A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial

OBJECTIVE: Both methadone and buprenorphine are effective therapy for heroin dependence. Efficacy is best documented for methadone maintenance therapy, but safety concerns limit its use. Buprenorphine offers lower overdose risk and improved access, but efficacy may be lower. The authors compared adaptive, buprenorphine-based stepped care to optimal methadone maintenance treatment. METHOD: This randomized controlled trial was undertaken 2004-2006. It consisted of a 24-day uniform double-blind induction phase followed by single-blind flexible dosing based on structured clinical criteria, for a total of 6 months. Ninety-six self-referred subjects with heroin dependence were randomly assigned to methadone or to stepped treatment initiated with buprenorphine/naloxone and escalated to methadone if needed. All subjects received intensive behavioral treatment. Primary outcome was retention in treatment. Secondary outcomes were completer analyses of problem severity (Addiction Severity Index) and proportion of urine samples free of illicit drugs. RESULTS: Overall, 6-month retention was 78%. Stepped treatment and methadone maintenance therapy outcomes were virtually identical. Among completers of stepped therapy, 46% remained on buprenorphine/naloxone. Proportion of urine samples free of illicit opiates increased over time and ultimately reached approximately 80% in both arms. Problem severity decreased significantly and uniformly in both arms. CONCLUSIONS: A stepped treatment of heroin dependence as described here appears equally efficacious compared to optimally delivered methadone maintenance therapy. Together with prior data on the advantageous safety of buprenorphine, this suggests that broad implementation of strategies using buprenorphine as first-line treatment should be considered.     

A randomized controlled trial of postcrisis suicide prevention

OBJECTIVE: This study tested the hypothesis that professionals' maintenance of long-term contact with persons who are at risk of suicide can exert a suicide-prevention influence. This influence was hypothesized to result from the development of a feeling of connectedness and to be most pertinent to high-risk individuals who refuse to remain in the health care system. METHODS: A total of 3,005 persons hospitalized because of a depressive or suicidal state, populations known to be at risk of subsequent suicide, were contacted 30 days after discharge about follow-up treatment. A total of 843 patients who had refused ongoing care were randomly divided into two groups; persons in one group were contacted by letter at least four times a year for five years. The other group-the control group-received no further contact. A follow-up procedure identified patients who died during the five-year contact period and during the subsequent ten years. Suicide rates in the contact and no-contact groups were compared. RESULTS: Patients in the contact group had a lower suicide rate in all five years of the study. Formal survival analyses revealed a significantly lower rate in the contact group (p=.04) for the first two years; differences in the rates gradually diminished, and by year 14 no differences between groups were observed. CONCLUSIONS: A systematic program of contact with persons who are at risk of suicide and who refuse to remain in the health care system appears to exert a significant preventive influence for at least two years. Diminution of the frequency of contact and discontinuation of contact appear to reduce and eventually eliminate this preventive influence.     

Intravenous immunoglobulin maintenance treatment in myasthenia gravis: A randomized,controlled trial sample size simulation

Introduction: In cases of exacerbation or crisis, myasthenia gravis (MG) patients can be treated with intravenous immunoglobulin (IVIg), plasmapheresis, or immunoadsorption. However, IVIg efficacy data in maintenance treatment are sparse. Methods: We prospectively observed 16 index patients with chronic and insufficiently controlled MG under standard immunosuppressant therapy and symptomatic treatment. The IVIg treatment response was measured using changes in quantitative myasthenia gravis (QMG) score and surrogates. Based on these results, a sample size calculation for a future randomized, controlled trial (RCT) was simulated. Results: There was an enduring decline in QMG score and other parameters of about 50% under IVIg maintenance treatment. RCT sample size calculation results in 73 or 33 patients per arm to detect at least a 20% vs. 30% clinical difference in QMG score. Conclusion: We recommend using the QMG score as a primary endpoint for an RCT of IVIg maintenance for chronic MG. Muscle Nerve 50: 999–1004, 2014     

A randomized controlled trial of cognitive remediation in schizophrenia

Individuals with schizophrenia have consistently been found to exhibit cognitive deficits, which have been identified as critical mediators of psychosocial functional outcomes. Recent reviews of cognitive remediation (CRT) have concluded that these deficits respond to training. This multi-site community study examined 40 individuals with schizophrenia who underwent cognitive remediation using the Neuropsychological Educational Approach to Remediation(1) (NEAR). Assessments using the same neuropsychological tests and measures of psychosocial outcome were made at four time points: baseline, before start of active intervention, end of active intervention and 4 months after end of active intervention. Dose of antipsychotic medication remained constant throughout the study period. After participating in NEAR, individuals showed significant improvements in verbal and visual memory, sustained attention and executive functioning. This effect persisted 4 months after the treatment ceased. The average effect size was mild to moderate. Social and occupational outcomes also improved from baseline to post-treatment, which persisted 4 months later. Our findings replicate those of previous studies that suggest that NEAR is effective in improving cognition in individuals with schizophrenia in a naturalistic and ecologically valid setting. Further it extends such findings to show a generalisation of effects to social/occupational outcomes and persistence of effects in the short term.     

Enhancing antiepileptic drug adherence: A randomized controlled trial

Suboptimal adherence to antiepileptic drug (AED) treatment is commonplace, and increases the risk of status epilepticus and sudden unexplained death in epilepsy. This randomized controlled trial was designed to demonstrate whether an implementation intention intervention involving the completion of a simple self-administered questionnaire linking the intention of taking medication with a particular time, place, and other activity can improve AED treatment schedule adherence. Of the 81 patients with epilepsy who were randomized, 69 completed a 1-month monitoring period with an objective measure of tablet taking (electronic registration of pill bottle openings, Medication Event Monitoring System [MEMS]). Intervention participants showed improved adherence relative to controls on all three outcomes: doses taken in total (93.4% vs. 79.1%), days on which correct dose was taken (88.7% vs. 65.3%), and doses taken on schedule (78.8% vs. 55.3%) (P < 0.01). The implementation intention intervention may be an easy-to-administer and effective means of promoting AED adherence.     

A randomized controlled trial of outpatient commitment in North Carolina

OBJECTIVE: A randomized controlled trial of outpatient commitment was conducted in North Carolina to provide empirical data on involuntary outpatient commitment and to evaluate its effectiveness in improving outcomes among persons with severe mental illnesses. METHODS: A total of 331 involuntarily hospitalized patients awaiting discharge under outpatient commitment were randomly assigned to be released or to undergo outpatient commitment. Each received case management services and outpatient treatment. Participants in both groups were monitored for one year. After the initial 90-day outpatient commitment order, a patient could receive a renewable 180-day extension. Patients in the control group were immune from outpatient commitment for one year. Information was obtained from self-reports and reports of several informants as well as from outpatient treatment, hospital, and arrest records. RESULTS: In most bivariate analyses, outcomes for the outpatient commitment group and the control group did not differ significantly when the duration of outpatient commitment was not taken into account. However, patients who underwent sustained outpatient commitment and who received relatively intensive outpatient treatment had fewer hospital admissions and fewer days in the hospital, were more likely to adhere to community treatment, and were less likely to be violent or to be victimized. Extended outpatient commitment was also associated with fewer arrests of participants with a combined history of multiple rehospitalizations and previous arrests. The intervention was particularly effective among individuals with psychotic disorders. CONCLUSIONS: Outpatient commitment can improve treatment outcomes when the court order is sustained and combined with relatively intensive community treatment. A court order alone cannot substitute for effective treatment in improving outcomes.     

Depressive symptoms during buprenorphine vs. methadone maintenance: findings from a randomised, controlled trial in opioid dependence

Research suggests that buprenorphine may possess antidepressant activity. The Beck Depression Inventory was completed at baseline and 3 months by heroin dependent subjects receiving either buprenorphine or methadone maintenance as part of a larger, pre-existing, double blind trial conducted by NDARC (Australia). Depressive symptoms improved in all subjects, with no difference between methadone and buprenorphine groups, suggesting no differential benefit on depressive symptoms for buprenorphine compared to methadone.     

Fluoxetine for poststroke depression ——A randomized placebo controlled clinical trial

BACKGROUND: Studies have demonstrated that poststroke depression(PSD) may be related with the disequilibrium between noradrenaline and 5-hydroxytryptamine (5-HT) caused by cerebral injury. The injured regions involve noradrenergic and 5-hydroxytryptaminergic neurons as well as conduction pathway. The levels of noradrenaline and 5-HT would be decreased. OBJECTIVE: To observe the effect of fluoxetine on preventing against PSD and recovery of neurologic function, and analyze the relationship of fluoxetine and the 5-HT level. DESIGN: A randomized controlled clinical trial. SETTING: Department of Neurology, First Hospital Affiliated to Soochow University. PARTICIPANTS: Ninety consecutive patients, 47 female and 43 male, were recruited who admitted to hospital for recent stroke in the Department of Neurology, First Affiliated Hospital of Soochow University between September 2003 and February 2005. Subjects were aged (64±7 ) years, ranging from 47 to 79 years old. They all met the diagnosis criteria of various cerebrovascular diseases formulated in the 4th National Cerebrovascular Disease Conference and confirmed as stroke by skull CT or MRI; The time from onset to tentative administration was less than 7 days; The patients had clear consciousness, without obvious language disorder. They were randomized into treatment group (n =48) and placebo group (n =42). METHODS: ①All the patients were given routine treatment according to treatment guideline of cerebrovascular disease after admission. Patients in the treatment group and placebo group received 20 mg/d fluoxetine and placebo (component: vitamin C) for 8 weeks, respectively. ② Neurologic deficit was assessed according to 24-item Hamilton Rating Scale for Depression (HAMD) and Activity of Daily Living Scale (ADL) before and at 2,4 and 8 weeks after test, separately; Meanwhile, the levels of platelet 5-HT and plasma 5-HT were determined. Grading criteria of HAMD intergral depression: non-depression < 8 points; mild depression 8–20 points; moderate depression 21–35 points; severe depression > 35 points. ADL was assessed with Barthel index score (full mark 100 points). Higher points indicated better incidence and smaller dependence. Neurologic deficit score was made according to scoring criteria of neurologic deficit formulated in 1995 4th National Cerebrovascular Disease Conference: a score of 0–15 indicated a mild focal neurologic deficit, a score of 16–30 a moderate focal neurologic deficit, and a score of 31–45 a severe focal deficit. MAIN OUTCOME MEASURES: Scores of HAMD, ADL and neurologic deficit, and levels of plasma and platelet 5-HT of patients from 2 groups before, 2,4 and 8 weeks after test. RESULRS: Seventy-three of 90 randomized patients participated in the final analysis. In the treatment group, 11 patients dropped out due to insufficient clinical response (n =4), somatic side effects (n =2), intervening medical illness (n =1), hypomania (n =3), and other reasons (n =2). In the placebo group, 6 patients existed due to insufficient clinical response (n =2), somatic side effects (n =1) and other reasons (n =3). ① Before treatment, there were no significant differences in scores of HAMD, DAL and neurologic deficit in patients between two groups (P > 0.05). After 8 weeks of treatment, the scores of HAMD, DAL and neurologic deficit in the treatment group were significantly different from those in the placebo group (12.6±5.3 vs. 16.3 ±3.7; 8.6±6.4 vs. 11.2±6.4; 60.4±12.5 vs. 52.3±13.5, P < 0.01). ② After 8 weeks of treatment, platelet 5-HT level of patients in the treatment group was significantly lower than that in the placebo group [(325.3± 110.5) mg/L vs. (653.6±138.4) mg/L, P < 0.05], while there were no significant differences in plasma 5-HT between two groups (P > 0.05). CONCLUSION: Early fluoxetine treatment obviously retards PSD. The increase of platelet 5-HT level promotes the recovery of neurologic function.     

Fluoxetine for poststroke depression A randomized placebo controlled clinical trial

BACKGROUND: Studies have demonstrated that poststroke depression(PSD) may be related with the disequilibrium between noradrenaline and 5-hydroxytryptamine (5-HT) caused by cerebral injury. The injured regions involve noradrenergic and 5-hydroxytryptaminergic neurons as well as conduction pathway. The levels of noradrenaline and 5-HT would be decreased. OBJECTIVE: To observe the effect of fluoxetine on preventing against PSD and recovery of neurologic function, and analyze the relationship of fluoxetine and the 5-HT level. DESIGN: A randomized controlled clinical trial. SETTING: Department of Neurology, First Hospital Affiliated to Soochow University. PARTICIPANTS: Ninety consecutive patients, 47 female and 43 male, were recruited who admitted to hospital for recent stroke in the Department of Neurology, First Affiliated Hospital of Soochow University between September 2003 and February 2005. Subjects were aged (64±7 ) years, ranging from 47 to 79 years old. They all met the diagnosis criteria of various cerebrovascular diseases formulated in the 4th National Cerebrovascular Disease Conference and confirmed as stroke by skull CT or MRI; The time from onset to tentative administration was less than 7 days; The patients had clear consciousness, without obvious language disorder. They were randomized into treatment group (n =48) and placebo group (n =42). METHODS: ①All the patients were given routine treatment according to treatment guideline of cerebrovascular disease after admission. Patients in the treatment group and placebo group received 20 mg/d fluoxetine and placebo (component: vitamin C) for 8 weeks, respectively. ② Neurologic deficit was assessed according to 24-item Hamilton Rating Scale for Depression (HAMD) and Activity of Daily Living Scale (ADL) before and at 2,4 and 8 weeks after test, separately; Meanwhile, the levels of platelet 5-HT and plasma 5-HT were determined. Grading criteria of HAMD intergral depression: non-depression < 8 points; mild depression 8–20 points; moderate depression 21–35 points; severe depression > 35 points. ADL was assessed with Barthel index score (full mark 100 points). Higher points indicated better incidence and smaller dependence. Neurologic deficit score was made according to scoring criteria of neurologic deficit formulated in 1995 4th National Cerebrovascular Disease Conference: a score of 0–15 indicated a mild focal neurologic deficit, a score of 16–30 a moderate focal neurologic deficit, and a score of 31–45 a severe focal deficit. MAIN OUTCOME MEASURES: Scores of HAMD, ADL and neurologic deficit, and levels of plasma and platelet 5-HT of patients from 2 groups before, 2,4 and 8 weeks after test. RESULRS: Seventy-three of 90 randomized patients participated in the final analysis. In the treatment group, 11 patients dropped out due to insufficient clinical response (n =4), somatic side effects (n =2), intervening medical illness (n =1), hypomania (n =3), and other reasons (n =2). In the placebo group, 6 patients existed due to insufficient clinical response (n =2), somatic side effects (n =1) and other reasons (n =3). ① Before treatment, there were no significant differences in scores of HAMD, DAL and neurologic deficit in patients between two groups (P > 0.05). After 8 weeks of treatment, the scores of HAMD, DAL and neurologic deficit in the treatment group were significantly different from those in the placebo group (12.6±5.3 vs. 16.3±3.7; 8.6±6.4 vs. 11.2±6.4; 60.4±12.5 vs. 52.3±13.5, P < 0.01). ② After 8 weeks of treatment, platelet 5-HT level of patients in the treatment group was significantly lower than that in the placebo group [(325.3±110.5) mg/L vs. (653.6±138.4) mg/L, P < 0.05], while there were no significant differences in plasma 5-HT between two groups (P > 0.05). CONCLUSION: Early fluoxetine treatment obviously retards PSD. The increase of platelet 5-HT level promotes the recovery of neurologic function.     

A randomized controlled trial of hemodilution therapy in acute ischemic stroke

Rapid hemodilution in the early phase of ischemic stroke by the combination of venesection (250-650 ml during the first 2 days) and administration of low-molecular weight dextran was evaluated in a prospective controlled trial. Fifty-two patients were randomized to hemodilution therapy and 50 to a control group; the two groups were comparable in important prognostic variables. Mean hemoglobin was reduced from 147 to 127 g/l, hematocrit from 43 to 37% and, in a subsample of patients, whole-blood viscosity at a shear rate of 23 sec-1 from 7.0 to 4.3 cps over the first 2 days. Hemodilution was then maintained by repeated dextran infusions. Of the hemodiluted patients, 85% improved in neurological scoring over the first 10 days as compared to 64% of the control patients (p less than 0.025). The case fatality rate during the first 3 months was little affected by hemodilution. Among the survivors, 8% of the hemodiluted and 31% of the non-hemodiluted patients were unable to walk at 3 months. The proportion of surviving patients still hospitalized at the 3-month follow-up was 13% in the hemodilution group and 39% in the control group (p less than 0.01). The combination of venesection and dextran 40 administration is thus an unsophisticated but effective way to achieve rapid hemodilution in patients with acute cerebral infarction, and it improves the overall clinical outcome over the first 3 months.     

A randomized, controlled trial of high-dose dextromethorphan in facial neuralgias

BACKGROUND: NMDA glutamate receptor antagonists such as ketamine and dextromethorphan reduce pain in certain neuropathic pain conditions. However, there have been no controlled trials of NMDA antagonists in facial neuralgias. METHODS: A randomized, double-blind, crossover trial compared 6 weeks of oral dextromethorphan with active placebo (low-dose lorazepam) in 19 patients, stratified into three groups: 11 with facial pain and possible trigeminal neuropathy, five with anesthesia dolorosa, and three with idiopathic trigeminal neuralgia. Dosage was titrated in each patient to the highest level reached without disrupting normal activities. RESULTS: Patients completing the trial included 10 with possible trigeminal neuropathy, four with anesthesia dolorosa, and two with trigeminal neuralgia. In patients with possible trigeminal neuropathy and anesthesia dolorosa, dextromethorphan decreased pain by a mean of only 2 to 4%, and these estimates were not significant. Both patients with trigeminal neuralgia had more pain during dextromethorphan treatment than during placebo treatment. Of three patients who demonstrated an analgesic response to dextromethorphan during the main trial, only one repeatedly responded in four subsequent confirmatory drug-placebo crossovers. CONCLUSIONS: Dextromethorphan shows little or no analgesic efficacy in pain due to possible trigeminal neuropathy and anesthesia dolorosa. Additional trials are necessary to conclusively evaluate the efficacy of NMDA-receptor antagonists in trigeminal neuralgia.