A double-blind, randomized, parallel group study to compare the efficacy, safety and tolerability of slow-release oral morphine versus methadone in opioid-dependent in-patients willing to undergo detoxification

Aims   Evaluation of the efficacy and safety of slow-release oral morphine (SROM) compared with methadone for detoxification from methadone and SROM maintenance treatment.
Design   Randomized, double-blind, double-dummy, comparative multi-centre study with parallel groups.
Setting   Three psychiatric hospitals in Austria specializing in in-patient detoxification.
Participants   Male and female opioid dependents (age > 18 years) willing to undergo detoxification from maintenance therapy in order to reach abstinence.
Interventions   Abstinence was reached from maintenance treatment by tapered dose reduction of either SROM or methadone over a period of 16 days.
Measurements   Efficacy analyses were based on the number of patients per treatment group completing the study, as well as on the control of signs and symptoms of withdrawal [measured using Short Opioid Withdrawal Scale (SOWS)] and suppression of opiate craving. In addition, self-reported somatic and psychic symptoms (measured using Symptom Checklist SCL-90-R) were monitored.
Findings   Of the 208 patients enrolled into the study, 202 were eligible for analysis (SROM: n  = 102, methadone: n  = 100). Completion rates were 51% in the SROM group and 49% in the methadone group [difference between groups: 2%; 95% confidence interval (CI): −12% to 16%]. The rate of discontinuation in the study was high mainly because of patients voluntarily withdrawing from treatment. No statistically significant differences between treatment groups were found in terms of signs and symptoms of opiate withdrawal, craving for opiates or self-reported symptoms. SROM and methadone were both well tolerated.
Conclusions   Detoxification from maintenance treatment with tapered dose reduction of SROM is non-inferior to methadone.     

Slow‐release oral morphine for maintenance treatment of opioid addicts intolerant to methadone or with inadequate withdrawal suppression

Aims Evaluation of the efficacy, safety and acceptability of slow‐release oral morphine (SROM) in opioid addicts intolerant to methadone or with inadequate withdrawal suppression. Design Prospective, open, non‐comparative multi‐centre study. Setting Twelve out‐patient Centres for Prevention and Treatment of Drug Addiction in Slovenia. Participants Male and female opioid addicts (age >18 years) under methadone maintenance therapy requiring a change of treatment in order to continue more effectively with maintenance. Interventions Maintenance therapy with methadone was switched to once‐daily SROM. Measurements Efficacy evaluations were based on the reduction of side effects and on the degree of suppression of opiate craving, signs and symptoms of withdrawal. In addition, self‐reported somatic and psychic symptoms (SCL‐27) as well as World Health Organization quality of life‐related (WHO QOL) parameters were monitored. Findings Thirty‐nine subjects intolerant to methadone and 28 subjects showing inadequate withdrawal suppression under methadone ≥90 mg/day were included as two separate groups in the efficacy analyses. Treatment was switched easily from methadone to SROM on a 1 : 8 ratio. Four‐week SROM treatment resulted in significant reduction of side effects reported under methadone. Signs and symptoms of opioid withdrawal as well as craving for opiates were improved significantly in patients with inadequate response to methadone. Physical and psychological wellbeing improved significantly under SROM treatment. SROM was tolerated very well. Conclusions Maintenance treatment with SROM appears to be a clinically useful alternative treatment in subjects not tolerating methadone or with inadequate withdrawal suppression.     

Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year

OBJECTIVE AND BACKGROUND: Increasing evidence suggests that low-dose theophylline has anti-inflammatory benefits and is safe in the treatment of COPD. This study aims to evaluate the efficacy and safety of low-dose, slow-release oral theophylline administered over a 1-year period in patients with COPD. METHODS: A randomized, double-blind, parallel-group, placebo-controlled trial was carried out. In total, 110 participants with COPD were randomly assigned to receive slow-release theophylline (100 mg b.i.d.) or placebo for 1 year. Use of medicine and symptoms recorded by diary cards; pulmonary function, exacerbations of COPD, quality of life and the use of rescue medicine were evaluated. Superiority test was used to estimate the efficacy. RESULTS: Of 110 participants, 85 (77.3%) complied with the protocol, with 42 subjects in theophylline and 43 subjects on placebo. In both intention-to-treat and per-protocol population analysis, greater improvement in pre-bronchodilator FEV(1) (P = 0.038 and P = 0.070, respectively), lower frequency of COPD exacerbations (P = 0.047 and P = 0.035, respectively), fewer days of COPD exacerbations (P = 0.045 and P = 0.046, respectively), lower frequency of clinical visits (P = 0.017 and P = 0.039, respectively), greater improvement in satisfaction with treatment (P = 0.014 and P = 0.004, respectively) were found in the theophylline group than in the placebo group. In per-protocol population, greater improvements in quality of life (P = 0.047) were also observed in the theophylline group and the mean time to the first exacerbation was delayed in theophylline group in comparison with placebo group (P = 0.047). Drug-related adverse events such as stomach discomfort (3.51%), headache (3.51%), insomnia (1.75%) and palpitation (1.75%) were found in the theophylline group. CONCLUSIONS: Low-dose, slow-release oral theophylline is effective and well-tolerated in the long term treatment of stable COPD, although it does not improve post-bronchodilator lung function.     

Slow-release oral morphine versus methadone: a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence

AIMS: To evaluate slow-release oral morphine (SROM) as an alternative maintenance pharmacotherapy to methadone for treatment of opioid dependence. DESIGN: Open-label crossover study. SETTING: Out-patient methadone maintenance programme. PARTICIPANTS: Eighteen methadone maintenance patients. Intervention Participants were transferred from methadone to SROM (once-daily Kapanol trade mark ) for approximately 6 weeks before resuming methadone maintenance. MEASUREMENTS: Patient outcomes were assessed (1) during the transition between medications (dose requirements, withdrawal severity) and (2) after at least 4 weeks on a stable dose of each drug (treatment preference, patient ratings of treatment efficacy and acceptability, drug use, health, depression and sleep). FINDINGS: Transfer from methadone to SROM was associated with relatively mild withdrawal for the first 5 days; the final mean SROM : methadone dose ratio was 4.6 : 1. Compared to methadone, SROM was associated with improved social functioning, weight loss, fewer and less troublesome side-effects, greater drug liking, reduced heroin craving, an enhanced sense of feeling 'normal' and similar outcomes for unsanctioned drug use, depression and health. The majority of subjects preferred SROM (78%) over methadone (22%). CONCLUSIONS: These findings provide justification for further evaluation of SROM as a maintenance pharmacotherapy for opioid dependence.     

Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial

AIM: The aim of this study is to define the efficacy of dihydrocodeine as an alternative to methadone in the maintenance treatment of opiate dependence. DESIGN: A pragmatic open-label randomized controlled study of patients recommended for opiate maintenance treatment to test equivalence of the two treatment options with follow-up continuing for up to 42 months after recruitment. SETTING: Assessment at either Edinburgh's Community Drug Problem Service or at two general practitioner practices with specialist drug community psychiatric nurses, then with shared care follow-up. PARTICIPANTS: Two hundred and thirty-five subjects (168 male, 67 female) with opiate dependence syndrome were recruited. Subjects selected were suitable for opiate maintenance treatment. Routine treatment was offered throughout. INTERVENTION: Patients were randomized to receive either methadone mixture 1 mg/ml or dihydrocodeine, 30 mg or 60 mg tablets. MEASUREMENTS: The primary outcome measure was retention in treatment. Eight secondary outcomes included total illicit opiate use, reported crime, physical health, mental health, injecting drug use, overdoses, selling drugs and being in education or work. Measures were compared over 42 months follow-up. FINDINGS: There was no difference in groups for retention in treatment at follow-up and there was improvement in all secondary outcomes from baseline. No significant difference in outcomes was found between randomized groups over time. Compliance with randomized treatment differed by randomized group and was affected by experiences in custody during follow-up. Those randomized to dihydrocodeine were more likely to switch treatments. CONCLUSIONS: These results, combined with existing clinical experience, provide evidence that dihydrocodeine is a viable alternative to methadone as a maintenance treatment for opiate dependence. Indirect comparisons with other studies show dihydrocodeine (and methadone) to be superior to placebo.     

Role of apathy in the effectiveness of weight management programmes

Aims: Obesity, which is at epidemic proportions in the USA, is associated with a higher risk of several co‐morbid diseases including, cardiovascular disease, cancer and sleep apnea. Weight loss and weight maintenance programmmes are difficult to sustain for long term. Mental health problems such as apathy may be a major factor in patients unsuccessful in adhering to weight loss programmes. We propose that treating apathy will result in better weight loss in obese patients. Methods: This was a randomized prospective pilot study. Obese patients (n = 101) were randomized in a 1:2:2 ratio to either (i) standard nutrition counselling; or (ii) the Department of Veterans Affairs weight loss programme called ‘motivate obese veterans everywhere ’ (MOVE); or (iii) methylphenidate treatment plus the MOVE programme together. The intervention was for 6 months (26 weeks). Results: For the within groups analysis, the absolute changes in weight (kg) are as follows, for MOVE (mean: ?1.84; 95% confidence interval (CI): ?4.56 to 0.87; p = 0.25), Methylphenidate (mean: ?4.61; 95% CI: ?7.90 to ?1.33; p = 0.04), standard nutrition counselling (mean: ?0.60; 95% CI: ?2.59 to 1.39; p = 0.21), which indicates that although all three groups lost weight, only the methylphenidate group achieved statistical significance. The between group differences of the relative change in weight were not statistically different. The apathy evaluation score and the patient activation measure improved in all groups. Conclusion: Together these data suggest that treating apathy might be an important factor in the success of weight management programmes.     

Comparative study of nizatidine and famotidine for maintenance therapy of erosive esophagitis

BACKGROUND: The therapeutic effect of combined administration of prokinetics and histamine H2 receptor antagonists (H2RA) in gastroesophageal reflux disease is reported to be superior to that of monotherapy with H2RA alone. In addition to its acid-suppressing effect, the H2RA nizatidine also has a prokinetic action by suppressing acetylcholine esterase. The present multicenter, randomized controlled study was performed to investigate whether nizatidine is superior to famotidine, which does not suppress acetylcholine esterase activity, in maintenance therapy for erosive esophagitis. In addition, the question as to whether the grade of erosive esophagitis affects the non-recurrence rate during the maintenance therapy with H2RA was also investigated. METHODS: Seventy-two patients with endoscopically healed erosive esophagitis after 8 weeks of initial treatment with proton pump inhibitors were randomly divided into two groups. Patients in the nizatidine group were treated with 150 mg nizatidine twice a day (b.i.d.), while patients in the famotidine group were treated with 20 mg famotidine b.i.d. for 6 months. At the end of therapy, and at the time when patients complained of symptoms, endoscopic investigations were repeated to find out whether the esophagitis had recurred. RESULTS: Nizatidine produced a significantly higher non-recurrence rate than famotidine (P = 0.049 in intention-to-treat [ITT] analysis). This difference of remission rate between nizatidine and famotidine was observed mainly in grade B esophagitis (P = 0.016 in ITT analysis). CONCLUSION: Nizatidine is a more effective H2RA than famotidine in the maintenance therapy of patients with reflux esophagitis.     

Key findings from the WHO collaborative study on substitution therapy for opioid dependence and HIV/AIDS

Aims Opioid substitution treatment has been studied extensively in industrialized countries, but there are relatively few studies in developing/transitional countries. The aim of this study was to examine the effectiveness of opioid substitution treatment (OST) in less resourced countries. Design Longitudinal cohort study. Setting Purposively selected OST sites in Asia (China, Indonesia, Thailand), Eastern Europe (Lithuania, Poland, Ukraine), the Middle East (Iran) and Australia. Participants Seven hundred and twenty-six OST entrants. Measurements Participants were interviewed at treatment entry, 3 and 6 months. Standardized instruments assessed drug use, treatment history, physical and psychological health, quality of life, criminal involvement, blood-borne virus (BBV) risk behaviours and prevalence of human immunodeficiency virus (HIV) and hepatitis C. Findings Participants were predominantly male, aged in their early 30s and had attained similar levels of education. Seroprevalence rates for HIV were highest in Thailand (52%), followed by Indonesia (28%) and Iran (26%), and lowest in Australia (2.6%). Treatment retention at 6 months was uniformly high, averaging approximately 70%. All countries demonstrated significant and marked reductions in reported heroin and other illicit opioid use; HIV (and other BBV) exposure risk behaviours associated with injection drug users (IDU) and criminal activity, and demonstrated substantial improvement in their physical and mental health and general wellbeing over the course of the study. Conclusions OST can achieve similar outcomes consistently in a culturally diverse range of settings in low- and middle-income countries to those reported widely in high-income countries. It is associated with a substantial reduction in HIV exposure risk associated with IDU across nearly all the countries. Results support the expansion of opioid substitution treatment.     

Mortality among opiate users: opioid maintenance therapy, age and causes of death

Aims   This study investigates how age of opioid users is related to causes of death prior to, during and after opioid maintenance treatment (OMT), and estimates risks of death from various causes in relation to age.
Design, setting and participants   Data on all opiate dependents in Norway (1997–2003) who applied for and were accepted for OMT ( n  = 3789) were cross-linked with the Norwegian death register. The total observation time was 10 934 person-years.
Findings   A total of 213 deaths was recorded. Of these, 73% were subject to autopsy, and causes of death were known for 208 cases: the overall death rate was 1.9%. Deaths were due to drug overdose (54%), somatic (32%) and traumatic causes (14%). Overdose deaths among all age groups were reduced during OMT but age had a differential effect upon risk when out of treatment. Younger opioid users were at greater risk of overdose before entering treatment; older users were at greater risk after leaving treatment. Older OMT patients were at higher risk of both somatic and traumatic deaths, and deaths during OMT were most likely to be due to somatic causes.
Conclusions   The high rates of overdose prior to and after treatment emphasize the need to provide rapid access to OMT, to retain patients in treatment and to re-enrol patients. The high prevalence among older patients of deaths due to somatic causes has implications for screening, treatment and referral, and may also lead to increased treatment costs.     

Naloxegol for the treatment of opioid-induced constipation

With increasing chronic opioid use, opioid-induced constipation (OIC) is a rapidly increasing clinical challenge. Naloxegol, an orally administered, peripherally-acting, µ-opioid receptor antagonist, was developed for the treatment of OIC. This drug profile summarizes published information and presentations at meetings on the effects of naloxegol in OIC. In animal studies, naloxegol was able to inhibit gastrointestinal opioid effects while preserving central analgesic actions and human pharmacodynamic studies were in agreement with such mode of action. Phase II and Phase III studies in patients with non-cancer OIC confirmed the efficacy of naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25 mg dose once daily. There were no signs of opioid withdrawal in these studies. Side effects were mainly gastrointestinal in origin, and usually transient and mild. A long-term safety study showed no new adverse events. The US FDA and EMA are currently evaluating the use of naloxegol in OIC.     

Meta分析评价我国美沙酮维持治疗门诊中干预活动的效果

目的综合评价中国美沙酮维持治疗门诊干预活动,对提高服药人员治疗依从性和恢复其社会功能的效果。方法在PubMed、万方数据库、中国期刊全文数据库(CNKI)检索中、英文发表的中国美沙酮维持治疗(MMT)门诊干预研究文献,共筛选出16篇。采用Meta分析方法,综合定量分析干预活动对减少脱失、减少偷吸毒品等的影响。结果脱失率、尿检阳性率和就业率三个指标纳入分析的分别有1 996人、775人和880人,其中干预组依次分别为1 038人、409人和419人,对照组依次分别为958人、366人和471人。干预组服药人员的脱失率和尿检阳性率分别较对照组降低了18%(95%CI:0.14～0.21,P<0.001)和27%(95%CI:0.17～0.37,P<0.001),而就业率升高26%(95%CI:0.14～0.38,P<0.001)。结论在MMT门诊内开展健康教育等干预活动,对提高服药人员的依从性及恢复其社会功能有较好的效果。     

Interferon alfa-2b versus no maintenance therapy during the plateau phase in multiple myeloma: a randomized study

This clinical trial was designed to investigate if maintenance therapy with alfa-interferon could prolong the plateau phase in patients with multiple myeloma. In addition, the tolerability of interferon treatment and its effect on survival were evaluated.
From September 1987 to September 1989 a total of 314 patients were accrued to a multi-institutional randomized clinical trial. All patients entered into the protocol received standard melphalan-prednisone (MP) induction therapy. Response was noted in 184 (59%) and a plateau phase achieved in 155 (49%). From the latter group, 125 eligible patients were randomized to either interferon alfa-2b or no maintenance. The patients were followed for an average of 51 months (minimum 36 months) from the time of randomization.
The plateau phase was significantly prolonged in the group of patients treated with interferon (median 13.9 v 5.7 months from the time of randomization; P < 0.0001). The interferon therapy was tolerated fairly well, moderate granulocytopenia and a chronic fatigue syndrome being the most frequent side-effects (22% v 18% W.H.O. grade 3 toxicity). The median survival from randomization was almost identical in both groups (36 v 35 months).
The study shows that interferon maintenance therapy given to multiple myeloma patients who have achieved a response to initial treatment with MP prolongs the plateau phase duration with tolerable toxicity. The clinical value of this finding should be interpreted with caution, because survival was not prolonged. Further studies are required to clarify the role of interferon in the treatment of multiple myeloma.