Epidemiological data, efficacy and safety of a paracetamol-tramadol fixed combination in the treatment of moderate-to-severe pain. SALZA: a post-marketing study in general practice.

OBJECTIVE: To evaluate the efficacy and safety of the paracetamol-tramadol combination (PTC) in treating moderate-to-severe pain, in patients aged 65 years and over within general practitioner (GP) practice centers. RESEARCH DESIGN AND METHODS: This was an observational, non-interventional, longitudinal, multicenter, open, non-comparative, prospective study. This intermediary analysis was of patients recruited before the French Health Authority confirmation (25th June, 2009) of the EMEA decision to withdraw all analgesics containing dextropropoxyphen. Trial registration information: This study has been submitted for approval to the CNIL and French Medical Council (CNOM) only. RESULTS: A total of 2663 patients aged 65 years or over were assessed 1 month after inclusion in the study. PTC was prescribed as first-line treatment in 30% of patients and, in the other cases, after failed or inadequate efficacy (69.8%), and/or as a result of safety problems (7.8%) with at least one other analgesic. During the month of the study period 14.7% of patients received an additional rescue analgesic. The study confirmed the efficacy of PTC with regard to pain intensity (-3.1 points reduction of pain scored 6.1 points on inclusion), pain relief (64.8% of patients experienced significant pain relief), patient satisfaction (90.5% of patients satisfied or completely satisfied) and clinical global impression evaluated by the patient (78.7% much or very much improved), regardless of the pain etiologies or duration of the underlying pathology. PTC was well-tolerated in this patient group, who had a mean age of 73.6 ± 6.6 years. A total of 119 patients (4.5%) reported at least one adverse event (AE). All were known and predictable AEs. This percentage is comparable to that found under similar conditions in patients of all ages (4.2%). CONCLUSIONS: PTC, due to the complementary action of its two analgesics, is effective in treating the different types of pain in a GP's practice setting and is well-tolerated, even in an elderly population. Study limitations include all those inherent to non-interventional and open-label observations.

[Liver and renal tolerance to paracetamol: 3 g or 4 g per day?]. / Tolérances hépatique et rénale du paracétamol: 3 g ou 4 g par jour?

OBJECTIVES: To compare the hepatic and renal safety profiles of two daily dosage regimens of paracetamol (acetaminophen) (3 g versus 4 g) in patients with painful chronic rheumatoid diseases. METHODS: Medical files of outpatients in the United Kingdom were investigated using an automated database. Two acetaminophen groups (3 g and 4 g) were compared with regard to demographic variables, treatments, associated diseases and occurrence of hepatorenal adverse events. Variables collected from the files for selected patients were also analyzed using the decision tree method to identify the specific variables best explaining the occurrence of hepatorenal adverse events. RESULTS: A total of 1.5 million medical files were investigated. Of the 7781 patients identified with paracetamol prescriptions for chronic rheumatoid disorders, 1868 (24%) were treated with 3 g/day and 5913 (76%) with 4 g/day. The mean overall duration of paracetamol exposure was 277 and 201 days respectively. No difference between the two acetaminophen groups was found with the numbers of patients with hepatorenal adverse events potentially related to acetaminophen intake (0.86%: group 3 g versus 0.68% group 4 g). Using the decision tree method, daily dosage of paracetamol (3 g or 4 g) was never identified as a discriminating variable capable of explaining the occurrence of hepatorenal adverse events. CONCLUSION: When risk factors are taken into account, such as concomitant chronic diseases, both daily dosages of paracetamol (3 g and 4 g) have a comparable hepatorenal safety profiles in rheumatology, even in elderly patients.

Time to onset of analgesia and analgesic efficacy of effervescent acetaminophen 1000 mg compared to tablet acetaminophen 1000 mg in postoperative dental pain: a single-dose, double-blind, randomized, placebo-controlled study.

This randomized, double-blind, placebo-controlled study compared the time to onset of analgesia and the analgesic efficacy of two formulations of acetaminophen 1000 mg--an effervescent solution and tablet--in 242 patients with moderate or severe pain following dental surgery. Onset of analgesia was determined using a two-stopwatch procedure. Analgesia was assessed over a 4-hour period. Treatments were compared using standard indexes of pain intensity and pain relief and summary measures. Both acetaminophen formulations were significantly more effective than their corresponding placebo for all efficacy assessments. The median time to onset of analgesia was significantly shorter with effervescent acetaminophen (20 minutes) compared to tablet acetaminophen (45 minutes). During the first 45 minutes after administration, effervescent acetaminophen was significantly more effective at each scheduled assessment time than tablet acetaminophen. The median time to meaningful pain relief was significantly shorter with effervescent acetaminophen (45 minutes) compared to tablet acetaminophen (60 minutes). At 4 hours after administration, the pain relief was significantly better with tablet acetaminophen than with effervescent acetaminophen. No other significant differences were observed between the active treatments. In conclusion, effervescent acetaminophen produces a significantly faster onset of analgesia than tablet acetaminophen.

[Efficacy and tolerance of an effervescent aspirin-metoclopramide combination in the treatment of a migraine attack. Randomized double-blind study using a placebo]. / Efficacité et tolérance de l'association effervescente aspirine-métoclopramide dans le traitement de la crise de migraine sans aura. Essai randomisé en double aveugle contre placebo.

OBJECTIVES: A double blind, randomized, multicenter, parallel group study was carried out to compare the efficacy and tolerance of aspirin 900 mg-metoclopramide 10 mg effervescent association (AAM) with those of placebo in the treatment of acute migraine attack. All patients were selected according to the International Headache Society criteria. METHODS: A total of 303 out-patients with an acute migraine attack were treated orally with either AAM (n = 152) or placebo (n = 151). RESULTS: The aspirin-metoclopramide association was significantly more effective than placebo at relieving headache (principal criterion) within 2 h of treatment (54.3% versus 25.9% : p < 0.001), producing entire resolution of acute migraine attack (14.2% versus 5.3% : p = 0.017), reducing the percentage of patients requiring rescue medication (44.3% versus 63.2% : p = 0.001) and increasing the percentage of patients able to resume their usual activities (44.1% versus 22.1% : p = 0.003). AAM also provided more frequent relief from associated symptoms as compared with placebo (37.4% versus 22.1% : p = 0.006). The therapeutic efficacy was rated as good or excellent by 39.7% of patients in the AAM group compared with 20.7% in the placebo group (p < 0.001). Moreover 64.2% of AAM treated patients said they would be prepared to take the treatment again compared with 46.4% who received placebo (p < 0.001). The percentage of patients reporting adverse events was not different between the two treatments (20.4% AAM versus 18.5% placebo : p = 0.684). The most commonly reported symptoms were gastro-intestinal disorders. Similar number of gastralgia occurred with AAM (n = 4) and placebo (n = 3). CONCLUSION: It is concluded that the aspirin-metoclopramide association may be used as a first intention treatment of acute migraine attack in out-patients.

[Iprindole: a functional link between serotonin and noradrenaline systems?]. / Iprindole: lien fonctionnel entre systèmes sérotoninergique et noradrénergique?

Iprindole is an active antidepressant in clinical practice but its mechanism of action has never been clearly defined. Serotoninergic regulation of noradrenergic neurons of locus coeruleus depends on 5-HT2 receptors. This regulatory action of the 5-HT system appears to facilitate the down-regulation of beta receptors. In behavioural tests involving the noradrenergic system, the role of iprindole, administered in subactive doses, was evaluated in the presence of subactive doses of fluvoxamine, a serotonin uptake inhibitor. Yohimbine is an alpha2 antagonist, inducing a dose-dependent toxicity. This test allows a rapid and selective screening of antidepressants with direct and indirect beta-agonist properties. Administration of iprindole displayed a toxicity of fluvoxamine in the presence of yohimbine. A 5-day pre-treatment of iprindole antagonized this potentiation unmasked after acute administration of iprindole. The down-regulation of beta receptors induced by a chronic treatment by iprindole could prevent the adrenergic expression of yohimbine's toxicity. But the down-regulation of 5-HT2 receptors also obtained with chronic treatment by iprindole, can explain this antagonism preventing fluvoxamine's action. Hypothermia induced by a high dose of apomorphine, depends on an activation of the noradrenergic system. During the interaction with fluvoxamine, iprindole unmasked an antagonism of this hypothermia due to apomorphine. The activity of a subactive dose of salbutamol, a direct beta-agonist, was evaluated in the presence of fluvoxamine on hypothermia induced by a high dose of apomorphine. The aim of this interaction was to define the beta-adrenergic property of iprindole more precisely.(ABSTRACT TRUNCATED AT 250 WORDS)

Has iprindole an alpha adrenergic activity?

1. Acute administration of iprindole potentiated the toxicity of 1-norepinephrine and increased the intensity of oxotremorine-induced tremors. 2. On the forced swimming test combination iprindole with imipramine reduced the duration of immobility. 3. The action of yohimbine on the locomotor activity was antagonized by a pre-injection of iprindole. 4. Iprindole increased and prolonged exophthalmia and loss of righting reflex induced by xylazine. 5 All these results seems indicate that iprindole has an indirect alpha 1 and alpha 2 adrenergic activity.

[Efficacy of tianeptine in the treatment of psychasthenia. A study versus placebo]. / Efficacité de la tianeptine dans le traitement de la psychasthénie. Etude versus placebo.

Tianeptine is an effective antidepressant with original neurochemical properties. Tianeptine increases the serotonin (5-HT) reuptake after acute and chronic treatment. The efficacy of tianeptine (T) versus placebo (P) was evaluated in the treatment of psychasthenia, because of the role of 5-HT in obsessive-compulsive disorders, the last state of psychasthenia in term of severity. Patients were recruited using the psychasthenia scale; then, their MADRS scores limited those who turned out to the depression. Mean inclusion MADRS scores where 12 (T) and 11.8 (P). Tianeptine is an effective treatment for patients suffering from psychasthenia. Tianeptine is more effective than placebo in global score and in sub-scores (asthenia and somatic symptoms) of the psychasthenia scale. In spite of weak inclusion scores in MADRS, patients taking tianeptine also showed significant improvement, greater than with placebo. The percentage of patients with a reduction equal to or greater than 50% of their MADRS score was significantly more important in tianeptine group. These results could be the illustration of the decrease in associated depressive symptoms or the result of an improvement of symptoms common to MADRS and psychasthenia scales. The same favorable results were obtained in symptoms of anxiety scored by HARS. In term of safety, tianeptine is equivalent to a placebo if we consider somatic complaints expressed by the patients, global improvement evaluated by the patient and the investigator, weight and blood pressure. Interruption of treatment for side-effects concerns the placebo group only (3 versus 0). This excellent safety is particularly well-adapted to the treatment of these out-patients.

[A scale to assess psychasthenia]. / Une échelle pour évaluer la psychasthénie.

"Psychasthenia exists--we meet it every day". Despite this affirmation, Pierre Janet's views remain unappreciated by international psychiatry. Psychasthenia is not included in the Diagnostic and Statistical Manual of Mental Disorders (DSM III-R). This pathology, described by Janet as both benign and terrible, is presently broken into many diagnostic categories with respect to the principal symptomatology of the patient. When a mood disorder is present, these patients can have diagnostic criteria for major depression or dysthymia. Patients with prevalent anxiety, phobia or obsessive-compulsive symptoms, must also be classified in having anxiety disorders. When somatic complaints are major symptoms, the patient's disease can be, on the whole, attributed to a somatoform disorder. This scale is a global evaluation of psychasthenia. It is made up of three lists of items. The first concerns asthenia or fatigue sine materia. The items in this group allow an evaluation of the physical and mental characteristics of asthenia associated with an inability of acting. Difficulties in mental concentration are measured by items in the second list. Mental processes are associated with doubts and waverings. They are interrupted by interferences caused by obsessions with recurrent and persistent ideas, impulses or images. Physical symptoms without organic pathology or a pathophysiologic mechanism constitute the neurasthenic part of psychasthenia. In the third list, somatic complaints are spelled out in a check-list of these potential symptoms. This scale can be used as a help in the diagnosis. Items 2, 3, 5, 25, 26 and 29 have a specific reference to the history of the disorder.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term administration of tianeptine in depressed patients after alcohol withdrawal.

Alcohol interferes with the central metabolism of the catecholamines and especially with indolamines (5-HT). Thus, the use of an antidepressant such as tianeptine, whose main neurochemical effect is to increase the reuptake of 5-HT, seems to be particularly indicated for the continued treatment of depressed patients after alcohol withdrawal. This study evaluated the therapeutic efficacy and acceptability during long-term administration of tianeptine in depressed patients (major depressive episode or dysthymic disorder) in a multicentre trial, after withdrawal from alcohol abuse or dependence. The results relate to 130 depressed patients, who abstained from alcohol and received treatment for a year. Only one patient dropped-out because of side-effects, and medication was interrupted in 5% of subjects because of alcoholic relapses. Prescribed in the long term, tianeptine did not produce orthostatic hypotension, changes in bodyweight, or alterations in the ECG. All changes found in haematological and biochemical investigations suggested an improvement in patients' physical state. This, and other studies, indicate that tianeptine appears to have the potential to be a safe antidepressant, which might be particularly useful in those patients who are susceptible to the side-effects of psychotropic drugs.

Long-term use of tianeptine in 380 depressed patients.

Tianeptine is a new tricyclic compound whose principal action is to increase the reuptake of serotonin. In a multicentre trial in which 380 depressed patients were treated for one year, tianeptine produced a significant reduction in the MADRS scores from day 14, with a sustained reduction maintained for up to 12 months; other measures of efficacy (HRSA, HSCL, and CGI) also reflected the improvement. Only 11% of patients withdrew because of recurrence of depression and 2% because of side-effects, which were mainly drowsiness, irritability, and gastrointestinal disturbance. Apart from a minor reduction in heart rate, unaccompanied by any conduction changes, no clinically relevant changes in vital signs or laboratory tests were seen. Seven subjects who attempted suicide by tianeptine overdose had favourable outcomes, in spite of also taking other psychotropic drugs or alcohol. No evidence of tolerance or withdrawal symptoms was seen after treatment was stopped. These results suggest that tianeptine has the potential to provide safe antidepressant activity in both the acute and chronic phases of treatment.

[Therapeutic effects of tianeptine in patients with depression and anxiety disorders with or without associated alcoholism]. / Effets thérapeutiques de la tianeptine chez des patients déprimés et anxieux avec ou sans alcoolisme associé.

Tianeptine is a new tricyclic antidepressant. Double blind studies comparing tianeptine with imipramine and amitriptyline have shown the effectiveness of tianeptine's antidepressor action, its properties of non-specific symptoms related to behaviour disorders (anxiety, inhibition ...) and its action on somatic complaints expressed by depressed patients. Tianeptine is an effective antidepressant in cases of depression with anxiety or alcoholism and also leads to good therapeutic response in cases of dysthemia. In depressions with melancholy and endogenous criteria, the expected percentage of responding patients has been observed with tianeptine. A reinforcement of the therapeutic effect has been demonstrated after 6 months of treatment. Its excellent clinical and parclinical acceptability, especially in long term treatment of patients at risk such as elderly depressed patients or alcoholic patients, makes tianeptine a first intention antidepressant.

[Cardiovascular tolerance to tianeptine]. / Acceptabilité cardiovasculaire de la tianeptine.

The cardiovascular effects of tianeptine were assessed by a specific placebo-controlled trial in healthy volunteers and by heart rate, blood pressure and electrocardiogram data analyses in five studies enrolling depressed patients. In two of these studies the effects of tianeptine were compared to those of amitriptyline. The three other studies were performed as open, long-term trials (up to one-year treatment) in large populations of patients (more than 3,300 patients). The findings show that tianeptine does not modify heart rate, blood pressure, conduction or ventricular function. Tianeptine was well tolerated in depressed patients and induced no significant changes at the current dosage in treatment periods from three-months to one-year even in elderly patients, patients with cardiovascular abnormalities or alcoholic patients. Fewer cases of orthostatic hypotension were observed than with other antidepressants. Suicide attempts with tianeptine overdosage did not lead to death due to cardiovascular complications.

[Tolerability of tianeptine in 170 patients with depression treated during one year]. / Acceptabilité de la tianeptine chez 170 patients déprimés traités un an.

Tianeptine, a new antidepressant, has a tricyclic molecular structure. Its main biochemical activity consists of an increase in the reuptake of 5 HT both in men and animals, after acute and chronic administration. Tianeptine demonstrated its antidepressive clinical efficacy in several double-blind versus reference drug trials. A multicentre open trial, including depressed patients enabled us to evaluate the safety of tianeptine and to control the maintenance of the therapeutic efficacy in the course of its long-term prescription. Depressed patients included showed a major depressive episode, single (296.22) or recurrent (296.32) without melancholia or psychotic features, or a dysthymic disorder (300.40), according to DSM III criteria. A minimum MADRS score of a least 25, and the informed consent of the patients were required. The dose of tianeptine was 3 tablets per day (12.5 mg/tablet) with the possibility of increasing to 4 or decreasing to 2 tablets per day, depending on the symptomatology. Therapeutic efficacy was evaluated by item 1 and 2 of the Global Clinical Impression (CGI), the Montgomery and Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HARS) and the Hopkins Symptom Check-List (HSCL). Clinical and paraclinical safety were evaluated by CGI item 3, standardized ratings of patients' complaints (CHESS 84), interruption for side effects, evaluation of blood pressure, weight, biological parameters, EKGs. This intermediate evaluation concerns the first 170 depressed patients treated over a one-year period as well as the total group of patients included (n = 447).(ABSTRACT TRUNCATED AT 250 WORDS)

Is iprindole an indirect betamimetic drug?

Iprindole, an active antidepressant in clinical use, has no effect on norepinephrine reuptake and does not bind to receptors of the noradrenergic system. Iprindole weakly antagonizes reserpine hypothermia and potentiates yohimbine toxicity. This effect is antagonized by propranolol but not by atenolol or metoprolol. In an acute dose, iprindole potentiates the effect of maprotiline on yohimbine toxicity. Beta 2-adrenergic agonists and antagonists specifically modify the effect of iprindole on spontaneous motility. These results indicate that iprindole has an indirect beta 2-mimetic effect.