[Misuse and dependence on prescription opioids: Prevention, identification and treatment]. / Mésusage et dépendance aux opioïdes de prescription : prévention, repérage et prise en charge.

Since the 1990s, the use of prescription opioids has largely spread, which has brought a real progress in the treatment of pain. The long-term use of prescription opioid is sometimes required, and may lead to pharmacological tolerance and withdrawal symptoms, i.e. pharmacological dependence on prescription opioids. Occasionally, this may also lead to misuse of prescription opioids (MPO). MPO preferentially occurs in vulnerable individuals, i.e., those with a young age, history of other addictive or psychiatric disorders, especially anxious and depressive disorders. MPO is associated with numerous complications, including an increased risk of fatal overdose. Prevention of MPO begins before the opioid prescription, with the identification of potential vulnerability factors. A planned and personalized monitoring should be systematically implemented. In vulnerable patients, contractualizing the prescription is warranted. During follow-up, the relevance of the prescription should be regularly reconsidered, according to the benefit observed on pain and the potential underlying signs of MPO. Patients with suspected MPO should be referred early to pain or addiction centers. The treatment of MPO should be based on multidisciplinary strategies, involving both the addiction and pain aspects: progressive opioid withdrawal, non-pharmacological measures against pain, or switching to medication-assisted treatment of addiction (i.e., buprenorphine or methadone).

Unaltered instrumental learning and attenuated body-weight gain in rats during non-rotating simulated shiftwork.

Exposure to shiftwork has been associated with multiple health disorders and cognitive impairments in humans. We tested if we could replicate metabolic and cognitive consequences of shiftwork, as reported in humans, in a rat model comparable to 5 wks of non-rotating night shifts. The following hypotheses were addressed: (i) shiftwork enhances body-weight gain, which would indicate metabolic effects; and (ii) shiftwork negatively affects learning of a simple goal-directed behavior, i.e., the association of lever pressing with food reward (instrumental learning), which would indicate cognitive effects. We used a novel method of forced locomotion to model work during the animals' normal resting period. We first show that Wistar rats, indeed, are active throughout a shiftwork protocol. In contrast with previous findings, the shiftwork protocol attenuated the normal weight gain to 76 ± 8 g in 5 wks as compared to 123 ± 15 g in the control group. The discrepancy with previous work may be explained by the concurrent observation that with our shiftwork protocol rats did not adjust their between-work circadian activity pattern. They maintained a normal level of activity during the "off-work" periods. In the control experiment, rats were kept active during the dark period, normally dominated by activity. This demonstrated that forced activity, per se, did not affect body-weight gain (mean ± SEM: 85 ± 11 g over 5 wks as compared to 84 ± 11 g in the control group). Rats were trained on an instrumental learning paradigm during the fifth week of the protocol. All groups showed equivalent increases in lever pressing from the first (3.8 ± .7) to the sixth (21.3 ± 2.4) session, and needed a similar amount of sessions (5.1 ± .3) to reach a learning criterion (≥ 27 out of 30 lever presses). These results suggest that while on prolonged non-rotating shiftwork, not fully reversing the circadian rhythm might actually be beneficial to prevent body-weight gain and cognitive impairments.

Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives.

There are three major types of sleep-disordered breathing (SDB) with respect to prevalence and health consequences, i.e. obstructive sleep apnoea syndrome (OSAS), Cheyne-Stokes respiration and central sleep apnoea (CSR-CSA) in chronic heart failure, and obesity hypoventilation syndrome (OHS). In all three conditions, hypoxia appears to affect body functioning in different ways. Most of the molecular and cellular mechanisms that occur in response to SDB-related hypoxia remain unknown. In OSAS, an inflammatory cascade mainly dependent upon intermittent hypoxia has been described. There is a strong interaction between haemodynamic and inflammatory changes in promoting vascular remodelling. Moreover, during OSAS, most organ, tissue or functional impairment is related to the severity of nocturnal hypoxia. CSR-CSA occurring during heart failure is primarily a consequence of cardiac impairment. CSR-CSA has deleterious consequences for cardiac prognosis and mortality since it favours sympathetic activation, ventricular ectopy and atrial fibrillation. Although correction of CSR-CSA seems to be critical, there is a need to establish therapy guidelines in large randomised controlled trials. Finally, OHS is a growing health concern, owing to the worldwide obesity epidemic and OHS morbidities. The pathophysiology of OHS remains largely unknown. However, resistance to leptin, obesity and severe nocturnal hypoxia lead to insulin resistance and endothelial dysfunction. In addition, several adipokines may be triggered by hypoxia and explain, at least in part, OHS morbidity and mortality. Overall, chronic intermittent hypoxia appears to have specific genomic effects that differ notably from continuous hypoxia. Further research is required to fully elucidate the molecular and cellular mechanisms.

A simple procedure for measuring pharyngeal sensitivity: a contribution to the diagnosis of sleep apnoea.

BACKGROUND: Patients with severe apnoea may have an impaired pharyngeal dilating reflex related to decreased pharyngeal sensitivity. The accuracy of a simple new procedure to measure pharyngeal sensitivity and to diagnose sleep disordered breathing (SDB) was investigated. METHODS: Pharyngeal disappearance and appearance sensory perception thresholds were measured by delivering different airflow rates on the soft palate using an intraoral device in 17 controls and 50 patients suffering from SDB evaluated by overnight polygraphy. The procedure was performed before (baseline) and after three successive administrations of a topical anaesthetic to sensitise the pharyngeal sensory impairment. Pharyngeal sensitivity was then evaluated according to SDB severity. SDB was classified as mild, moderate or severe according to the relative proportion of obstructive apnoeas-hypopnoeas and the amount of desaturation. RESULTS: Patients had higher baseline disappearance and appearance sensory thresholds than controls (mean (SD) 0.62 (0.44) v 0.26 (0.06) l/min and 0.85 (0.40) v 0.40 (0.19) l/min, p<0.001, respectively). Such differences were enhanced by topical anaesthesia. Impairment of pharyngeal sensitivity and the number of patients with impaired sensitivity increased from the least to the most severe SDB group as indicated by the test sensitivity for a respiratory disturbance index of >20/hour (50%, 73.7% and 88.5% in the mild, moderate, and severely affected groups, respectively). CONCLUSIONS: This simple and safe procedure showed that impairment of pharyngeal sensitivity is correlated with severity of SDB. Using this test in routine clinical practice may simplify the diagnosis of sleep apnoea, particularly for the most severe patients.

Participación de la proteína caltrin de vesícula seminal en el proceso de fertilización. Estudio IN VITRO / Participation of the seminal proteina caltrin of vesicula in the fertilization process. Study in Vitro

Se investigó mediante estudios in vitro la participación de la proteina caltrin I (calcium transport inhibitor) de rata en el proceso de fertilización. Para ello, se analizó el efecto de la proteína sobre dos procesos fundamentales que experimentan los espermatozoides previamente a la fertilización: la capacitación y la reacción acrosomal. Mediante inmunofluorescencia indirecta e inmunocitoquimica y microscopía electrónica se estudió detalladamente la distribucción de la proteína caltrin I unida a la membrana plasmática de los espermatozoides antes y después de la exocitosis acrosomal inducida por el ionóforo de CA2+ A23187. Se desarrolló un protocolo para llevar a cabo la fertilización in vitro en rata y con esta metodología se estudió el efecto de caltrin I sobre el reconocimiento e interacción espermatozoide-ovocito, la penetración de la zona pelucida y la fusión de las gametas

Participación de la proteína caltrin de vesícula seminal en el proceso de fertilización. Estudio IN VITRO / Participation of the seminal proteina caltrin of vesicula in the fertilization process. Study in Vitro

Se investigó mediante estudios in vitro la participación de la proteina caltrin I (calcium transport inhibitor) de rata en el proceso de fertilización. Para ello, se analizó el efecto de la proteína sobre dos procesos fundamentales que experimentan los espermatozoides previamente a la fertilización: la capacitación y la reacción acrosomal. Mediante inmunofluorescencia indirecta e inmunocitoquimica y microscopía electrónica se estudió detalladamente la distribucción de la proteína caltrin I unida a la membrana plasmática de los espermatozoides antes y después de la exocitosis acrosomal inducida por el ionóforo de CA2+ A23187. Se desarrolló un protocolo para llevar a cabo la fertilización in vitro en rata y con esta metodología se estudió el efecto de caltrin I sobre el reconocimiento e interacción espermatozoide-ovocito, la penetración de la zona pelucida y la fusión de las gametas

Toxicity of the Clitocybe amoenolens mushroom in the rat.

Ingestion of Clitocybe amoenolens, a mushroom collected in Savoie (France), induced erythermalgia in 5 patients. To assess C. amoenolens toxicity, increasing doses were given randomly to 4 rats corresponding to 1 to 25 fold the dose eaten by the most severely poisoned patient. The 2 rats receiving the highest doses had loss of bodyweight, locomotor disability and erythema of the toes. Examination of sciatic nerves showed decreased axon density and neuronal fiber degeneration. Oral administration of C. amoenolens to rats led to lesions that might be explained by the presence of acromelic acid A, a kainate analogue.

Charcot-Marie-Tooth disease and sleep apnoea syndrome: a family study.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a genetically heterogeneous group of hereditary motor and sensory polyneuropathies in which sleep apnoea has rarely been reported and no causal relation shown. We looked for an association between the most common subtype of CMT disease (CMT1A) and sleep apnoea syndrome. METHODS: Having diagnosed sleep apnoea and CMT in one family member (index case), we prospectively investigated 13 further members not previously suspected of having neuropathy or apnoeas. All had a neurological examination, electroneuromyography, polysomnography, and genetic testing for CMT disease. FINDINGS: 11 of the 14 family members had the autosomal dominant demyelinating form of CMT disease with PMP22 gene duplication on chromosome 17. Whatever their neurological disability, all 11 individuals had sleep apnoea syndrome with a mean (SD) apnoea-hypopnoea index of 46.6/h (28.5) of sleep (normal value <15/h). The remaining three family members were free from neuropathy and sleep apnoea syndrome. Sleep apnoea and neuropathy severity were highly correlated; the compound muscle action potential (CMAP) amplitude of the median nerve was inversely correlated with the apnoea-hypopnoea index (r=-0.69, p=0.029). The severity of neuropathy and sleep apnoea were higher in male CMT individuals and were correlated with age and body mass index. No wake or sleep diaphragmatic dysfunction was shown. INTERPRETATION: We think that sleep apnoea syndrome is related to a pharyngeal neuropathy. Upper airway dysfunction, previously described in the CMT2C subtype, might be a clinical expression of the CMT1A subtype, to which familial susceptibility could predispose.

Peripheral neuropathy in sleep apnea. A tissue marker of the severity of nocturnal desaturation.

Because chronic obstructive pulmonary disease (COPD) is well known to induce peripheral neuropathy and resistance to ischemic nerve conduction failure (RICF), we performed a case-control study examining peripheral nerve function during ischemia in 17 patients with severe obstructive sleep apnea (OSA) without daytime hypoxemia and 10 control subjects. Median nerve conduction was studied before, during, and after a 30-min period of ischemia. Preischemic sensory and mixed nerve potential amplitudes and sensory conduction velocity were lower in OSA patients than in control subjects despite higher supramaximal stimulation. During ischemia, seven OSA patients manifested RICF (OSA-RICF), whereas both the other 10 patients, who were nonresistant to ischemic conduction failure (OSA-NR), and control subjects did not. OSA-RICF patients had the lowest initial nerve-potential amplitude, whereas OSA-NR patients had a response intermediate between that of control subjects and OSA-RICF patients. OSA-RICF patients had a lower mean nocturnal SaO2 and a higher body mass index (BMI) and duration of SaO2 < 70% than did OSA-NR patients. Seven patients (four OSA-RICF and three OSA-NR) were reevaluated after at least 2 mo of treatment with nasal continuous positive airway pressure (nCPAP). RICF disappeared in all OSA-RICF patients, whereas preischemic nerve conduction parameters were unchanged in both OSA-RICF and OSA-NR patients. Thus OSA patients have peripheral nerve dysfunction whose severity is partly related to the level of nocturnal hypoxemia. Abnormal preischemic nerve conduction suggests axonal lesions, whereas RICF, which appears to be a sensitive but nonspecific tissue marker of the severity of hypoxemia, may result from adaptative mechanisms.

Dextromethorphan and dextrorphan in rats: common antitussives--different behavioural profiles.

Dextromethorphan (DM), a widely used and well-tolerated centrally acting antitussive, has been tested in several clinical trials for its antiepileptic and neuroprotective properties. However, the use of DM in these new clinical indications requires higher doses than antitussive doses, which may therefore induce phencyclidine (PCP)-like side-effects (memory and psychotomimetic disturbances) through its metabolic conversion to the active metabolite dextrorphan (DX), a more potent PCP-like non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor than DM. Thus, we compared the behavioural effects in rats of intraperitoneal administration of DM and DX on motor activity in an open field and on learning and memory in the Morris water maze. DM (20, 30, 40 mg/kg) produced a dose-dependent decrease in both locomotion and stereotyped behaviour with a slight ataxia for the highest dose. DX (20, 30, 40 mg/kg) induced a dose-dependent increase in locomotion and stereotypies (swaying, turning) with moderate ataxia. Assessments of learning and memory were performed with lower doses of DM (10, 20, 30 mg/kg) and DX (5, 10, 15 mg/kg) because of motivational deficits (40 mg/kg of DM, 20-40 mg/kg of DX) and motor disorders (30, 40 mg/kg of DX) in the cue learning procedure. DX (10, 15 mg/kg) impaired spatial learning with a long-lasting effect for the highest dose whereas 5 mg/kg of DX and DM (10-30 mg/kg) did not. Only 15 mg/kg of DX appeared to slightly impair working memory. DM (10-30 mg/kg) and DX (5-15 mg/kg) did not impair reference memory. Thus, the two antitussives DM and DX induced different behavioural effects suggesting sedative effects for DM and PCP-like effects for DX. However, PCP-like side-effects with DM remain possible through its metabolic conversion to DX, with very high doses and/or in extensive metabolizers and/or in aged subjects prone to cognitive dysfunction. Therefore, the identification of DM metabolism phenotype, an adapted prescription and a pharmacological modulation of the DM metabolism may avoid adverse effects.

Evaluation of dextromethorphan and dextrorphan as a preventive treatment of soman toxicity in mice.

Phencyclidine-like drugs are effective against convulsions and brain lesions related to soman intoxication but induce severe side effects. The well tolerated antitussive dextromethorphan (DM) and its metabolite dextrorphan (DX) have antiepileptic and neuroprotective properties that we evaluated in mice against 2 LD50 of soman in a three-drug pretreatment (atropine sulfate and oxime HI-6 plus DM: 20-50 mg/kg or DX: 10-40 mg/kg i.p). Neuroprotection was evaluated by measurement of hippocampal omega 3 binding site density. DM and DX have weak anticonvulsant and neuroprotective activities which are counterbalanced at high doses by an increased mortality due to respiratory distress for DM and by ataxia for DX. Thus DM and DX do not appear to be appropriate for the pretreatment of soman intoxication.

[Capillary and cavernous hemangioma disclosed by painful amyotrophy of the thigh]. / Hémangiome capillaire et caverneux révélé par une amyotrophie douloureuse de la cuisse.

We report the case of an intramuscular cavernous and capillary hemangioma of the thigh revealed by pains evolving for 2 years and by an amyotrophy. After 21 months of investigation, the surgical excision and the histological examination only established the dia Thigh MRI. T1-weighted axial and sagittal sections with gadolinium infusion.

Discriminative stimulus properties of dextromethorphan in rats.

Male Sprague-Dawley rats were trained to discriminate dextromethorphan (DM, 30 mg/kg, ip) from saline using a standard two-lever, fixed ratio 10, food reinforcement procedure. The DM-saline discrimination was acquired, and a range of doses of DM produced a dose-related generalization to the DM-lever choice. Stimulus generalization tests were conducted with dextrorphan, an active metabolite of DM, and with drugs selected from different pharmacological families. Dextrorphan induced a full generalization to DM, but only at a dose higher than the DM training dose. Morphine, a mu opiate receptors agonist, and U 50488, a kappa opiate receptors agonist, failed to substitute for DM. Cyclazocine, a benzomorphan derivative, with high affinity for sigma receptors, was able to produce a complete generalization to DM, without a change in the number of rats responding. Dizocilpine (MK 801), a phencyclidine-like drug, produced a complete generalization, but only at a dose that markedly reduced the number of rats responding. Carbetapentane and caramiphen, antitussive drugs with high affinity for the 'specific DM receptors', failed to substitute for DM. These results show that the discriminative stimulus of DM, did not result primarily from its metabolism to dextrorphan; and the discriminative stimulus properties of DM appear to more closely resemble those of cyclazocine than those of the other drugs tested. This suggests a role of sigma receptors in the mediation of the DM stimulus. These experimental data are discussed with reference to the cyclazocine-like subjective effects produced in man by large doses of DM.

[Intracranial dural fistula with spinal cord venous drainage. Apropos of 2 cases]. / Les fistules durales intracrâniennes a drainage veineux périmédullaire. A propos de deux observations.

The authors report 2 new cases of intracranial dural fistula draining into spinal veins. Comparisons with 19 other published cases showed that dural fistulae of the spine share common features with intracranial fistulae. The first case concerned a 78-year old woman presenting with a thoraco-lumbar myelopathy which proceeded by increasingly severe bouts and ended within 6 months in a flaccid sensorimotor paraplegia with urinary incontinence. Paraclinical examinations consisted of MRI, myelography and spinal as well as cerebral arteriography. MRI and thoraco-lumbar myelography displayed marks of dilated retrospinal vessels. Spinal arteriography showed no arteriovenous malformation, but the venous return of Adamkiewicz artery was not visible. Diagnosis was made by cerebral arteriography which demonstrated an intracranial arteriovenous fistula in the occipital region, draining into the posterior spinal vein. Treatment was endovascular and consisted of embolization by micro-coils, but clinical improvement was mediocre. Six months later, as the clinical picture was getting worse a second arteriography was performed. It showed recanalization of the fistula which was embolized again, using both coils and particles. No improvement in spinal cord deficit was observed. The second case was that of a 42-year old man presenting with paraparesis, tetrapyramidal syndrome, sensory deficit at T9, peribuccal dysaesthesias and genito-urinary sphincteral disorders, all gradually getting worse. The paraclinical exploration was the same as in the first case. MRI and myelography showed retrospinal vascular impressions. Spinal arteriography was normal, except for the lack of venous return of Adamkiewicz artery. Cerebral arteriography detected an intracranial dural arteriovenous fistula in the occipital region, draining into the anterior and posterior spinal veins. Treatment was surgical, consisting of exclusion of the arteriovenous fistula. Partial clinical improvement was noted. These two cases, compared with those of the literature, shared a number of features with spinal dural arteriovenous fistulae: they occur in middle-aged and predominantly male patients, and the clinical signs of ascending myelopathy are caused by the same physiopathological mechanism of spinal vein hyperpressure. Lesions of the medulla oblongata or the cervical spinal cord are found only in intracranial arteriovenous fistulae draining into spinal veins. Diagnosis is based on data provided by myelography (impressions of dilated and sinous vessels) and MRI (low-intensity perispinal signals, widening of the conus medullaris with high-intensity centrospinal signal); spinal cord angiography only shows a lack of venous return of Adamkiewicz artery without any other abnormality, whereas cerebral arteriography confirmed the diagnosis of intracranial dural arteriovenous fistula draining into spinal veins.