Evaluating a systematic voiding programme for patients with urinary incontinence after stroke in secondary care using soft systems analysis and Normalisation Process Theory: findings from the ICONS case study phase.

BACKGROUND: Urinary incontinence (UI) affects between 40 and 60% of people in hospital after stroke, but is often poorly managed in stroke units. OBJECTIVES: To inform an exploratory trial by three methods: identifying the organisational context for embedding the SVP; exploring health professionals' views around embedding the SVP and measuring presence/absence of UI and frequency of UI episodes at baseline and six weeks post-stroke. DESIGN: A mixed methods single case study included analysis of organisational context using interviews with clinical leaders analysed with soft systems methodology, a process evaluation using interviews with staff delivering the intervention and analysed with Normalisation Process Theory, and outcome evaluation using data from patients receiving the SVP and analysed using descriptive statistics. SETTING: An 18 bed acute stroke unit in a large Foundation Trust (a 'not for profit' privately controlled entity not accountable to the UK Department of Health) serving a population of 370,000. PARTICIPANTS: Health professionals and clinical leaders with a role in either delivering the SVP or linking with it in any capacity were recruited following informed consent. Patients were recruited meeting the following inclusion criteria: aged 18 or over with a diagnosis of stroke; urinary incontinence (UI) as defined by the International Continence Society; conscious; medically stable as judged by the clinical team and with incontinence classified as stress, urge, mixed or 'functional'. All patients admitted to the unit during the intervention period were screened for eligibility; informed consent to collect baseline and outcome data was sought from all eligible patients. RESULTS: Organisational context: 18 health professionals took part in four group interviews. Findings suggest an environment not conducive to therapeutic continence management and a focus on containment of UI. Embedding the SVP into practice: 21 nursing staff took part in six group interviews. Initial confusion gave way to embedding of processes facilitated by new routines and procedures. Patient outcome: 43 patients were recruited; 28 of these commenced the SVP. Of these, 6/28 (21%) were continent at six weeks post-stroke or discharge. CONCLUSION: It was possible to embed the SVP into practice despite an organisational context not conducive to therapeutic continence care. Recommendations are made for introducing the SVP in a trial context.

A systematic review of repetitive functional task practice with modelling of resource use, costs and effectiveness.

OBJECTIVES: To determine whether repetitive functional task practice (RFTP) after stroke improves limb-specific or global function or activities of daily living and whether treatment effects are dependent on the amount of practice, or the type or timing of the intervention. Also to provide estimates of the cost-effectiveness of RFTP. DATA SOURCES: The main electronic databases were searched from inception to week 4, September 2006. Searches were also carried out on non-English-language databases and for unpublished trials up to May 2006. REVIEW METHODS: Standard quantitative methods were used to conduct the systematic review. The measures of efficacy of RFTP from the data synthesis were used to inform an economic model. The model used a pre-existing data set and tested the potential impact of RFTP on cost. An incremental cost per quality-adjusted life-year (QALY) gained for RFTP was estimated from the model. Sensitivity analyses around the assumptions made for the model were used to test the robustness of the estimates. RESULTS: Thirty-one trials with 34 intervention-control pairs and 1078 participants were included. Overall, it was found that some forms of RFTP resulted in improvement in global function, and in both arm and lower limb function. Overall standardised mean difference in data suitable for pooling was 0.38 [95% confidence interval (CI) 0.09 to 0.68] for global motor function, 0.24 (95% CI 0.06 to 0.42) for arm function and 0.28 (95% CI 0.05 to 0.51) for functional ambulation. Results suggest that training may be sufficient to have an impact on activities of daily living. Retention effects of training persist for up to 6 months, but whether they persist beyond this is unclear. There was little or no evidence that treatment effects overall were modified by time since stroke or dosage of task practice, but results for upper limb function were modified by type of intervention. The economic modelling suggested that RFTP was cost-effective. Given a threshold for cost-effectiveness of 20,000 pounds per QALY gained, RFTP is cost-effective so long as the net cost per patient is less than 1963 pounds. This result showed some sensitivity to the assumptions made for the model. The cost-effectiveness of RFTP tends to stem from the relatively modest cost associated with this intervention. CONCLUSIONS: The evidence suggests that some form of RFTP can be effective in improving lower limb function at any time after stroke, but that the duration of intervention effect is unclear. There is as yet insufficient good-quality evidence to make any firm recommendations for upper limb interventions. If task-specific training is used, adverse effects should be monitored. While the effectiveness of RFTP is relatively modest, this sort of intervention appears to be cost-effective. Owing to the large number of ongoing trials, this review should be updated within 2 years and any future review should include a comparison against alternative treatments. Further research should evaluate RFTP upper limb interventions and in particular constraint-induced movement therapy, address practical ways of delivering RFTP interventions, be directed towards the evaluation of suitable methods to maintain functional gain, and be powered to detect whether RFTP interventions are cost-effective.

Treatment of urinary incontinence after stroke in adults.

BACKGROUND: Urinary incontinence can affect 40-60% of people admitted to hospital after a stroke, with 25% still having problems on hospital discharge and 15% remaining incontinent at one year. OBJECTIVES: To determine the optimal methods for treatment of urinary incontinence after stroke in adults. SEARCH STRATEGY: We searched the Cochrane Incontinence and Stroke Groups specialised registers (searched 15 March 2007 and 5 March 2007 respectively), CINAHL (January 1982 to January 2007), national and international trial databases for unpublished data, and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials evaluating the effects of interventions designed to promote continence in people after stroke. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment were undertaken by two reviewers working independently. Disagreements were resolved by a third reviewer. MAIN RESULTS: Twelve trials with a total of 724 participants were included in the review. Participants were from a mixture of settings, age groups and phases of stroke recovery. BEHAVIOURAL INTERVENTIONS: Three trials assessed behavioural interventions, such as timed voiding and pelvic floor muscle training. All had small sample sizes and confidence intervals were wide. SPECIALISED PROFESSIONAL INPUT INTERVENTIONS: Two trials assessed variants of professional input interventions. Results tended to favour the intervention groups: in a small trial in early rehabilitation, fewer people had incontinence at discharge from hospital after structured assessment and management than in a control group (1/21 vs. 10/13; RR 0.06, 95% CI 0.01 to 0.43); in the second trial, assessment and management by Continence Nurse Advisors was associated with fewer participants having urinary symptoms (48/89 vs. 38/54; RR 0.77, 95% CI 0.59 to 0.99) and statistically significantly more being satisfied with care. COMPLEMENTARY THERAPY INTERVENTIONS: Three small trials all reported fewer participants with incontinence after acupuncture therapy (overall RR 0.44; 95% 0.23 to 0.86), but there were particular concerns about study quality. PHARMACOTHERAPY AND HORMONAL INTERVENTIONS: There were three small trials that included groups allocated meclofenoxate, oxybutinin or oestrogen. There were no apparent differences other than in the trial of meclofenoxate where fewer participants had urinary symptoms in the active group than in the control group (9/40 vs. 27/40; RR 0.33, 95% CI 0.18 to 0.62). AUTHORS' CONCLUSIONS: Data from the available trials are insufficient to guide continence care of adults after stroke. However, there was suggestive evidence that professional input through structured assessment and management of care and specialist continence nursing may reduce urinary incontinence and related symptoms after stroke. Better quality evidence is required of the range of interventions that have been suggested for continence care after stroke.

Repetitive task training for improving functional ability after stroke.

BACKGROUND: The active practice of task-specific motor activities is a component of current approaches to stroke rehabilitation. OBJECTIVES: To determine if repetitive task training after stroke improves global, upper or lower limb function, and if treatment effects are dependent on the amount, type or timing of practice. SEARCH STRATEGY: We searched the Cochrane Stroke Trials Register (October 2006), The Cochrane Library, MEDLINE, EMBASE, CINAHL, AMED, SportDiscus, Science Citation Index, Index to Theses, ZETOC, PEDro, and OT Seeker (to September 2006), and OT search (to March 2006). We also searched for unpublished/non-English language trials, conference proceedings, combed reference lists, requested information on bulletin boards, and contacted trial authors. SELECTION CRITERIA: Randomised/quasi-randomised trials in adults after stroke, where the intervention was an active motor sequence performed repetitively within a single training session, aimed towards a clear functional goal, and where the amount of practice could be quantified. DATA COLLECTION AND ANALYSIS: Two authors independently screened abstracts, extracted data and appraised trials. Assessment of methodological quality was undertaken for allocation concealment, blinding, loss to follow up and equivalence of treatment. We contacted trial authors for additional information. MAIN RESULTS: Fourteen trials with 17 intervention-control pairs and 659 participants were included. PRIMARY OUTCOMES: results were statistically significant for walking distance (mean difference (MD) 54.6, 95% CI 17.5 to 91.7); walking speed (standardised mean difference (SMD) 0.29, 95% CI 0.04 to 0.53); sit-to-stand (standard effect estimate 0.35, 95% CI 0.13 to 0.56); and of borderline statistical significance for functional ambulation (SMD 0.25, 95% CI 0.00 to 0.51), and global motor function (SMD 0.32, 95% CI -0.01 to 0.66). There were no statistically significant differences for hand/arm function, or sitting balance/reach. SECONDARY OUTCOMES: results were statistically significant for activities of daily living (SMD 0.29, 95% CI 0.07 to 0.51), but not for quality of life or impairment measures. There was no evidence of adverse effects. Follow-up measures were not significant for any outcome at six or twelve months. Treatment effects were not modified by intervention amount or timing, but were modified by intervention type for lower limbs. AUTHORS' CONCLUSIONS: Repetitive task training resulted in modest improvement in lower limb function, but not upper limb function. Training may be sufficient to impact on daily living function. However, there is no evidence that improvements are sustained once training has ended. The review potentially investigates task specificity rather more than repetition. Further research should focus on the type and amount of training, and how to maintain functional gain.

Prevention and treatment of urinary incontinence after stroke in adults.

BACKGROUND: Urinary incontinence can affect 40-60% of people admitted to hospital after a stroke, with 25% still having problems on hospital discharge and around 15% remaining incontinent at one year. OBJECTIVES: To determine the optimal methods for prevention and treatment of urinary incontinence after stroke in adults. SEARCH STRATEGY: We searched the Cochrane Incontinence and Stroke Groups specialised registers (searched 15 December 2004 and 26 October 2004, respectively), CINAHL (January 1982 to November 2004), national and international trial databases for unpublished data, and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials evaluating the effects of interventions designed to promote continence in people after stroke. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment were undertaken by two reviewers working independently. Disagreements were resolved by a third reviewer. MAIN RESULTS: Seven trials with a total of 399 participants were included in the review. Participants were from a mixture of settings, age groups and phases of stroke recovery. No two trials addressed the same comparison. Four trials tested an intervention against usual care, including acupuncture, timed voiding, and two types of specialist professional intervention. One cross-over trial tested an intervention (oestrogen) against placebo. One trial tested a specific intervention (oxybutynin) against another intervention (timed voiding), and one trial tested a combined intervention (sensory-motor biofeedback plus timed voiding) against a single component intervention (timed voiding alone). Reported data were insufficient to evaluate acupuncture or timed voiding versus usual care, oxybutynin versus timed voiding, or sensory motor biofeedback plus timed voiding versus usual care. Evidence from a single small trial suggested that structured assessment and management of care in early rehabilitation may reduce the number of people with incontinence at hospital discharge (1/21 versus 10/13; RR 0.06, 95% CI 0.01 to 0.43), and have other benefits. Evidence from another trial suggested that assessment and management of care by Continence Nurse Practitioners in a community setting may reduce the number of urinary symptoms (48/89 versus 38/54; RR 0.77, 95% CI 0.59 to 0.99), and increase satisfaction with care. AUTHORS' CONCLUSIONS: There was suggestive evidence that specialist professional input through structured assessment and management of care and specialist continence nursing may reduce urinary incontinence after stroke. Data from trials of other physical, behavioural, complementary and anticholinergic drug interventions are insufficient to guide continence care of adults after stroke.

Predicting spasticity after stroke in those surviving to 12 months.

OBJECTIVE: To measure muscle tone in a cohort of patients 12 months after stroke and develop a preliminary model, using data recorded routinely after stroke, to predict who will develop spasticity. DESIGN: A cohort study. SETTING: Initially hospitalized but subsequently community-dwelling stroke survivors in Liverpool, United Kingdom. SUBJECTS: One hundred and six consecutively presenting stroke patients surviving to 12 months. MAIN OUTCOME MEASURES: Spasticity measured at a range of joints using the Tone Assessment Scale. RESULTS: The Tone Assessment Scale revealed spasticity in 38 (36%) patients and more severe spasticity in 21 (20%) of the 106 patients. Logistic regression analysis revealed that lower day 7 Barthel Index score and early arm or leg weakness were significant predictors of abnormal muscle tone; and lower day 7 Barthel Index score, left-sided weakness and ever smoked to be significant predictors of more severe muscle tone. CONCLUSIONS: Using the models, it may be possible to predict whether or not spasticity will develop in patients 12 months after stroke. The utility of the models is aided by their use of predictor variables that are routinely collected as part of stroke care in hospital and which are easy to measure. The models need testing prospectively in a new cohort of patients in order to test their validity, reliability and utility and to determine if other data could improve their efficiency.

Prevalence of spasticity post stroke.

OBJECTIVES: To establish the prevalence of spasticity 12 months after stroke and examine its relationship with functional ability. DESIGN: A cohort study of prevalence of spasticity at 12 months post stroke. SETTING: Initially hospitalized but subsequently community-dwelling stroke survivors in Liverpool, UK. SUBJECTS: One hundred and six consecutively presenting stroke patients surviving to 12 months. MAIN OUTCOME MEASURES: Muscle tone measured at the elbow using the Modified Ashworth Scale and at several joints, in the arms and legs, using the Tone Assessment Scale; functional ability using the modified Barthel Index. RESULTS: Increased muscle tone (spasticity) was present in 29 (27%) and 38 (36%) of the 106 patients when measured using the Modified Ashworth Scale and Tone Assessment Scale respectively. Combining the results from both scales produced a prevalence of 40 (38%). Those with spasticity had significantly lower Barthel scores at 12 months (p < 0.0001). CONCLUSION: When estimating the prevalence of spasticity it is essential to assess both arms and legs, using both scales. Despite measuring tone at several joints, spasticity was demonstrated in only 40 (38%) patients, lower than previous estimates.

The COSTAR wheelchair study: a two-centre pilot study of self-propulsion in a wheelchair in early stroke rehabilitation. Collaborative Stroke Audit and Research.

OBJECTIVE: It is uncertain whether self-propulsion in a wheelchair should be encouraged or discouraged in the early stages of stroke rehabilitation. DESIGN: A two-centre pilot study to assess the feasibility of performing a multicentre randomized controlled trial on this subject. SETTING: Clatterbridge and Aintree Stroke Rehabilitation Units, Merseyside, UK. SUBJECTS: Forty early stroke patients (mean age 67 years) in whom it was uncertain whether self-propulsion in a wheelchair should be encouraged were studied. INTERVENTION: A central randomization service at Newcastle University was used to determine the policy about wheelchair provision and use for each patient. They were allocated to either an 'encouraged to self-propel' or a 'discouraged from self-propulsion group'. OUTCOME MEASURES USED: Independent outcome assessment was performed by postal questionnaire and telephone interview using the Barthel ADL Scale, Nottingham Extended ADL Scales and the shortened General Health Questionnaire (GHQ-12) at 3 and 12 months. Patient's length of stay and their Ashworth tone score were also measured either at three months or when they were discharged from hospital. RESULTS: After considerable preparation time it was possible to conduct a trial on self-propulsion in early stroke rehabilitation in the two-pilot centres. No major differences were found between the pilot groups for any of the outcome measures. CONCLUSIONS: A multicentre randomized controlled trial to assess this question is feasible but further work is being conducted before proceeding, to satisfy the concerns expressed to our group regarding the appropriateness of the intervention and the outcome measures.

Reliability of measurements of muscle tone and muscle power in stroke patients.

OBJECTIVES: to establish the reliability of the modified Ashworth scale for measuring muscle tone in a range of muscle groups (elbow, wrist, knee and ankle; flexors and extensors) and of the Medical Research Council scale for measuring muscle power in the same muscle groups and their direct antagonists. DESIGN: a cross-sectional study involving repeated measures by two raters. We estimated reliability using the kappa statistic with quadratic weights (Kw). SETTING: an acute stroke ward, a stroke rehabilitation unit and a continuing care facility. SUBJECTS: people admitted to hospital with an acute stroke-35 patients, median age 73 (interquartile range 65-80), 20 men and 15 women. RESULTS: inter- and intra-rater agreement for the measurement of power was good to very good for all tested muscle groups (Kw = 0.84-0.96, Kw = 0.70-0.96). Inter- and intra-rater agreement for the measurement of tone in the elbow, wrist and knee flexors was good to very good (Kw = 0.73-0.96, Kw = 0.77-0.94). Inter- and intra-rater agreement for the measurement of tone in the ankle plantarflexors was moderate to good (Kw = 0.45-0.51, Kw = 0.59-0.64). CONCLUSIONS: the Medical Research Council scale was reliable in the tested muscle groups. The modified Ashworth scale demonstrated reliability in all tested muscle groups except the ankle plantarflexors. If reliable measurement of tone at the ankle is required for a specific purpose (e.g. to measure the effect of therapeutic intervention), further work will be necessary.

Time-weighted nursing demand is a better predictor than midnight census of nursing supply in an intensive care unit.

PURPOSE: Labor costs are the largest fraction of operating costs in an intensive care unit (ICU). Estimation of appropriate nursing supply is frequently based on the midnight census of patients, which is a "snapshot" view of the ICU. We postulated that the midnight census would not correlate as well as time-weighted nursing demand (a calculation of need for nursing staff) with the actual number of nurses who were required to staff the ICU (nursing supply). The purpose of this study was to compare the correlation between midnight census and actual nursing supply with the correlation between time-weighted nursing demand and nursing supply. MATERIALS AND METHODS: We measured nursing activity, midnight census, and actual nursing supply for each of 77 consecutive days in a 14-bed medical-surgical ICU within a 450-bed tertiary care teaching hospital. We calculated time-weighted nursing demand based on 1:1 nursing for ICU patients, 1:2 nursing for step-down patients, 0.5 additional nurse hours for each cardiac arrest, and 0.5 additional nurse hours for each new admission to the ICU. RESULTS: There was a correlation between midnight census and nursing supply (r2 = .42, P<.0001) and between nursing demand and nursing supply (r2 = .83, P<.0001). The correlation coefficient for the relationship between nursing demand and nursing supply was significantly greater than that for the relationship between midnight census and nursing supply (P<.01). CONCLUSIONS: Time-weighted nursing demand is a better predictor than midnight census of nursing supply in an ICU.

Reliability of the Tone Assessment Scale and the modified Ashworth scale as clinical tools for assessing poststroke spasticity.

OBJECTIVES: To establish reliability of the Tone Assessment Scale and modified Ashworth scale in acute stroke patients. SETTING: A North Liverpool university hospital. PATIENTS: Eighteen men and 14 women admitted with acute stroke and still in hospital at the study start date (median age, 74 yrs; median Barthel score, 8). MAIN OUTCOME MEASURES: The modified Ashworth scale and the Tone Assessment Scale. STUDY DESIGN: The 32 patients were examined with both scales on the same occasion by two raters (interrater comparison) and on two occasions by one rater (intrarater comparison). RESULTS: The reliability of the modified Ashworth scale was very good (kappa = .84 for interrater and .83 for intrarater comparisons). The reliability of the Tone Assessment Scale was not as strong as the modified Ashworth scale, with marked variability in the assessment of posture (kappa = .22 to .50 for interrater and .29 to .55 for intrarater comparisons) and associated reaction (kappa/kappaW = -.05 to .79 for interrater and .19 to .83 for intrarater comparisons). However, those aspects of the Tone Assessment Scale that addressed response to passive movement and that are scored similarly to the modified Ashworth scale showed good to very good interrater reliability (kappaW = .79 to .92) and good to very good intrarater reliability (kappaW = .72 to .86), except for the question related to movement at the ankle where agreement was only moderate (kappaW = .59). CONCLUSIONS: The modified Ashworth scale is reliable. The section of the Tone Assessment Scale relating to response to passive movement is reliable at various joints, except the ankle. It may assist in studies on the prevalence of spasticity after stroke and the relationship between tone and function. Further development of a measure of spasticity at the ankle is required. The Tone Assessment Scale is not reliable for measuring posture and associated reactions.

Practice guideline for arterial blood gas measurement in the intensive care unit decreases numbers and increases appropriateness of tests.

OBJECTIVE: To test the hypothesis that implementation of a practice guideline for blood gas measurement would decrease numbers and increase appropriateness of tests (according to criteria in the guideline) for up to 1 yr after introduction of the guideline. DESIGN: Numbers of tests and appropriateness of each test were measured retrospectively during each of five periods: two baseline periods 2 yrs and 1 yr before introduction of the guideline and three follow-up periods 2 to 3 months, 6 to 7 months, and 12 to 13 months after introduction of the guideline. SETTING: A ten-bed multidisciplinary intensive care unit (ICU) within a 500-bed tertiary teaching hospital. PATIENTS: A random sample of 30 patients admitted to the ICU during each of the periods specified above. INTERVENTIONS: The nominal group process was used to develop a new guideline and a multipronged educational approach was used to facilitate implementation of the guideline. MEASUREMENTS AND MAIN RESULTS: At 2 to 3 months, test numbers decreased from 4.9 +/- 1.6 to 3.1 +/- 1.8 (SD) tests/patient/day and to 2.4 +/- 1.2 tests/patient/day at 12 to 13 months. Appropriateness increased from a mean of 44% at baseline to 78% at 2 to 3 months and 79% at 12 to 13 months. There were no differences in Acute Physiology and Chronic Health Evaluation scores or ICU mortality among the patient groups and no differences in number of ventilator days or time to wean from ventilation. Cost-minimization analysis showed that the incremental cost-saving 1 yr after introduction of the guideline was $19.18 per patient per day. CONCLUSIONS: Implementation of this guideline for arterial blood gas measurement increases efficiency of test utilization without prolonging mechanical ventilation or affecting outcome.

Effects of the CCKB antagonist L-365, 260 on benzodiazepine withdrawal-induced hypophagia in rats.

The effect of the selective CCKB antagonist L-365, 260 on chlordiazepoxide (CDP) withdrawal-induced hypophagia was assessed in two related studies in rats pretreated for 21 days with CDP at doses escalated from 10 to 30 mg/kg per day (b.i.d). L-365, 260 was studied at doses from 0.001 to 10 mg/kg (b.i.d). There was no evidence that L-365, 260 at any dose alleviated CDP withdrawal-induced hypophagia. These data contrast with reports that CCKB antagonists alleviate behavioural benzodiazepine (BZ) withdrawal symptoms considered to be indicative of "anxiogenesis". Presumably, such positive effects of CCKB antagonists are due to "functional antagonism", with enhanced anxiety during BZ withdrawal being attenuated by anxiolytic actions of CCKB antagonists. Collectively, studies with CCKB antagonists and other agents involving a number of different BZ withdrawal signs suggest that BZ withdrawal is a heterogeneous syndrome, with various different underlying mechanisms. CCKB antagonists appear to alleviate only a subset of possible BZ withdrawal signs.

Assessment of the benzodiazepine-like dependence potential in rats of the putative 5-HT(1A) agonist anxiolytic S-20499.

The dependence potential of the putative 5-HT(1A) agonist anxiolytic S-20499 was assessed in rats in a study in which the benzodiazepine chlordiazepoxide (CDP) was used as a "positive control". S-20499 was administered b.i.d. (at 10.00 and 16.00h) for 21 days, at constant doses of either 0.5, 3 or 18mg/kg i.p. Subsequently, spontaneous withdrawal from S-20499 was studied over 7 days. Acutely, S-20499 decreased body weight and food intake and complete tolerance developed to these effects. When S-20499 was withdrawn there was no evidence of any effect on body weight or food intake. CDP was also administered b.i.d. (at 10.00 and 16.00h) for 21 days at doses escalated from 10 to 30mg/kg i.p. CDP differed from S-20499 in some of its acute effects, stimulating body weight and food intake. In contrast to S-20499 withdrawal, CDP withdrawal induced weight loss and aphagia. Acutely, S-20499 resembled CDP in inducing hypothermia. Full tolerance developed to this effect of both drugs. However, only CDP withdrawal induced hyperthermia. Thus S-20499 appeared to be devoid of benzodiazepine-like dependence potential after administration for a relatively long period of time, at doses that are substantially greater than "anxiolytic doses" in rats.

Assessment of the dependence potential of the potent high-efficacy 5-HT1A agonist S-14506 in rats.

This study assessed the dependence potential of S-14506 [ 1- [ 2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxy napthyl) piperazine], a novel, potent 5-HT(1A) full agonist with anxiolytic and antidepressant actions in animal models. The dependence potential of S-14506 was compared with that of the benzodiazepine (BZ) chlordiazepoxide (CDP). BZ withdrawal caused weight loss, aphagia and hyperthermia after chronic b.i.d. treatment for 21 days. None of these withdrawal effects were seen after similar b.i.d. S-14506 treatment at high doses. However, the acute pharmacological actions of CDP and S-14506 differed on a number of indices. Specifically, CDP increased food intake and body weight, whilst S-14506 decreased these measures, possibly due to the induction of the serotonin syndrome. Of particular interest was the observation that S-14506 induced marked hypothermia, to which complete tolerance developed very rapidly (after only 1 day). The observation of marked, rapid tolerance to S-14506-induced hypothermia, in conjunction with the absence of withdrawal hyperthermia after prolonged chronic treatment at high doses, suggests that tolerance to this effect of S-14506 can be dissociated from dependence. Collectively, the data reported suggest that the full 5-HT(1A) agonist S-14506 is devoid of dependence potential, other human and animal studies having previously suggested that partial 5-HT(1A) agonists typically induce no, or minimal, dependence.

Actions of ritanserin, a 5-HT(2/1C) antagonist, in benzodiazepine-dependent rats.

The effects of ritanserin on spontaneous benzodiazepine (BZ) withdrawal-induced weight loss, anorexia and hypodipsia were studied. Groups of female rats initially received i.p. injections b.i.d. (11.00 and 17.00h) of either saline or chlordiazepoxide (CDP). CDP doses increased by 2mg/kg/day from 10mg/kg to a final does of 30mg/kg. Treatment was maintained for 26 days. Over the next 6 days animals were either treated b.i.d. with vehicle, CDP, or ritanserin at one of three doses (0.16,0.63 and 2.5mg/kg). In CDP-pretreated animals subsequently treated with vehicle, significant weight loss, anorexia and hypodipsia were seen, relative to controls. In saline-pretreated animals ritanserin had no effect on body weight. However, CDP withdrawal-induced weight loss was actually exacerbated by ritanserin, in a dose-related fashion. Thus, ritanserin potentiated withdrawal-induced weight loss, by a process which did not involve functional (additive) effects of withdrawal and ritanserin treatment. Ritanserin stimulated food intake in saline-pretreated animals. Despite this effect it failed to alleviate CDP withdrawal-induced anorexia. However, in contrast to the weight loss index, no evidence was obtained for potentiation of withdrawal-induced anorexia. In saline-pretreated animals ritanserin had no effect on water intake, nor did it alleviate or potentiate CDP withdrawal-hypodipsia. Thus the effects of ritanserin on somatic BZ withdrawal signs depended upon the specific sign studied, different signs showing potentiation or no effect. However, for none of the signs studied was there any evidence that ritanserin alleviated the effect of CDP withdrawal. 5-HT(2/1C) antagonists may therefore be of limited value in the treatment of somatic aspects of the BZ withdrawal syndrome. They may even exacerbate some BZ withdrawal signs, although a full characterization of the effects of such drugs on BZ withdrawal requires that a number of other different withdrawal signs and symptoms should be studied, since it seems likely that different BZ withdrawal signs involve different underlying mechanisms.

Evidence for a dissociation between benzodiazepine withdrawal signs.

The relationship between benzodiazepine-withdrawal induced weight loss and conditioned taste aversion was studied. Rats were treated with chlordiazepoxide (CDP) for 10 days (n = 37) or with vehicle (n = 39). Significant withdrawal-induced weight loss was observed. On day 11 all animals received an intra-oral infusion of saccharin. In a subsequent saccharin vs water choice test significant withdrawal-induced conditioned taste aversion was observed, as CDP pretreated animals drank less saccharin than controls. The two withdrawal indices were not correlated in the CDP pretreated animals [r = + 0.05], despite the fact that we studied a large group of rats. These data are in agreement with suggestions that drug withdrawal syndromes may be heterogeneous phenomena with a number of different underlying neural mechanisms.