A Randomized, Double-Blind, Placebo-Controlled Trial of Naproxen With or Without Orphenadrine or Methocarbamol for Acute Low Back Pain.

STUDY OBJECTIVE: In US emergency departments (EDs), patients with low back pain are often treated with nonsteroidal anti-inflammatory drugs and muscle relaxants. We compare functional outcomes among patients randomized to a 1-week course of naproxen+placebo versus naproxen+orphenadrine or naproxen+methocarbamol. METHODS: This was a randomized, double-blind, comparative effectiveness trial conducted in 2 urban EDs. Patients presenting with acute, nontraumatic, nonradicular low back pain were enrolled. The primary outcome was improvement on the Roland-Morris Disability Questionnaire (RMDQ) between ED discharge and 1 week later. All patients were given 14 tablets of naproxen 500 mg, to be used twice a day, as needed for low back pain. Additionally, patients were randomized to receive a 1-week supply of orphenadrine 100 mg, to be used twice a day as needed, methocarbamol 750 mg, to be used as 1 or 2 tablets 3 times per day as needed, or placebo. All patients received a standardized 10-minute low back pain educational session before discharge. RESULTS: Two hundred forty patients were randomized. Baseline demographic characteristics were comparable. The mean RMDQ score of patients randomized to naproxen+placebo improved by 10.9 points (95% confidence interval [CI] 8.9 to 12.9). The mean RMDQ score of patients randomized to naproxen+orphenadrine improved by 9.4 points (95% CI 7.4 to 11.5). The mean RMDQ score of patients randomized to naproxen+methocarbamol improved by 8.1 points (95% CI 6.1 to 10.1). None of the between-group differences surpassed our threshold for clinical significance. Adverse events were reported by 17% (95% CI 10% to 28%) of placebo patients, 9% (95% CI 4% to 19%) of orphenadrine patients, and 19% (95% CI 11% to 29%) of methocarbamol patients. CONCLUSION: Among ED patients with acute, nontraumatic, nonradicular low back pain, combining naproxen with either orphenadrine or methocarbamol did not improve functional outcomes compared with naproxen+placebo.

Intrathecal orphenadrine elicits spinal block in the rat.

The purpose of this study was to estimate the local anesthetic effect of orphenadrine, an anti-muscarinic agent, in spinal anesthesia and its comparison with the local anesthetic lidocaine. After the rat was injected intrathecally, the spinal block of orphenadrine and lidocaine was constructed in a dosage-dependent fashion. The potency and duration of spinal anesthesia with orphenadrine were compared with that of lidocaine. Our data demonstrated that orphenadrine and lidocaine elicited dose-dependent spinal blockades on the motor function, sensory, and proprioception. On the 50% effective dose (ED50) basis, the ranks of potency in motor function, nociception, and proprioception were orphenadrine>lidocaine (P<0.01). At equipotent doses (ED25, ED50, ED75), the block duration elicited by orphenadrine was greater than that elicited by lidocaine (P<0.01). Orphenadrine, but not lidocaine, exhibited longer duration of nociceptive/sensory blockade than that of motor blockade at equipotent doses. Ineffective-dose orphenadrine as adjuvant did not enhance spinal anesthesia with lidocaine. The preclinical data revealed that orphenadrine with a more sensory-selective action over motor block exhibited more potent and longer spinal anesthesia when compared to lidocaine.

Liver tumor promoting effect of orphenadrine in rats and its possible mechanism of action including CAR activation and oxidative stress.

Orphenadrine (ORPH), an anticholinergic agent, is a cytochrome P450 (CYP) 2B inducer. CYP2B inducers are known to have liver tumor-promoting effects in rats. In this study, we performed a rat two-stage liver carcinogenesis bioassay to examine the tumor-promoting effect of ORPH and to clarify its possible mechanism of action. Male rats were given a single intraperitoneal injection of N-diethylnitrosamine (DEN) as an initiation treatment. Two weeks after DEN administration, rats were fed a diet containing ORPH (0, 750, or 1,500 ppm) for 6 weeks. One week after the ORPH-administration rats were subjected to two-thirds partial hepatectomy for the acceleration of hepatocellular proliferation. The number and area of glutathione S-transferase placental form-positive foci significantly increased in the DEN-ORPH groups. Real-time RT-PCR revealed increased mRNA expression levels of Cyp2b1/2, Mrp2 and Cyclin D1 in the DEN-ORPH groups and of Gpx2 and Gstm3 in the DEN-High ORPH group. Microsomal reactive oxygen species (ROS) production and oxidative stress markers such as thiobarbituric acid-reactive substances and 8-hydroxydeoxyguanosine were increased in the DEN-High ORPH group. Immunohistochemically, constitutively active/androstane receptor (CAR) were clearly localized in the nuclei of hepatocytes in the DEN-ORPH groups. These results suggest that ORPH causes nuclear translocation of CAR resulting in the induction of the liver tumor-promoting activity. Furthermore, oxidative stress resulting from ROS production is also involved in the liver tumor-promoting activity of ORPH.

Enhanced liver tumor promotion activity in rats subjected to combined administration of phenobarbital and orphenadrine.

Phenobarbital (PB) and orphenadrine (ORPH) are cytochrome P450 (CYP) 2B inducers and have liver tumor-promoting effects in rats. In this study, we performed a rat two-stage liver carcinogenesis bioassay to examine the tumor-promoting effect of PB and ORPH co-administration. Twelve male rats per group were given an intraperitoneal injection of N-diethylnitrosamine (DEN) for initiation. Two-week after DEN administration, rats were given PB (60 or 120 ppm in drinking water), ORPH (750 or 1,500 ppm in diet) or 60 ppm PB+750 ppm ORPH for 6-week. One-week after the PB/ORPH treatment, all rats were subjected to two-thirds partial hepatectomy. To evaluate the effect of the combined administration, we used two statistical models: a heteroadditive model and an isoadditive model. In the heteroadditive model, the net values of the number and area of glutathione S-transferase placental form (GST-P) positive foci, Cyp2b1/2, Gstm3 and Gpx2 mRNA levels, microsomal reactive oxygen species (ROS) production and thiobarbituric acid-reactive substances level in the PB+ORPH group were significantly higher than the sum of the net values of those in the Low PB and Low ORPH groups. In the isoadditive model, the average values of the area of GST-P positive foci and PCNA positive hepatocyte ratio and Gstm3 mRNA level in the PB+ORPH group were significantly higher than the average values of those in the High PB and High ORPH groups. These results suggest that PB and ORPH co-administration causes synergistic effects in liver tumor-promoting activity in rats resulting from oxidative stress due to enhanced microsomal ROS production.

The use of antipsychotic and anticholinergic antiparkinson drugs in Norway after the withdrawal of orphenadrine.

AIMS: Extrapyramidal side-effects induced by antipsychotic drugs are treated with dose reduction or substitution with another antipsychotic drug or by the addition of anticholinergic antiparkinson agents. The withdrawal of orphenadrine from the Norwegian market provided a possibility to investigate to what degree these alternative measures were taken in clinical practice. METHODS: Data were drawn from the Norwegian Prescription Database on the sales of antipsychotics and one of the two anticholinergic antiparkinson agents marketed in 2004, orphenadrine and biperiden, to a total of 39 758 outpatients. The patients were reinvestigated in 2007. The consequences of the withdrawal of orphenadrine from the Norwegian market in 2005 regarding dosing, switching and cessation of antipsychotics and use of anticholinergics were assessed for orphenadrine users compared with biperiden users. RESULTS: Of the patients originally using orphenadrine, 28.4% stopped using the drug without reducing the antipsychotic dose or replacing orphenadrine with another anticholinergic agent. The corresponding number for biperiden users was 19.3%. Only 11.8% of patients switched to another antipsychotic drug, but they used significantly lower antipsychotic doses than those who stayed on the same drug. CONCLUSION: The use of anticholinergic antiparkinson agents could be seen as superfluous for at least one-third of patients.

Determination of orphenadrine plasma levels using HPLC with diode array detection and a novel solid-phase extraction procedure in psychiatric patients.

Orphenadrine is an antimuscarinic agent mainly used for the treatment of parkinsonism and to alleviate the neuroleptic syndrome induced by antipsychotic drugs. A new, rapid analytical method, based on liquid chromatography with diode array detection (DAD), has been developed and applied to the determination of orphenadrine in plasma of schizophrenic patients for therapeutic drug monitoring and toxicological purposes. The chromatographic separation was performed on a pentafluorophenyl reversed phase column with a mobile phase composed of acetonitrile-phosphate buffer mixture. DAD detection was carried out at 220 nm. A careful and rapid solid-phase extraction procedure on cyanopropyl cartridges was chosen for plasma sample purification and pre-concentration obtaining good extraction yield values for the analyte (>96.0%). The assays showed a linear response for orphenadrine (30-1000 ng mL(-1)). The method is also precise and selective. Thus, the method developed seems to be suitable for routine analysis of orphenadrine in psychiatric patients. Moreover, it was applied to plasma samples from a psychotic patient who had tried to poison himself with 1000 mg of orphenadrine and was undergoing polypharmacy.

Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine.

Orphenadrine is a drug acting on multiple targets, including muscarinic, histaminic, and NMDA receptors. It is used in the treatment of Parkinson's disease and in musculoskeletal disorders. It is also used as an analgesic, although its mechanism of action is still unknown. Both physiological and pharmacological results have demonstrated a critical role for voltage-gated sodium channels in many types of chronic pain syndromes. We tested the hypothesis that orphenadrine may block voltage-gated sodium channels. By using patch-clamp experiments, we evaluated the effects of the drug on whole-cell sodium currents in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels, as well as on whole-cell tetrodotoxin (TTX)-resistant sodium currents likely conducted by Nav1.8 and Nav1.9 channel subtypes in primary culture of rat DRG sensory neurons. The results indicate that orphenadrine inhibits sodium channels in a concentration-, voltage- and frequency-dependent manner. By using site-directed mutagenesis, we further show that orphenadrine binds to the same receptor as the local anesthetics. Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide. Low, clinically relevant orphenadrine concentration produces a significant block of Nav1.7, Nav1.8, and Nav1.9 channels, which are critical for experiencing pain sensations, indicating a role for sodium channel blockade in the clinical efficacy of orphenadrine as analgesic compound. On the other hand, block of Nav1.1 and Nav1.5 may contribute to the proconvulsive and proarrhythmic adverse reactions, especially observed during overdose.

Effects of cytochrome P450 inducers and inhibitors on the pharmacokinetics of intravenous furosemide in rats: involvement of CYP2C11, 2E1, 3A1 and 3A2 in furosemide metabolism.

OBJECTIVES: It has been reported that the non-renal clearance of furosemide was significantly faster in rats pretreated with phenobarbital but was not altered in rats pretreated with 3-methylcholanthrene. However, no studies on other cytochrome P450 (CYP) isozymes have yet been reported in rats. METHOD: Furosemide 20 mg/kg was administered intravenously to rats pretreated with various CYP inducers--3-methylcholanthrene, orphenadrine citrate and isoniazid, inducers of CYP1A1/2, 2B1/2 and 2E1, respectively, in rats--and inhibitors--SKF-525A (a non-specific inhibitor of CYP isozymes), sulfaphenazole, cimetidine, quinine hydrochloride and troleandomycin, inhibitors of CYP2C6, 2C11, 2D and 3A1/2, respectively, in rats. KEY FINDINGS: The non-renal clearance of furosemide was significantly faster (55.9% increase) in rats pretreated with isoniazid, but slower in those pretreated with cimetidine or troleandomycin (38.5% and 22.7% decreases, respectively), than controls. After incubation of furosemide with baculovirus-infected insect cells expressing CYP2C11, 2E1, 3A1 or 3A2, furosemide was metabolized via CYP2C11, 2E1, 3A1 and 3A2. CONCLUSIONS: These findings could help explain possible pharmacokinetic changes of furosemide in various rat disease models (where CYP2C11, 2E1, 3A1 and/or CYP3A2 are altered) and drug-drug interactions between furosemide and other drugs (mainly metabolized via CYP2C11, 2E1, 3A1 and/or 3A2).

The use and potential abuse of anticholinergic antiparkinson drugs in Norway: a pharmacoepidemiological study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Anticholinergic antiparkinson drugs are used to ameliorate extrapyramidal symptoms caused by either Parkinson's disease or antipsychotic drugs, but their use in the treatment of Parkinson's disease is assumed to be in decline. Patients with psychotic conditions have a high prevalence of abuse of drugs, including anticholinergic antiparkinson drugs. WHAT THIS STUDY ADDS: Anticholinergic antiparkinson drugs in Norway were primarily prescribed to patients using antipsychotic medication. The risk of abuse of this group of drugs was small, even among patients who probably abused other drugs. AIMS: The use of anticholinergic antiparkinson drugs is assumed to have shifted from the therapy of Parkinson's disease to the amelioration of extrapyramidal adverse effects induced by antipsychotic drugs. There is a considerable body of data suggesting that anticholinergic antiparkinson drugs have a potential for abuse. The aim was to investigate the use and potential abuse of this class of drugs in Norway. METHODS: Data were drawn from the Norwegian Prescription Database on sales to a total of 73 964 patients in 2004 of biperiden and orphenadrine, and use in patients with Parkinson's disease or in patients who were also prescribed antipsychotic agents. Possible abuse of these drugs was assessed by the level of use, skewedness of use, indications of drug-seeking behaviour and concomitant use of benzodiazepine tranquillizers, a group of prescription drugs with a recognized potential for abuse. RESULTS: Anticholinergic antiparkinson drugs were prescribed to 4.5% of all outpatients who used antipsychotic drugs. This outnumbered sales to patients with Parkinson's disease by >20 to 1. We found indications of abuse of benzodiazepine tranquillizers among patients using antipsychotics, but there were no clear indications of abuse of anticholinergics, even among patients who were strongly suspected of abuse of benzodiazepines. CONCLUSIONS: Anticholinergic antiparkinson drugs were used primarily by patients with psychotic illnesses. These patients have a very high prevalence of legal and illegal drug abuse, but the risk of abuse of anticholinergic antiparkinson drugs seemed small.

Pharmacokinetic, metabolism and withdrawal time of orphenadrine in camels (Camelus dromedarius) after intravenous administration.

The pharmacokinetics of orphenadrine (ORPH) following a single intravenous (i.v.) dose was investigated in six camels (Camelus dormedarius). Orphenadrine was extracted from the plasma using a simple sensitive liquid-liquid extraction method and determined by gas chromatography/mass spectrometry (GC/MS). Following i.v. administration plasma concentrations of ORPH decline bi-exponentially with distribution half-life (t(1/2)(alpha)) of 0.50+/-0.07h, elimination half-life (t(1/2)(beta)) of 3.57+/-0.55h, area under the time concentration curve (AUC) of 1.03+/-0.10g/hl(-1). The volume of distribution at steady state (Vd(ss)) 1.92+/-0.22lkg(-1), volume of the central compartment of the two compartment pharmacokinetic model (V(c)) 0.87+/-0.09lkg(-1), and total body clearance (Cl(T)) of 0.60+/-0.09l/hkg(-1). Three orphenadrine metabolites were identified in urine samples of camels. The first metabolite N-desmethyl-orphenadrine resulted from N-dealkylation of ORPH with molecular ion m/z 255. The second N,N-didesmethyl-orphenadrine, resulted from N-didesmethylation with molecular ion m/z 241. The third metabolite, hydroxyl-orphenadrine, resulted from the hydroxylation of ORPH with molecular ion m/z 285. ORPH and its metabolites in camel were extensively eliminated in conjugated form. ORPH remains detectable in camel urine for three days after i.v. administration of a single dose of 350mg orphenadrine aspartate.

Efficacy and safety of combined piroxicam, dexamethasone, orphenadrine, and cyanocobalamin treatment in mandibular molar surgery.

Third molar extraction is a common procedure frequently accompanied by moderate or severe pain, and involves sufficient numbers of patients to make studies relatively easy to perform. The aim of the present study was to determine the efficacy and safety of the therapeutic combination of 10 mg piroxicam, 1 mg dexamethasone, 35 mg orphenadrine citrate, and 2.5 mg cyanocobalamin (Rheumazin) when compared with 20 mg piroxicam alone (Feldene) in mandibular third molar surgery. Eighty patients scheduled for removal of the third molar were included in this randomized and double-blind study. They received (vo) Rheumazin or Feldene 30 min after tooth extraction and once daily for 4 consecutive days. Pain was determined by a visual analogue scale and by the need for escape analgesia (paracetamol). Facial swelling was evaluated with a measuring tape and adverse effects and patient satisfaction were recorded. There was no statistically significant difference in facial swelling between Rheumazin and Feldene (control group). Both drugs were equally effective in the control of pain, with Rheumazin displaying less adverse effects than Feldene. Therefore, Rheumazin appears to provide a better risk/benefit ratio in the mandibular molar surgery. Since the side effects resulting from nonsteroidal anti-inflammatory drug administration are a severe limitation to the routine use of these drugs in clinical practice, our results suggest that Rheumazin can be a good choice for third molar removal treatment.

Efficacy and safety of combined piroxicam, dexamethasone, orphenadrine, and cyanocobalamin treatment in mandibular molar surgery

Third molar extraction is a common procedure frequently accompanied by moderate or severe pain, and involves sufficient numbers of patients to make studies relatively easy to perform. The aim of the present study was to determine the efficacy and safety of the therapeutic combination of 10 mg piroxicam, 1 mg dexamethasone, 35 mg orphenadrine citrate, and 2.5 mg cyanocobalamin (Rheumazin®) when compared with 20 mg piroxicam alone (Feldene®) in mandibular third molar surgery. Eighty patients scheduled for removal of the third molar were included in this randomized and double-blind study. They received (vo) Rheumazin or Feldene 30 min after tooth extraction and once daily for 4 consecutive days. Pain was determined by a visual analogue scale and by the need for escape analgesia (paracetamol). Facial swelling was evaluated with a measuring tape and adverse effects and patient satisfaction were recorded. There was no statistically significant difference in facial swelling between Rheumazin and Feldene (control group). Both drugs were equally effective in the control of pain, with Rheumazin displaying less adverse effects than Feldene. Therefore, Rheumazin appears to provide a better risk/benefit ratio in the mandibular molar surgery. Since the side effects resulting from nonsteroidal anti-inflammatory drug administration are a severe limitation to the routine use of these drugs in clinical practice, our results suggest that Rheumazin can be a good choice for third molar removal treatment.

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.

Analgesic effects of low-dose intravenous orphenadrine in the state of capsaicin hyperalgesia. A randomised, placebo-controlled, double-blind cross-over study using laser somatosensory evoked potentials obtained from capsaicin-irritated skin in healthy volunteers.

The present investigation aimed to elucidate the analgesic efficacy of 30 mg of intravenous orphenadrine citrate (CAS 4682-36-4) in a human pain model. Eighteen healthy female and male subjects were enrolled and received single infusions of 30 mg orphenadrine citrate and matching placebo in two periods which were separated by a 1 week washout period. The study was designed as a randomised, double-blind, placebo-controlled, two-period, cross-over trial. The intended neurogenic inflammation and hyperalgesia were induced by topical, occlusive application of 1% capsaicin solution (INCI: Capsicum frutescens, containing capsaicinoides from Capsicum annuum annuum, CAS 84603-55-4) for 30 min on defined skin areas of the back. The pain response to CO2 laser pulses applied to the capsaicin pre-treated skin was measured by event related Vertex-EEG recordings. This technique allowed studying the influence of orphenadrine citrate on the (central) P2-component and the (peripheral) Ni-component of the pain response (LSEP). Both, orphenadrine citrate and placebo were given as intravenous infusions over 60 min. Orphenadrine citrate exerted a significant reduction in central and peripheral components of the pain response when compared to placebo. The effect on the central component was highly significant and more pronounced than the peripheral effect of the drug. The analgesic effect developed fast, was already present during infusion, was ongoing, and exceeded the observational period of 4 h after start of infusion. In summary, orphenadrine citrate was able to exert an analgesic/anti-hyperalgesic effect in a low-dose paradigm (30 mg dose) which was predominantly due to central/spinal mechanisms in this capsaicin model with laser somatosensory evoked potentials.

[Diclofenac 75mg. and 30 mg. orfenadine (Neodolpasse) versus placebo and piroxicam in postoperative analgesia after arthroscopy]. / Diklofenak 75 mg s orfenadinem 30 mg (NEODOLPASSE) versus placebo a piroxikam v pooperacní analgezii u artroskopií.

PURPOSE OF THE STUDY: Arthroscopy is often performed in an out-patient department or as one-day surgery. Opioids often used as postoperative analgesics may have unwanted side effects that may postpone the patient's discharge from hospital. This study was designed to evaluate a substitute for the most frequently used opioid pethidine. For pain relief, non-steroid anti-inflammatory drugs are recommended, but they offer a limited choice for parenteral administration. We used a new agent (Neodolpasse) based on diclophenac and orphenadine, and compared its efficacy with piroxicam and placebo. METHODS: A total of 119 patients scheduled for knee joint arthroscopy were included in this prospective study. In a randomized, double-blind manner, they received piroxicam (P), Neodolpasse (combining 75 mg diclophenac and 30 mg orphenadine; N) or placebo (C). The number of patients in groups P, N and C were 44, 35 and 40, respectively. The effect of therapy was evaluated on the basis of the following criteria: duration of post-operative analgesia until a request for another analgesic, pain intensity (0-10 VAS), side effects and the patient's satisfaction with analgesia. The efficacy was evaluated for 24 hours after arthroscopy; premedication and analgesia induction and administration followed the same anesthetic protocol in all groups. The ethic committee approved the study and patients gave their informed consent. The results were statistically evaluated using the ANOVA analysis of variance completed by a multiple comparison of levels of significance according to Bonferroni. The presence of side and unwanted effects was analyzed by the chi-square of Fisher's exact test. A p value les than 0.05 was regarded as statistically significant. RESULTS: There were significant differences in the number of patients not requiring further analgesic medication after arthroscopy (P 52.3% vs. C (11.7%) p < 0.05, N (68.6%) vs. C p < 0.001), lower average postoperative pain (0 to 10-point scale, P 2.4 vs. C 2.9 p < 0.05, N 1.5 vs. C p < 0.05) and fewer side effects (N vs. both P and C, p < 0.05). DISCUSSION: The combination of diclophenac with orphenadine for intravenous application has only recently been available in the Czech Republic. The addition of a central muscle relaxant to a peripheral analgesic has a better effect than diclophenac alone. This may also account for a longer duration of analgesia in comparison with piroxicam reported to have significantly longer analgesic effects. The new medication also had fewer side effects. It was interesting to record that even the patients who had more pain and shorter postoperative analgesia were satisfied with the therapy provided. CONCLUSIONS: The main result of this study is the finding that Neodolpasse significantly reduces the intensity of postoperative pain and increases the duration of postoperative analgesia after knee joint arthroscopy.

Upregulation of cytochromes P450 2B in rat liver by orphenadrine.

1 The alkylamine drug orphenadrine (ORPH) is an inducer and inhibitor of the microsomal cytochrome P450 (CYP) system in mammals. This study evaluated the selectivity of CYP induction by ORPH in rat liver. 2 Immunoblot analysis indicated that ORPH was a selective inducer of the phenobarbitone (PB)-inducible CYP2B in rat liver. CYP2B protein was increased to approximately 14-fold of levels in untreated rat liver. By comparison PB increased CYP2B expression 40-fold. Corresponding increases in the activity of CYP2B-dependent androstenedione 16beta-hydroxylation were measured in microsomes from ORPH and PB-induced rats. 3 Northern analysis indicated that CYP2B1/2 mRNA was increased in ORPH-induced rat liver. Consistent with this finding, ORPH was found to activate a PB-responsive enhancer module in constitutive androstane receptor (CAR)-transfected Hep G2 cells. 4 Other alkylamines like troleandomycin impair CYP turnover. We tested whether ORPH induction of CYP2B may include a post-translational component. In PB-pretreated animals ORPH administration delayed the loss of CYP2B after PB withdrawal, but no evidence for altered turnover was found. 5 These studies establish ORPH as a selective inducer of CYP2B in rat liver. Induction appears to be mediated pretranslationally by CAR activation of CYP2B gene transcription. Post-translational stabilisation by an ORPH metabolite does not elicit induction. Induction of CYP2B may influence pharmacokinetic interactions involving ORPH.

[Results of efficacy study with diclofenac/orphenadrine infusions in patients with musculoskeletal diseases and functional disorders]. / Ergebnisse einer Anwendungsbeobachtung mit Diclofenac/Orphenadrin-Infusionen bei Patienten mit muskuloskelettalen Krankheiten und Funktionsstörungen.

During a post-marketing surveillance study, 641 patients (age range 18 to 86 years) with painful rheumatic diseases, mostly of vertebral etiology, were given ready-for-use infusions containing a combination of the non-steroid antiphlogistic agent diclofenac (75 mg) and the muscle relaxing agent orphenadrine (30 mg) parenterally for 7 days. The goal of the study was to investigate efficacy, tolerability, and acceptance of this intravenous therapy in wide use in physicians' practices. At the end of treatment, the global evaluation resulted in a score of 1.6 on a scale of 1 (very good) to 4 (insufficient). The tolerability score was 1.3 and the acceptability score was 1.5. Only 20 patients (3.1%) had adverse effects, most of which were of gastrointestinal nature. The medication proved appropriate for use in the treatment of painful spine syndromes, inflammatory osteoarthritis, painful osteoporosis, post-operative conditions, and extra-articular rheumatism and could represent a first step towards multi-factorial therapeutic management of these diseases.