investigations of the Interaction Mechanism Between Orphenadrine Hydrochloride and Bovine Serum Albumin by Spectroscopic and Voltammetric Techniques.

The interaction of orphenadrine hydrochloride (ORD) with the model protein, bovine serum albumin (BSA), was investigated using a variety of spectroscopic techniques such as steady-state fluorescence, ultraviolet-visible, Fourier transform infrared, 3-D spectroscopy, and electrochemical methods under physiological conditions. Stern-Volmer plots were used to calculate fluorescence quenching at various temperatures. The findings point to a static quenching mechanism between ORD and BSA. At various reaction times, the binding sites (n) and binding constants (K) of ORD to BSA were recorded. Thermodynamic parameters ∆H0, ∆S0 and ∆G0 between ORD and BSA were calculated and reported. The average binding distance (r) between the donor (BSA) and acceptor (ORD) molecules was predicted using Förster's theory. Three-dimensional fluorescence spectra, Fourier transform infrared spectra, and synchronous fluorescence studies all supported the alternations in protein structure following the interaction with ORD. A displacement study using site probes such as warfarin, ibuprofen, and digitoxin confirmed ORD binding at Sudlow's site I of BSA. The effect of common metal ions such as Cu2+, Ni2+, Ca2+, Co2+, and Zn2+ on binding constant values was investigated and reported.

Artificial intelligence algorithms predict the efficacy of analgesic cocktails prescribed after orthopedic surgery.

BACKGROUND: Mixtures ('cocktails') of various analgesics are more effective in controlling post-operative pain because of potential synergetic effects. Few studies have investigated such effects in large combinations of analgesics and no studies have determined the probabilities of effectiveness. METHODS: We used one-hot encoding of the categorical variables reported pain levels and the administered cocktails (from a total of eight analgesics) and then applied an unsupervised neural network and then the unsupervised DBSCAN algorithm to detect clusters of cocktails. We used Bayesian statistics to classify the effectiveness of these cocktails. RESULTS: Of the 61 different cocktails administered to 750 patients, we found that four combinations of three to four analgesics were by far the most effective. All these cocktails contained Metamizole and Paracetamol; three contained Hydromorphone and two contained Diclofenac and one Diclofenac-Orphenadrine. The ML probability that these cocktails decreased pain levels ranged from 0.965 to 0.981. Choice of a most effective cocktail involves choosing the optimum in a 4-dimensional parameter space: maximum probability of efficacy, confidence interval about maximum probability, fraction of patients with increase in pain levels, relative number of patients with successful pain level decrease. CONCLUSIONS: We observed that administering one analgesic or at most two is not effective. We found no statistical indicators that interactions between analgesics in the most effective cocktails decreased their effectiveness. Pairs of most effective cocktails differed by the addition of only one analgesic (Diclofenac-Orphenadrine for one pair and Hydromorphone for the other). We conclude that the listed cocktails are to be recommended.

The Cumulative Use of Muscle Relaxants and the Risk of Alzheimer's Disease: A Nationwide Case-Control Study.

BACKGROUND: Use of pharmacological treatments is one possible modifiable risk factor for cognitive disorders. OBJECTIVE: To investigate if the use of muscle relaxants is associated with the risk of Alzheimer's disease (AD). METHODS: The study was performed in a nested case-control design. Altogether 70,718 community-dwelling residents of Finland who received AD diagnosis in 2005-2011 were included as cases (the MEDALZ study). Each case was matched with four controls without AD by age, sex, and region of residence (N = 282,858). Data was extracted from Prescription register (1995-2012), Special Reimbursement register (1972-2012), and Hospital Discharge register (1972-2012). Drug use periods were modeled with PRE2DUP-method. Defined daily dose (DDD) was used to quantify the use. Analyses were conducted for any muscle relaxant use, and drug specific analyses were done for orphenadrine and tizanidine. A five-year lag window prior to the diagnosis was used, and results analyzed with conditional logistic regression. RESULTS: The use of any muscle relaxant was associated with the risk of AD, aOR (95% CI) 1.04 (1.02-1.07). Stronger associations were observed with longer use (>366 days, aOR 1.12 (1.03-1.21)) than shorter use (1-365 days aOR, 1.04 (1.02-1.06)) compared to non-users. Dose-response was not observed. Tizanidine was not associated with AD, whereas cumulative exposure of orphenadrine (≥101 DDDs) was associated with the risk of AD, aOR 1.19 (1.07-1.32). CONCLUSION: Muscle relaxant use was associated with the risk of AD and higher exposure to orphenadrine showed increased risk. Further studies on higher doses and longer durations of use are warranted.

Intravenous diclofenac and orphenadrine for the treatment of postoperative pain after remifentanil-based anesthesia : A double-blinded, randomized, placebo-controlled study.

BACKGROUND: Postoperative intravenous diclofenac reduces patient opioid demand and is commonly used in surgical units. Orphenadrine is mainly used in combination with diclofenac for musculoskeletal injuries and postoperative pain control. The objective of this study was to compare the analgesic efficacy of diclofenac-orphenadrine, diclofenac alone and saline. METHODS: We performed a double-blind, randomized, placebo-controlled, parallel-group, single-center clinical study investigating the opioid-sparing effect of a combination of diclofenac and orphenadrine versus diclofenac alone versus isotonic saline solution. Initially 72 patients were included and received total intravenous anesthesia during cruciate ligament surgery. All patients were postoperatively treated with a patient-controlled analgesia (PCA) device containing hydromorphone. Pharmacological safety was assessed by laboratory parameters, vital signs, and delirium detection scores. RESULTS: There was no significant difference between the groups in cumulative dose of PCA analgesics required after 24 h postsurgery, with 5.90 mg (SD ± 2.90 mg) in the placebo group, 5.73 mg (SD ± 4.75 mg) in the diclofenac group, and 4.13 mg (SD ± 2.57 mg) in the diclofenac-orphenadrine group. Furthermore, there was no significant difference between the groups in cumulative dose of PCA analgesics required 2 h postsurgery (n = 65). Mean dose of hydromorphone required after 2 h was 1.54 mg (SD ± 0.57 mg) in the placebo group, 1.56 mg (SD ± 1.19 mg) in the diclofenac-only group, and 1.37 mg (SD ± 0.78 mg) in the diclofenac-orphenadrine group. However, when comparing the diclofenac-orphenadrine group and the diclofenac group combined to placebo there was a significant reduction in PCA usage in the first 24 h postsurgery. In total, there were 25 adverse events reported, none of which were rated as severe. CONCLUSION: Orphenadrine-diclofenac failed to significantly reduce postoperative opioid requirements. However, in an exploratory post hoc analysis the diclofenac-orphenadrine and the diclofenac group combined versus placebo showed a tendency to reduce opioid demand in postoperative pain control. Further research is required to determine the value of orphenadrine as an adjuvant in a multimodal approach for postoperative pain management.

[Analgesic and opioid-sparing effects of a fixed combination of diclofenac and orphenadrine in the early postoperative period in cardiac surgery patients]. / Anal'geticheskii i opioidsberegayushchii effekty fiksirovannoi kombinatsii diklofenaka i orfenadrina v rannem posleoperatsionnom periode u kardiokhirurgicheskikh bol'nykh.

OBJECTIVE: Evaluation of the effectiveness of a multimodal scheme of postoperative analgesia based on a fixed combination of orphenadrine and diclofenac against the background of patient-controlled analgesia with morphine in the early postoperative period in cardiac surgery patients. MATERIAL AND METHODS: A prospective, randomized, comparative study evaluated two analgesic regimens. In 20 patients (group 1), «Neodolpasse¼ (a fixed combination of 30 mg Orphenadrine and 75 mg Diclofenac) was administered immediately after trachea extubation. The second injection was performed at VAS>50 mm not earlier than 12 hours after the first one. Patient-controlled analgesia (PCA) with morphine was started 2 hours after extubation, 20 patients of group 2 who were used PCA with Morphine as monotherapy. The intensity of pain taking into account the motor activity of patients was assessed a 100 mm visual-analog scale (VAS), as an additional objective criterion for the effectiveness of analgesia, the method of incentive spirometry was used. RESULTS: A decrease in the severity of pain according to VAS from an average of 41 to 19 mm (p=0.036) was achieved already by the 1st hour from the start of Neodolpasse infusion, and in 80% of patients this effect persisted for 24 hours. 2 patients (10%) needed the administration of the 2nd dose after 12 hours. The infusion of Morphine was started 2 hours after extubation, a significant decrease in pain intensity was noted only at 4th hour, a significant decrease in pain intensity was noted only by 4 hours, and significant differences in the severity of pain in the comparison groups persisted at almost all stages of the study. The analgesic effect of the combination of orphenadrine and diclofenac had a positive effect on the function of respiration system with an increase in MILC by 1.5 times from the beginning of the study. In group 2, the observed adverse effects were associated with the use of Morphine and depended on its dose. No adverse effects of Neodolpasse were noted. The total 24 hour consumption of Morphine at PCA averaged 22.6 mg, and in the Neodolpasse group - 9.35 mg (p<0.001). CONCLUSION: There were demonstrated high analgesic efficacy, safety and significant opioid-sparing effect of a fixed combination of orphenadrine and diclofenac in the early postoperative period of cardiac surgery patients.

Occurrence, ecological risk assessment and prioritization of pharmaceuticals and abuse drugs in estuarine waters along the São Paulo coast, Brazil.

The pollution of the surface waters by pharmaceuticals and personal care products (PPCPs) has attracted worldwide attention, but data regarding their occurrence and potential risks for the aquatic biota on tropical coastal rivers of South America are still scarce. In this context, the occurrence and the preliminary ecological risk assessment of eleven pharmaceuticals of various therapeutic classes (including cocaine and its primary metabolite, benzoylecgonine) were investigated, for the first time, in five rivers of São Paulo, southeast Brazil, covering a coastline of about 140 km, namely Perequê River, Itinga River, Mongaguá River, Itanhaém River and Guaraú River. Although these five rivers are born in well-preserved areas of the Atlantic rainforest biome, on its way to sea and when they cross the urban perimeter, they receive untreated sewage discharges containing a complex mixture of contaminants. In addition, a "persistence, bioaccumulation and toxicity" (PBT) approach allowed to pre-select the priority PPCPs to be monitored in this coastline. Identification of several PPCPs in the samples was done using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Ten PPCPs were successfully quantified in all five rivers, namely caffeine (9.00-560.00 ng/L), acetaminophen (

Comparative Risk of Opioid Overdose With Concomitant Use of Prescription Opioids and Skeletal Muscle Relaxants.

BACKGROUND AND OBJECTIVES: The concomitant use of prescription opioids and skeletal muscle relaxants has been associated with opioid overdose, but little data exist on the head-to-head safety of these drug combinations. The objective of this study was to compare the risk of opioid overdose among patients on long-term opioid therapy who concurrently initiate skeletal muscle relaxants. METHODS: We conducted an active comparator cohort study spanning 2000 to 2019 using healthcare utilization data from 4 US commercial and public insurance databases. Individuals were required to have at least 180 days of continuous enrollment and at least 90 days of continuous prescription opioid use immediately before and on the date of skeletal muscle relaxant initiation. Exposures were the concomitant use of prescription opioids and skeletal muscle relaxants, and the main outcome was the hazard ratio (HR) and bootstrapped 95% CI of opioid overdose resulting in an emergency department visit or hospitalization. The primary analysis quantified opioid overdose risk across 7 prescription opioid-skeletal muscle relaxant therapies and a negative control outcome (sepsis) to assess potential confounding by unmeasured illicit opioid use. Secondary analyses evaluated two-group and five-group comparisons in patients with similar baseline characteristics; individuals without previous recorded substance abuse; and subgroups stratified by baseline opioid dosage, benzodiazepine codispensing, and oxycodone or hydrocodone use. RESULTS: Weighted HR of opioid overdose relative to cyclobenzaprine was 2.52 (95% CI 1.29-4.90) for baclofen; 1.64 (95% CI 0.81-3.34) for carisoprodol; 1.14 (95% CI 0.53-2.46) for chlorzoxazone/orphenadrine; 0.46 (95% CI 0.17-1.24) for metaxalone; 1.00 (95% CI 0.45-2.20) for methocarbamol; and 1.07 (95% CI 0.49-2.33) for tizanidine in the 30-day intention-to-treat analysis. Findings were similar in the as-treated analysis, 2-group and 5-group comparisons, and patients without previous recorded substance abuse. None of the therapies relative to cyclobenzaprine were associated with sepsis, and no subgroups indicated an increased risk of opioid overdose. DISCUSSION: Concomitant use of prescription opioids and baclofen relative to cyclobenzaprine is associated with opioid overdose. Clinical interventions may focus on prescribing alternatives in the same drug class or providing access to opioid antagonists if treatment with both medications is necessary for pain management.

First report on the occurrence of pharmaceuticals and cocaine in the coastal waters of Santa Catarina, Brazil, and its related ecological risk assessment.

The worldwide occurrence of pharmaceuticals and personal care products (PPCPs) in aquatic ecosystems is reason for public concern. These emerging micropollutants include a large and diverse group of organic compounds, with continuous input, high environmental persistence and potential threat to biota and human health. The aim of this study was to evaluate, for the first time, the occurrence of twenty-seven PPCPs of various therapeutic classes (including cocaine and its primary metabolite, benzoylecgonine), in the coastal waters of Santa Catarina, southern Brazil. Water samples were taken in November 2020, during the low tide periods, at eight sampling points located along the coast of Santa Catarina, covering its entire geographical extension. Sampling was carried out in triplicate and at different depths of the water column. Nine compounds were detected through liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS): caffeine (12.58-119.80 ng/L), diclofenac (1.34-7.92 ng/L), atenolol (1.13-2.50 ng/L), losartan (0.43-3.20 ng/L), acetaminophen (0.21-10.04 ng/L), orphenadrine (0.07-0.09 ng/L), cocaine (0.02-0.17 ng/L), benzoylecgonine (0.01-1.1 ng/L) and carbamazepine (0.02-0.27 ng/L). The highest occurrence of these compounds was detected in the northern and central coastal region of Santa Catarina, namely in Penha and Palhoça cities. Moreover, the risk assessment showed that almost compounds (atenolol, benzoylecgonine, carbamazepine, cocaine and orphenadrine) presented no ecological risk in the recorded concentrations. However, a few compounds suggest low (caffeine and diclofenac) to moderate (acetaminophen and losartan) risk taking into consideration the acute and chronic effects for the three trophic levels (algae, crustacean and fish) tested. These compounds are usually found in areas with high population density, aggravated by tourism, because of the sanitary sewage and solid waste. Although in low concentrations, the occurrence of these chemical compounds can imply deleterious effects on the environmental health of Santa Catarina coastal zone, and therefore deserve more attention by the public authorities and environmental agencies.

[Efficiency and safety of a fixed combination of Orphenadrine and Diclofenac for postoperative analgesia in cardiac surgery patients]. / Effektivnost' i bezopasnost' ispol'zovaniya fiksirovannoi kombinatsii orfenadrina i diklofenaka dlya posleoperatsionnoi analgezii u kardiokhirurgicheskikh bol'nykh.

OBJECTIVE: Evaluation of the safety and effectiveness of the use of a fixed combination of orphenadrine and diclofenac for analgesia in the early postoperative period of cardiac surgery patients. MATERIAL AND METHODS: There were two analgesia regimens evaluated in a retrospective comparative study. In 23 patients (group 1), Neodolpasse (a fixed combination of 30 mg orphenadrine and 75 mg diclofenac) was administered immediately after trachea extubation. When the severity of pain in VAS increased to more than 50 mm, so 20 mg trimeperidine was administered. In group 2 of 20 patients analgesia in group 2 was performed with patient-controlled analgesia (PCA) with Promedol (trimeperidine) as monotherapy. The intensity of pain was assessed a 100 mm visual-analog scale (VAS) and 5-channel verbal scale (VS) for assessment the severity of the pain syndrome during the patient's moving activity. RESULTS: A decrease in the severity of the pain syndrome according to VAS from 68.31 to 21.96 mm (p<0.001) was achieved by the first hour after the start of the infusion of Neodolpasse persisted for 24 hours of 65% patients. 4 patients (35%) needed the administration of the 2nd dose after 12 hours. The infusion of trimeperidine was started 2 hours after extubation, a significant decrease in pain intensity was noted only at 6th hour, and further differences in the severity of pain in the comparative groups did not significantly differ. In group 2, the observed adverse effects were associated with the use of trimeperidine and depended on its dose. No adverse effects of Neodolpasse were noted. In the Neodolpasse group no adverse effects of the treatment was noted. The total 24 hour consumption of trimeperidine at PCA averaged 72.3 mg, and in the Neodolpasse group - 6.96 mg (p=0.00042). CONCLUSION: There were demonstrated safety, high analgesic efficacy and significant opioid-sparing effect of a fixed combination of Orphenadrine and Diclofenac in the early postoperative period of cardiac surgery patients within the framework of the inclusion and exclusion criteria accepted in the study.

Intravenous ibuprofen versus diclofenac plus orphenadrine in orthognathic surgery: a prospective, randomized, double-blind, controlled clinical study.

OBJECTIVES: The aim of this prospective, randomized, double-blind, controlled clinical study was to evaluate the analgesic effect of ibuprofen versus diclofenac plus orphenadrine on postoperative pain in orthognathic surgery. MATERIAL AND METHODS: Patients who underwent orthognathic surgery were randomized into two groups to receive intravenously either 600 mg of ibuprofen (I-group) or 75 mg diclofenac plus 30 mg orphenadrine (D-group), both of which were given twice daily. Additionally, both groups were given metamizole 500 mg. Rescue pain medication consisted of acetaminophen 1000 mg and piritramide 7.5 mg as needed. To assess the pain intensity, the primary end point was the numeric rating scale (NRS) recorded over the course of the hospital stay three times daily for 3 days. RESULTS: One hundred nine patients were enrolled (age range, 18 to 61 years) between May 2019 and November 2020. Forty-eight bilateral sagittal split osteotomies (BSSO) and 51 bimaxillary osteotomies (BIMAX) were performed. Surgical subgroup analysis found a significant higher mean NRS (2.73 vs.1.23) in the BIMAX D-group vs. I-group (p = 0.015) on the third postoperative day. Additionally, as the patient's body mass index (BMI) increased, the mean NRS (r = 0.517, p = 0.001) also increased. No differences were found between age, gender, length of hospital stay, weight, operating times, number of patients with complete pain relief, acetaminophen or piritramide intake, and NRS values. No adverse events were observed. CONCLUSION: The results of this study demonstrate that ibuprofen administration and lower BMI were associated with less pain for patients who underwent bimaxillary osteotomy on the third postoperative day. Therefore, surgeons may prefer ibuprofen for more effective pain relief after orthognathic surgery. CLINICAL RELEVANCE: Ibuprofen differs from diclofenac plus orphenadrine in class and is a powerful analgetic after orthognathic surgery.

The Relative Efficacy of Seven Skeletal Muscle Relaxants. An Analysis of Data From Randomized Studies.

BACKGROUND: Low back pain (LBP) causes 2.6 million visits to U.S. emergency departments (EDs) annually. These patients are often treated with skeletal muscle relaxants (SMRs). OBJECTIVES: The goal of this study was to determine whether efficacy of SMRs is associated with age, sex, or baseline LBP severity. METHODS: This was a planned analysis of data from 4 randomized studies of patients with acute nonradicular LBP. Patients were enrolled during an ED visit and followed-up 1 week later. The primary outcome was improvement in the Roland-Morris Disability Questionnaire (RMDQ) between ED discharge and the 1-week follow-up. We compared the change in RMDQ among 8 groups: placebo, baclofen, metaxalone, tizanidine, diazepam, orphenadrine, methocarbamol, and cyclobenzaprine. All patients also received a nonsteroidal anti-inflammatory drug. We performed analysis of variance to determine statistically significant differences between medications and linear regression to determine the association of age, sex, and baseline severity with the primary outcome. RESULTS: The mean improvement in RMDQ per group was placebo 10.5 (95% confidence interval [CI] 9.5-11.5), baclofen 10.6 (95% CI 8.6-12.7), metaxalone 10.3 (95% CI 8.1-12.4), tizanidine 11.5 (95% CI 9.5-13.4), diazepam 11.1 (95% CI 9-13.2), orphenadrine 9.5 (95% CI 7.4-11.5), methocarbamol 8.1 (95% CI 6.1-10.1), and cyclobenzaprine 10.1 (95% CI 8.3-12). The between-group differences were not statistically significantly different. Results were similar regardless of age, sex, and baseline severity. Higher baseline RMDQ was associated with greater clinical improvement (B coefficient 5.7, p < 0.01). Adverse medication effects were more common with cyclobenzaprine than with placebo (p < 0.01). CONCLUSIONS: Among patients in the ED with acute LBP treated with a nonsteroidal anti-inflammatory drug, SMRs do not improve outcomes more than placebo. Neither age, sex, nor baseline impairment impacts these results.

[Clinical experience with the use of a fixed combination of diclofenac and orphenadrine in the treatment of acute pain syndrome]. / Klinicheskii opyt primeneniya fiksirovannoi kombinatsii diklofenaka i orfenadrina v terapii ostrogo bolevogo sindroma.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and muscle relaxants (MR) are successfully used to relieve pain, both in monotherapy and in combinations. The use of fixed drug combinations not only greatly facilitates daily clinical practice and increases patient adherence, but due to the potentiation of pharmacological effects, it allows to achieve better treatment results. This paper presents 3 clinical cases of successful inpatient use of a fixed combination of diclofenac 75 mg and orphenadrine 30 mg in the form of an infusion solution (NEODOLPASSE) for relief of acute back musculoskeletal pain syndrome.

[The efficacy of the combination of diclofenac and orphenadrine in the treatment of dorsalgia]. / Effektivnost' kombinatsii diklofenaka i orfenadrina v terapii dorsalgii.

The high prevalence of dorsalgia and dorsopathy among the adult population makes a significant contribution to the structure of the financial burden of health care systems. The use of non-steroidal anti-inflammatory drugs (NSAIDs) as the basis for the pharmacotherapy of dorsopathy is recommended by most international clinical guidelines. The pharmacodynamic effects of NSAIDs underlie the clinical efficacy of this group of drugs in patients with pain of musculoskeletal origin, while monotherapy is not always accompanied by the rapid development of a persistent analgesic effect. An urgent direction in the therapy of dorsopathies may include combination of NSAIDs with analgesic drugs of other pharmacological groups capable of additive action. The fixed combination of diclofenac, 75 mg, and orphenadrine, 50 mg, allows achieving an effective analgesic effect in patients with lower back pain of various etiologies. It was demonstrated in a series of clinical cases that included 4 patients with dorsopathy who were treated at the City Clinical Hospital No. 24, Moscow in 2020.