[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.

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.

[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.

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.

Reduction of tinnitus severity by the centrally acting muscle relaxant cyclobenzaprine: an open-label pilot study.

Tinnitus, the phantom perception of sounds, is a highly prevalent disorder. Although a wide variety of drugs have been investigated off label for the treatment of tinnitus, there is no approved pharmacotherapy. We report an open-label exploratory pilot study to assess the effect of muscle relaxants acting on the central nervous system on tinnitus patients. Cyclobenzaprine at high (30 mg) and low doses (10 mg), orphenadrine (100 mg), tizanidine (24 mg) and eperisone (50 mg) were administered to a maximum of 20 patients per group over a 12-week period. High-dose cyclobenzaprine resulted in a significant reduction in the Tinnitus Handicap Inventory (THI) score between baseline and week 12 in the intention-to-treat sample. On the other hand, other treatments were not effective. These results were confirmed in an explorative analysis where baseline corrected THI and Clinical Global Impression scores at week 12 were compared between groups. The present open trial presents a new promising pharmacotherapy for tinnitus that should be validated in placebo-controlled double-blind trials.

[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.

[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.

[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.

Opiate sparing effect of fixed combination of diclophenac and orphenadrine after unilateral total hip arthroplasty: A double-blind, randomized, placebo-controlled, multi-centre clinical trial.

Multimodal pain management combines analgesics to improve analgesia and reduce side effects. This study investigates the fixed combination of diclophenac and orphenadrin (Neodolpasse(®) Infusion Solution) in patients after unilateral total hip arthroplasty (THA). This prospective, randomized, double-blind, placebo-controlled, multi-centre clinical study enrolled 120 patients receiving patient-controlled analgesia (PCA). Isotonic saline was infused as placebo. The primary efficacy goal was defined as reduction of PCA analgesics used over the first 24 h post-surgery. The study used a three-stage group sequential test design with two interim analyses. Analgesia was monitored by visual analogue scale and verbal rating. Infusion of the Neodolpasse(®) Infusion Solution resulted in a significant reduction in the PCA analgesic requirements by approximately 30% (38.7 ± 21.3 mg vs. 55.9 ± 31.1 mg; p = 0.0004) while maintaining adequate analgesia and patient safety. This study demonstrates that Neodolpasse(®) Infusion Solution significantly reduces PCA analgesic requirements without compromising analgesic effectiveness and safety in THA patients.

[Diclofenac/orphenadrine as a combined analgetic in post-operative relief of pain]. / Diclofenac/orphenadrin kombinált analgetikum a posztoperatív fájdalomcsillapításban.

The authors compared the potency, safety and tolerability of combined infusion containing non-steroid anti-inflammation diclofenac and central muscle relaxant orphenadrine, and those of tramadol HCl, during postoperative pain relief after low and middle category operations. The test was an open, group- and self-controlled, prospective, randomised, IV. phase clinical test. The involved 60 patients were given analgesics for 74 days. The patients were divided into three groups: those in group A ( n = 19) were given diclofenac-orphenadrine, those in group B ( n = 30) tramadol, while those in group C ( n = 11) both diclofenac-orphenadrine and tramadol. The received data were statistically analysed. For the assessment of the analgesics' potency, the visual analogue scale (VAS) was used. As a result of the treatment, VAS values in all three groups decreased significantly ( p < 0.001) both in inactive (-2.5, -3.7, -3.0) and active (-3.0, -3.8, -3.4) state, so pain relief was successful. This was also supported by the analysis of cardiovascular parameters. At the end of the treatment, both the patients and the physicians considered potency significantly ( p < 0.05 and p < 0.01) better in group A which received only diclofenac-orphenadrine infusion. Analysing the quantity of used analgesics, the quantity of tramadol administered as a complement in group C was significantly smaller than in group B receiving only tramadol ( B: 87.5 mg, C: 61.5 mg, p < 0.01), which means that diclofenac-orphenadrine infusion increased the analgesic effect of tramadol. Laboratory parameters measured at the beginning and at the end of treatment were inside physiological limits, as side effects nausea and vomiting were observed in 3 cases. Based on all this, diclofenac-orphenadrine infusion is considered an effective and safe analgesic which is easy to administer and to combine in pain relief after small and middle category operations.

Are there alternatives to the use of quinine to treat nocturnal leg cramps?

OBJECTIVE: To review the efficacy and tolerability profiles of quinine in nocturnal and dialysis-associated leg cramps and to examine potential alternative agents. DATA SOURCES: Selection and extraction: a MEDLINE/PubMed, English-language literature search from 1966 to the present using quinine, leg cramps, vitamin E, verapamil, muscle relaxants, gabapentin as search terms. DATA SYNTHESIS: Quinine, an alkaloid originally isolated from the cinchona tree, has been used for many years to treat/prevent leg cramps. In the mid-1990s, the Food and Drug Administration (FDA) banned over-the-counter availability of quinine and marketing of prescription quinine products for leg cramps. In early 2007, FDA banned all prescription quinine products other than Qualaquin. FDA acted in this manner because of a perception that quinine is not effective for this condition and that its risk potential far exceeds its efficacy potential. Efficacy trials for quinine in leg cramps have numerous design flaws that have resulted in poor quality data, producing both positive and negative findings. Two meta-analyses have reached different conclusions. Superimposed on the questionable efficacy of quinine is the well-known toxicity profile of the drug, involving the hematologic, renal, neurologic, cardiac, and endocrine systems. CONCLUSION: Are there any alternatives to quinine for leg cramps? Data are available supporting the potential efficacy of verapamil, gabapentin, carisoprodol, and orphenadrine in the general population, and vitamin E in the dialysis population. One or more of these agents should be tried before resorting to a time-limited (four- to six-week) trial of quinine for the treatment/prevention of leg cramps.

Anticholinergic drug-induced delirium in an elderly Alzheimer's dementia patient.

Drug-induced delirium is a common matter in the elderly and anticholinergics, together with a number of different drugs, may significantly contribute to the delirium onset, especially in demented people. We report a case of a probable anticholinergic drug-induced delirium in an elderly patient. An 80-year-old man with Alzheimer's dementia presented with wandering, depressed mood with crying, somatic worries, anedonism and suicide recurrent ideas. A first external psychiatric assessment led to the diagnosis of melancholic depression and therapy with haloperidol 2mg/day, orphenadrine 100mg daily, amitriptyline 40 mg/day, lorazepam 2mg/day was started. Two weeks later patient suddenly developed delirium, characterized by nocturnal agitation, severe insomnia, daytime sedation, confusion, hallucinations and persecutory delusions. These symptoms progressively worsened, with the consequent caregiver's stress. A geriatric consultation excluded the main causes of delirium, therefore both Operative Units of Pharmacovigilance and Psychiatry were activated, for a clinical pharmacological and psychiatric assessment. Haloperidol, amitriptyline and orphenadrine were promptly dismissed. The patient began a treatment with quetiapine 25mg/day for two days, then twice a day, and infusion of saline 1000 ml/day for two days; psychiatric symptoms gradually diminished and therapy with galantamine was begun. We postulate that this clinical report is suggestive for an anticholinergic drug- induced delirium since the Naranjo probability scale indicated a probable relationship between delirium and drug therapy. In conclusion, a complete geriatric, pharmacological, and psychiatric evaluation might be necessary in order to reduce the adverse drug reactions in older patients treated with many drugs.

Comparison of the analgesic effects of a fixed-dose combination of orphenadrine and diclofenac (Neodolpasse) with its single active ingredients diclofenac and orphenadrine: a placebo-controlled study using laser-induced somatosensory-evoked potentials from capsaicin-induced hyperalgesic human skin.

OBJECTIVE: The aim of this study was to investigate the analgesic efficacy of Neodolpasse, a fixed-dose combination of orphenadrine and diclofenac, compared with those of its single active ingredients in a human pain model. METHODS: The study was designed as a randomised, double-blind, placebo-controlled, four-period crossover study. Twenty-four healthy female and male subjects received single infusions of Neodolpasse, orphenadrine, diclofenac or saline solution over 60 minutes. Infusions were separated by a 1-week washout period. Neurogenic inflammation and hyperalgesia were induced by topical occlusive application of a 1% capsaicin solution for 30 minutes on defined skin areas on the back. The pain response to CO2 laser pulses applied to the capsaicin-pretreated skin was measured by event-related vertex EEG recordings. This allowed us to study the influence of a single infusion on the central P2- and peripheral N1-components of laser-induced somatosensory-evoked potentials (LSEP) as a measure of pain response. RESULTS: Although none of the active treatments had a significant effect on the peripheral N1-component, all active treatments reduced the P2-component of the LSEP, reflecting central/spinal analgesic (anti-hyperalgesic) effects. These effects were statistically significant for orphenadrine (p < 0.0001) and for the combination of orphenadrine and diclofenac (p < 0.0013). The single ingredient diclofenac reduced the P2-component by a value just below clinical relevance (p < 0.0848). CONCLUSION: This study demonstrated the efficacy of Neodolpasse in a human pain model. The observed effect was mainly caused by central mechanisms and was found to be superior for the fixed-dose combination of orphenadrine and diclofenac compared with the individual ingredients. Both components contributed to the effect of the combination in an additive fashion, which can be explained by the different molecular mechanisms of action of each drug.

Impaired cognitive shifting in parkinsonian patients on anticholinergic therapy.

In this study we established that cognitive shifting, an ability that is known to be affected in PD, is more impaired in PD patients, treated with anticholinergics, than in de novo patients. Eleven PD patients on anticholinergic monotherapy were compared with 30 de novo patients. The groups did not differ with respect to age, duration and severity of PD, and depression, nor with respect to general intelligence or attention. We assessed cognitive shifting with three different card-sorting tests. The patients on anticholinergics showed a poorer performance on all card-sorting tests than the de novo patients did. The patients on anticholinergics needed significantly more trials in two card-sorting tests and discovered significantly less categories in total. There was also a significant difference in memory performance, but memory performance did not correlate with any score on the card-sorting tests. This indicates that the performance on card-sorting tests and the memory performance were independent.

Orphenadrine prevents 3-nitropropionic acid-induced neurotoxicity in vitro and in vivo.

1. Previous studies indicate that 3-nitropropionic acid (3-NPA) neurotoxicity involves the excitotoxic activation of N-methyl-D-aspartate (NMDA) receptors. Thus, we examined the effect of orphenadrine (an anticholinergic drug with NMDA receptor antagonist properties) on 3-NPA neurotoxicity in both cultured rat cerebellar granule cells (CGCs) and in rats. 2. Orphenadrine protected CGCs from 3-NPA-induced mortality, as assessed by both the neutral red viability assay and laser scanning cytometry, using propidium iodide staining. 3. For rats, two indirect markers of neuronal damage were used: the binding of [(3)H]-PK 11195 to the peripheral-type benzodiazepine receptor (PBR), a microglial marker, and expression of the 27 kD heat-shock protein (HSP27), a marker of activated astroglia. Systemic administration of 3-NPA (30 mg kg(-1) per day for 3 days) induced a 170% increase in [(3)H]-PK 11195 binding, and expression of HSP27. 4. Both the increase in [(3)H]-PK 11195 and HSP 27 expression were prevented by previous administration of 30 mg kg(-1) per day of orphenadrine for 3 days. Lower doses (10 and 20 mg kg(-1)) had no protective effect. Orphenadrine also reduced 3-NPA-induced mortality in a dose-dependent manner. 5. We propose that orphenadrine or orphenadrine-like drugs could be used to treat neurodegenerative disorders mediated by overactivation of NMDA receptors.

Neuronal sensitization and its behavioral correlates in a rat model of neuropathy are prevented by a cyclic analog of orphenadrine.

N-methyl-D-aspartic acid (NMDA) is an agonist at the homonymous receptor implicated in the development of neuronal sensitization and its behavioral correlates. An effective modulation of the NMDA effects, achieved also by uncompetitive antagonists, could contribute to controlling pain symptoms in several neuropathic syndromes. Because nefopam is a known analgesic derivative of orphenadrine and of its congener diphenhydramine, both uncompetitive NMDA receptor antagonists, we tested the effect of nefopam on the developing pain and neuronal anomalies in an animal model of chronic pain with NMDA receptor involvement. A single intraperitoneal injection of nefopam was administered twenty minutes prior to the chronic constriction injury of the sciatic nerve (CCI rats). In the first 10 days, nefopam (30 mg/kg) significantly decreased behavioral signs of neuropathic pain and the stimulus-evoked electrophysiological anomalies in recordings at 14 days, with only slight manifestation afterwards. The dose of 20 mg/kg was ineffective. Nefopam injected after constriction was ineffective. In normal non-operated rats, Nefopam had no effect on the electrophysiological and behavioral parameters. Iontophoretic nefopam (1 mM, 50-80 nA, positive current) in normal rats did not change the spontaneous neuronal activity, but reduced the mean response to noxious stimuli and the concurrent iontophoretic NMDA evoked activity. In CCI rats, iontophoretic nefopam did not significantly modify the spontaneous hyperactivity but reduced significantly both the frequency of the responses to noxious stimuli, and the duration of the afterdischarge. We propose that nefopam exerts a preventive analgesic effect, with a possible role in modulating NMDA receptor-mediated effects in central sensitization.

Visual hallucinations and delirium during treatment with amantadine (Symmetrel).

In 13 elderly patients, 12 of whom had Parkinson's disease, visual hallucinations and delirium developed as a side effect of amantadine hydrochloride (Symmetrel) therapy. The symptoms promptly disappearred when amantadine was discontinued. Thereafter, each parkinsonian patient was treated satisfactorily with levo-dopa. Treatment with a combination of amantadine and an anticholinergic agent increases the likelihood of delirium because of the hazard of retention of urine. Although amantadine is effective in the treatment of Parkinson's disease in the elderly, the incidence of delirium as a complication seems higher in this age group.

A phase II antiemetic combination (COMD) for cisplatin-induced nausea and vomiting.

Thirteen patients resistant to high-dose metoclopramide (greater than or equal to 5 emetic episodes in 24 h following chemotherapy) were treated in the subsequent course of CDDP chemotherapy with COMD (chlorpromazine, orphenadrine, metoclopramide, dexamethasone). A statistically significant reduction in the number of vomiting episodes was obtained, and 69% of patients showed a better acceptance of CDDP treatment. Subsequently, the same antiemetic combination was administered to 31 untreated patients receiving CDDP alone for the first time: 67.7% obtained complete protection from vomiting with minimal toxicity. According to our experience, COMD is an efficacious and well-tolerated antiemetic combination in cisplatin-treated patients; however, further studies with larger numbers of patients are required to confirm these preliminary results.