Separate and combined effects of the GABA(B) agonist baclofen and Δ9-THC in humans discriminating Δ9-THC.

BACKGROUND: Our previous research with the GABA reuptake inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ9-THC. The aim of the present study was to determine the potential involvement of the GABA(B) receptor subtype by assessing the separate and combined effects of the GABA(B)-selective agonist baclofen and Δ9-THC using pharmacologically specific drug-discrimination procedures. METHODS: Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received baclofen (25 and 50mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. RESULTS: Δ9-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on a psychomotor performance task. Baclofen alone (50 mg) substituted for the Δ9-THC discriminative stimulus, and both baclofen doses shifted the discriminative-stimulus effects of Δ9-THC leftward/upward. Similar results were observed on other cannabinoid-sensitive outcomes, although baclofen generally did not engender Δ9-THC-like subjective responses when administered alone. CONCLUSIONS: These results suggest that the GABA(B) receptor subtype is involved in the abuse-related effects of Δ9-THC, and that GABA(B) receptors were responsible, at least in part, for the effects of tiagabine-induced elevated GABA on cannabinoid-related behaviors in our previous study. Future research should test GABAergic compounds selective for other GABA receptor subtypes (i.e., GABA(A)) to determine the contribution of the different GABA receptors in the effects of Δ9-THC, and by extension cannabis, in humans.

[A system of prescriptions without drug approval: example of baclofen]. / Un dispositif de prescriptions hors-AMM : exemple du baclofène.

Baclofen is an anti-spastic drug that acts as an agonist of GABA-B receptors. It also seems to decrease the appetence for alcohol (anti-craving effect), although this effect has not been certified by Authorities for drug approval in France (AMM). However, baclofen receives a great deal of demand by patients hoping to reduce their alcohol consumption. Nonetheless, the lack of AMM and the high doses of baclofen supposed to exert an anti-craving effect often discourage practitioners from prescribing this drug in current medical practice. Therefore, it is preferable for a drug like baclofen to be prescribed under specific regulations. As such, certain criteria similar to those required in clinical trials are necessary to protect patients as well as the prescribing doctors. The criteria that are proposed here are: the use of drugs without AMM approval as a last resort (all other treatments must have failed), the collegiate decision for the drug prescription, good knowledge of the potency of the drug as well as good record keeping of patients and proper supervision. The departments of addiction, pharmacology and pharmacovigilance of the University Hospital of Lille, France present here a medical process named "multidisciplinary consultations for resort treatments of addictions" (CAMTEA). This process is designed to meet all the above mentioned criteria and to allow the use of baclofen as an anti-craving drug in safest conditions. If this proves to be successful with baclofen, it is possible to extend the use of CAMTEA to other drugs without AMM approval in addictologic pathologies.

Emerging drugs for insomnia: new frontiers for old and novel targets.

BACKGROUND: Insomnia is the most prevalent sleep disorder, with up to 50% of the US adult population reporting symptoms of insomnia on a weekly basis and approximately 12% with insomnia disorder. Comorbid conditions such as depression and anxiety are frequent. Insomnia is more common with older age, female gender and socioeconomic status. Traditionally, therapy has focused on GABA(A) receptor agonists, and off-label antidepressant and antihistamine use. OBJECTIVE: With increased understanding of complex neural networks involved in sleep and wake, hypnotics are being developed to target a broader variety of receptors with increasing selectivity. This review summarizes promising compounds in Phase II and III trials with evidence supporting efficacy for treatment of insomnia. METHODS: 5-HT(2A) and 5-HT(2C) antagonists, melatonergic (MT1/MT2) agonists, orexin receptor (OX1/OX2) antagonists, as well as GABA(A) receptor agonists are reviewed and summarized. Data are collected from PubMed and Pharmaprojects database searches, company websites, recent scientific meeting presentations and abstracts. RESULTS/CONCLUSIONS: A variety of drugs targeting several pathways, including GABA(A) agonism, MT1/MT2 agonism, 5-HT(2A) antagonism, OX1/OX2 antagonism and others, are in Phase II and III trials. More work should be done to understand the impact of these drugs in certain populations and in the context of comorbid conditions.

[Assessment of spasticity therapy with baclofen pump in children]. / Ocena wyników leczenia spastycznosci u dzieci za pomoca pompy baklofenowej.

THE AIM OF THE STUDY: The aim of this study was to assess of treatment of spasticity in children with baclofen pump, before and after pump implantation. MATERIAL AND METHOD: In a group of 17 patients with spastic hemiparesis, with a different etiology, 2 groups were separated. In the group of 12 the most injured children, spasticity was measured by The Modified Ashworth Scale, before and after baclofen pump implantation. In the group of 5 patients spasticity was assessed by The Modified Ashworth Scale, functional benefits were evaluated with the Barthel index score, and the digree of disability with the Rankin Scale. RESULTS: In the group of 12 patients, after pump implantation, was observed reduction in spasticity to 2 points in the Modified Ashworth Scale and this effect improves general ease of care and passive excersises. In the second group 3 of 5 patients, have started to walk alone or with orthopedic help. CONCLUSION: Intrathecal baclofen therapy resulted in the good effects in treatment of spasticity in the both groups.

Medical comorbidity in women and men with bipolar disorders: a population-based controlled study.

OBJECTIVE: Rarely has validated information on chronic medical comorbidity been presented for persons with bipolar disorder. To deliver appropriate health services, it is important to understand the prevalence of chronic medical conditions in this population. This study examines chronic medical comorbidity using validated methodology in persons with bipolar disorder. METHODS: This is a retrospective study of a 100% sample of administrative claims (1996-2001) from Wellmark Blue Cross Blue Shield. Three thousand five hundred fifty-seven subjects had bipolar I disorder and did not have claims for schizophrenia or schizoaffective disorder. Controls had no documented claims for psychiatric conditions. Using validated methodology, inpatient and outpatient claims were used to determine prevalence of 44 chronic medical conditions. Odds ratios (ORs) were adjusted for age, gender, residence, and nonmental healthcare utilization. RESULTS: Persons with bipolar disorder were young (mean age, 38.8 years) and significantly more likely to have medical comorbidity, including three or more chronic conditions (41% versus 12%, p < .001) compared with controls. Elevated ORs were found for conditions spanning all organ systems. Hyperlipidemia, lymphoma, and metastatic cancer were the only conditions less likely to occur in persons with bipolar disorder. CONCLUSION: Bipolar disorders are associated with substantial chronic medical burden. Familiarity with conditions affecting this population may assist in programs aimed at providing medical care for the chronically mentally ill.

Refractory heartburn to proton pump inhibitors: epidemiology, etiology and management.

Patients with refractory heartburn to proton pump inhibitors (PPIs) represent a distinctive group which is difficult to manage. In a systematic review of the relative literature we found that approximately 20% of patients with erosive esophagitis and 15-25% of patients with normal endoscopy and abnormal 24-hour esophageal pH monitoring continue to report heartburn despite treatment with standard dose PPIs. Furthermore, approximately 30-40% of patients with normal endoscopy and 24-hour pH studies and 15-20% of patients with Barrett's esophagus have refractory heartburn to double dose PPIs. In such cases, compliance to therapy, duodeno-gastroesophageal reflux, gastro-esophageal motility disorders and eradication of Helicobacter pylori infection may contribute to symptoms. Based on the available evidence, we suggested an algorithm for the evaluation and management of these patients.

[Value of intrathecal baclofen in the treatment of severe tetanus in the tropical milieu]. / Place du baclofene intrathecal dans le traitement du tetanos grave en milieu tropical.

Tetanus continues to be a cause of high mortality in developing countries, where resources for muscle relaxation and respiratory support are not readily available. Baclofen, a GABAB receptor agonist, directly restores physiologic inhibition of alpha motoneuron, that is blocked by tetanus toxin. Its use has been suggested at high dosage by intrathecal (i.t.) route, as part of the treatment of tetanus-induced contractures, and to limit the need for general anesthesia and for tracheal intubation in afflicted patients. This review reports personal experience and focuses on published data about i.t. baclofen for severe tetanus. Although statistical analysis are difficult to perform, i.t. baclofen appears to be effective in resolving muscle rigidity and in avoiding the need for deep sedation and for tracheal intubation, thus achieving lower mortality. Nevertheless, i.t. baclofen has a narrow therapeutic range, and a large interindividual pharmacodynamic variability. Thus, its use should be reserved for patients who would have been intubated without it. I.t. baclofen is a fairly simple and cost-effective modality, with significant advantages for management of severe tetanus, especially in tropical environment.

Cost analysis of the treatment of severe spinal spasticity with a continuous intrathecal baclofen infusion system.

OBJECTIVE: The purpose of our study was to analyse and evaluate the costs of continuous intrathecal baclofen administration as a modality in the treatment of severe spasticity in the Netherlands. DESIGN: A cost analysis was conducted as part of a prospective, multicentre, multidisciplinary, randomised and placebo-controlled clinical trial. The study covered the period from December 1991 to September 1995. The data on medical consumption and costs were collected over a 3-year period from different sources: administrative databases of health insurance companies, hospital registries and a patient survey. These data were structured by means of a flowchart analysis of the medical decision-making by specialists and general practitioners (GPs). They included data on in- and outpatient care, home care and care in nursing homes. The cost analysis was conducted using data from 18 patients included in the trial and from 15 so-called 'match' patients. The latter group are patients with comparable diseases leading to spasticity and living in comparable circumstances. Next to absolute costs (direct and indirect) of care and treatment for the 2 groups of patients, cost differences between the 2 groups were considered (differential cost analysis). SETTING: Per patient cost data, collected prospectively for 2 years during the phase of clinical evaluation, and retrospectively 1 year before implantation. The data were collected on patients from in- and outpatient care, home care and care in nursing home settings. PATIENTS AND PARTICIPANTS: The trial patients (8 men) had a mean age of 46 years; 11 patients had multiple sclerosis and 7 patients had spinal cord injuries. The match patients (7 men) had a mean age of 48 years; 9 patients had multiple sclerosis and 6 patients had spinal cord injuries. INTERVENTIONS: Trial patients were treated with a subcutaneously implanted programmable continuous infusion pump (SynchroMed, Medtronic), filled with baclofen (a muscle relaxant) to treat patients with chronic disabling spasticity who did not respond to a maximum dose of oral baclofen, dantrolene and tizanidine. MAIN OUTCOME MEASURES AND RESULTS: An analysis of hospital stay between both groups showed a significant difference during the implantation year. The average number of hospital days per patient in the year in the treated group was 31.5 days and in the match group was 18.7 days. Significant cost differences between both groups in the year that started with pump implantation and the following year can be attributed mostly to the costs of implantation of the pump and related hospitalisation days. The total costs of patient selection, testing, implanting the pump and follow-up amounted to $US28,473 for the first year. Savings must be taken into consideration as well. The savings of direct costs were due to withdrawal of oral medication (estimated annual total of between $US1950 and $US2800 per patient). Indirect savings on employment and nursing home costs, amounted annually to $US1047 and $US5814, respectively. Scenarios make it possible to consider policy consequences. The case of 'extending' the indications for this treatment to a larger population has been calculated and visualised. CONCLUSIONS: The costs of the therapy (continuous intrathecal infusion of baclofen) can be attributed mostly to implantation of the pump and related hospitalisation days. Savings originated from withdrawal of oral medication, job preservation and avoidance or delay of admission to a nursing home.