Recent advances in the treatment of opioid use disorders–focus on long-acting buprenorphine formulations

Oral methadone or sublingual buprenorphine are first-line medications for pharmacotherapy of opioid use disorders (OUDs). Three long-acting buprenorphine depot or implant formulations are currently available for the treatment of OUDs: (1) CAM 2038 (Buvidal) for subcutaneous weekly and monthly application; (2) RBP-6000 (Sublocade™) as a monthly depot formulation; and (3) A six-month buprenorphine implant [Probuphine™]. The pharmacology, clinical efficacy and prospects of these medications are discussed.     

Switching from depot antipsychotic drugs to olanzapine in patients with chronic schizophrenia

BACKGROUND: Patients with chronic schizophrenia (DSM-IV criteria) often receive depot antipsychotic medications to assure longer administration and better compliance with their treatment regimen. This study evaluated whether patients stabilized on depot antipsychotic medication could be successfully transitioned to oral olanzapine. METHOD: In a 3-month open-label study, 26 clinically stable patients with schizophrenia taking depot antipsychotics for over 3 years were randomly assigned to continue on their current depot dose or to switch to oral olanzapine. Clinical ratings (Positive and Negative Syndrome Scale [PANSS], Global Assessment of Functioning [GAF] scale, and Clinical Global Impressions [CGI] scale) and side effect parameters (Abnormal Involuntary Movement Scale [AIMS], Barnes Akathisia Scale, AMDP-5 scale, vital signs, and weight) were obtained monthly. RESULTS: Oral olanzapine patients (N = 13) demonstrated significant clinical improvement over the depot control group (N = 13) from baseline to 3-month endpoint (PANSS total, p =.012; PANSS general, p =.068; PANSS negative, p =.098; CGI-Improvement, p =.007; CGI-Severity, p =.026; GAF, p =.015). Side effect rating scales showed no statistical differences between the 2 groups (AIMS, Barnes Akathisia Scale, AMDP-5, vital signs). The depot control group showed no statistical superiority in any measure except weight change (p =.0005). After 3 months, all olanzapine patients preferred olanzapine to their previous depot medications and chose to continue on olanzapine treatment. CONCLUSION: Clinicians may expect clinical improvement when switching chronically psychotic patients from traditional depot antipsychotic drugs to oral olanzapine. Switching may be completed within a 4-week period with relative compliance being maintained and patients preferring oral olanzapine to their previous depot medications.     

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Substance Use and Related Disorders. Part 2: Opioid dependence

Abstract

Objectives. To develop evidence-based practice guidelines for the pharmacological treatment of opioid abuse and dependence. Methods. An international task force of the World Federation of Societies of Biological Psychiatry (WFSBP) developed these practice guidelines after a systematic review of the available evidence pertaining to the treatment of opioid dependence. On the basis of the evidence, the Task Force reached a consensus on practice recommendations, which are intended to be clinically and scientifically meaningful for physicians who treat adults with opioid dependence. The data used to develop these guidelines were extracted primarily from national treatment guidelines for opioid use disorders, as well as from meta-analyses, reviews, and publications of randomized clinical trials on the efficacy of pharmacological and other biological treatments for these disorders. Publications were identified by searching the MEDLINE database and the Cochrane Library. The literature was evaluated with respect to the strength of evidence for efficacy, which was categorized into one of six levels (A–F). Results. There is an excellent evidence base supporting the efficacy of methadone and buprenorphine or the combination of buprenorphine and naloxone for the treatment of opioid withdrawal, with clonidine and lofexidine as secondary or adjunctive medications. Opioid maintenance with methadone and buprenorphine is the best-studied and most effective treatment for opioid dependence, with heroin and naltrexone as second-line medications. Conclusions. There is enough high quality data to formulate evidence-based guidelines for the treatment of opioid abuse and dependence. This task force report provides evidence for the efficacy of a number of medications to treat opioid abuse and dependence, particularly the opioid agonists methadone or buprenorphine. These medications have great relevance for clinical practice.     

Adherence assessments and the use of depot antipsychotics in patients with schizophrenia

BACKGROUND: Antipsychotic medications significantly ameliorate the symptoms of schizophrenia, but patients are often noncompliant with these medications. Research evidence supports the use of depot antipsychotics in noncompliant patients. METHOD: Between January 9, 1991, and December 19, 1995, 1307 veterans with schizophrenia or schizoaffective disorder (ICD-9) were enrolled in a study of enhanced psychosocial programming at 14 Veterans Administration Medical Centers. All had a history of high inpatient use. At enrollment, clinicians listed patient medications, rated patient compliance, and completed a Brief Psychiatric Rating Scale (BPRS) and Global Assessment of Functioning (GAF). Patients reported medication side effects. We describe depot antipsychotic use among these patients and examine the relationship between depot use, assessed compliance, and patient characteristics. RESULTS: At enrollment, 18% of patients in this cohort were receiving depot antipsychotics; however, clinicians reported that 49% had been noncompliant with medication in the past year. Depot use varied significantly with treatment site; African Americans were more likely to receive depot antipsychotics and less likely to receive atypical antipsychotics than white patients. Patients on depot and oral agents had similar levels of psychiatric symptoms, but patients on depot antipsychotics were more likely to receive high doses and complain of side effects. CONCLUSION: Clinicians prescribed depot antipsychotics relatively infrequently, despite high rates of noncompliance and high levels of inpatient use. Variation in use with treatment site and ethnic group suggests barriers to implementing research-based recommendations for depot use in noncompliant patients. Quality improvement programs should consider facilitating the appropriate use of depots.     

Use of depot antipsychotic medications for medication nonadherence in schizophrenia

Objectives: To describe factors associated with initiation of depot antipsychotic medications in psychiatric outpatients with schizophrenia and recent medication nonadherence. Methods: A national sample of psychiatrists reported on adult outpatients with schizophrenia who were nonadherent with oral antipsychotic medications in the last year. Results: In total, 17.6% of psychiatrists initiated depot antipsychotic injections. Initiation was significantly and positively associated with public insurance, prior inpatient admission, proportion of time nonadherent, average or above average intellectual functioning, and living in a mental health residence. Use was inversely associated with using second-generation antipsychotics and other oral psychotropic medications prior to medication nonadherence. Psychiatrists who were male, nonwhite, and more optimistic about managing nonadherence were more likely to initiate depot injections. Conclusions: Initiation of depot injections is a joint function of patient, physician, treatment, and setting factors. Use of long-acting preparations in this population is uncommon despite clinical recommendations urging their use.     

Injections of depot antipsychotic medications in patients suffering from schizophrenia: do they hurt?

INTRODUCTION: Long-acting depot injections of antipsychotic medications are an important way to monitor treatment noncompliance in patients suffering from schizophrenia. Pain and discomfort at the injection site may result in patients' refusal of depot injections. The present study is a pilot study that attempts a systematic characterization of injection site pain. METHOD: Thirty-four consecutive outpatients suffering from DSM-IV-defined schizophrenia or schizoaffective disorder and treated with depot antipsychotic medications were evaluated. The pain they suffered from the injections was quantified using a visual analog scale. This evaluation was made 5 minutes before the injection, 5 minutes after. 2 days after, 10 days after, and before the next injection. Patients were also administered a modified version of the Rating of Medication Influences scale that included a specific question on the possible relationship between injection-associated pain and future compliance to depot treatment. RESULTS: The depot injections cause pain, which is maximal immediately after the injection, declines substantially 2 days after, and disappears by the tenth day after the injection. A correlation exists between reported injection site pain and the effect it has on patients' attitude toward the depot injection as reported by the patients. Zuclopenthixol depot injection is more painful than other depot medications. CONCLUSION: Depot injections are painful. The pain they inflict has a typical course, and medication type is among the factors that influence this pain. This pain might have an effect on patients' attitude toward depot injections and thus is of importance in the management of patients suffering from schizophrenia.     

Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs methadone

BACKGROUND: Cocaine abuse occurs in 40% to 60% of patients entering opioid maintenance treatment, and effective pharmacotherapies are needed for this combined dependence. METHODS: This 13-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of desipramine hydrochloride (0 or 150 mg/d) plus buprenorphine hydrochloride (12 mg/d) or methadone hydrochloride (65 mg/d) in 180 opioid-dependent cocaine abusers (124 men, 56 women). Supervised urine samples were obtained thrice weekly, and self-reported cocaine and heroin use was reported once weekly. Desipramine plasma levels were determined at weeks 4 and 10. RESULTS: In men, opioid abstinence was increased more rapidly over time when treated with methadone than with buprenorphine, whereas cocaine abstinence was increased more with buprenorphine than with methadone. In women, opioid abstinence was increased the least rapidly when treated with buprenorphine plus placebo, while cocaine abstinence was increased more rapidly over time when treated with methadone than with buprenorphine. Regardless of sex or opioid medication, desipramine increased opioid and cocaine abstinence more rapidly over time than placebo. Self-reported opioid use confirmed these findings. Desipramine plasma levels were higher in women than in men, particularly those on buprenorphine maintenance. Higher desipramine plasma levels were associated with greater opioid, but not cocaine, abstinence. CONCLUSIONS: Desipramine may be a useful adjunctive medication in facilitating opioid and cocaine abstinence in opioid-maintained patients. The efficacy of opioid medications to treat opioid or cocaine dependence may differ by sex. These findings highlight the importance of including sex as a factor when examining treatment outcome in these types of trials.     

Buprenorphine Modulates Methamphetamine-Induced Dopamine Dynamics in the Rat Caudate Nucleus

Methamphetamine (METH) abuse and addiction present a major problem in the United States and globally. Oxidative stress associated with exposure to METH mediates to the large extent METH-evoked neurotoxicity. While there are currently no medications approved for treating METH addiction, its pharmacology provides opportunities for potential pharmacotherapeutic adjuncts to behavioral therapy in the treatment of METH addiction. Opioid receptor agonists can modulate the activity of dopamine neurons and could, therefore, modify the pharmacodynamic effects of METH in the dopaminergic system. Efficacy of the adjunctive medication with buprenorphine has been demonstrated in the treatment of cocaine addiction extending beyond opiate addiction. We investigated the interactions of morphine (10 mg/kg) and buprenorphine (0.01 and 10 mg/kg) with METH (2 mg/kg) affecting striatal dopaminergic transmission. The extracellular concentration of dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined using brain microdialysis coupled with high performance liquid chromatography with electrochemical detection (HPLC-ED) in the caudate nucleus of adult, awake, male Sprague–Dawley rats. Compared to METH alone, extracellular DA release was prolonged for 140 min without changes in DA peak-effect by combined treatment with morphine/METH. Morphine did not change DOPAC efflux evoked by METH. On the other hand, both buprenorphine doses attenuated the METH-induced DA peak-effect. However, whereas high buprenorphine dose extended DA outflow for 190 min, the low-dose abbreviated DA release. High buprenorphine dose also shortened METH-induced decrease in DOPAC efflux. Data confirm that opiates modulate dopaminergic neurotransmission evoked by METH. Alteration of dopaminergic response to METH challenge under buprenorphine may suggest effectiveness of buprenorphine treatment in METH addiction.     

Comparison of pharmacological treatments for opioid-dependent adolescents: a randomized controlled trial

CONTEXT: The prevalence of heroin and other opioid use has markedly increased among adolescents in the last decade; however, virtually no research has been conducted to identify effective treatments for this population. OBJECTIVE: To evaluate the relative efficacy of 2 pharmacotherapies, the partial opioid agonist buprenorphine hydrochloride and the centrally active alpha(2)-adrenergic blocker clonidine hydrochloride, in the detoxification of opioid-dependent adolescents. DESIGN, SETTING, AND PATIENTS: A double-blind, double-dummy, parallel-groups randomized controlled trial conducted in a university-based research clinic from October 2001 to December 2003. Patients were a volunteer sample of 36 adolescents who met DSM-IV criteria for opioid dependence (ages 13-18 years eligible). INTERVENTIONS: Participants were randomly assigned to a 28-day, outpatient, medication-assisted withdrawal treatment with either buprenorphine or clonidine. Both medications were provided along with thrice weekly behavioral counseling and incentives contingent on opiate abstinence. Postdetoxification, all participants were offered the opportunity for continued treatment with the opiate antagonist, naltrexone hydrochloride. MAIN OUTCOME MEASURES: Treatment retention, opiate abstinence, and human immunodeficiency virus risk behavior, along with measures of withdrawal and medication effects. RESULTS: A significantly greater percentage of adolescents who received buprenorphine were retained in treatment (72%) relative to those who received clonidine (39%) (P<.05). For those in the buprenorphine group, a significantly higher percentage of scheduled urine test results were opiate negative (64% vs 32%; P = .01). Participants in both groups reported relief of withdrawal symptoms and drug-related human immunodeficiency virus risk behavior. Those in the buprenorphine condition generally reported more positive effects of the medication. No evidence of opioid intoxication or psychomotor impairment was observed. Sixty-one percent of participants in the buprenorphine condition and 5% of those in the clonidine group initiated treatment with naltrexone. CONCLUSION: Combining buprenorphine with behavioral interventions is significantly more efficacious in the treatment of opioid-dependent adolescents relative to combining clonidine and behavioral interventions.     

Opioid maintenance therapy suppresses alcohol intake in heroin addicts with alcohol dependence: preliminary results of an open randomized study

An open randomized study lasting 12 months was performed to evaluate the efficacy of methadone or buprenorphine to suppress alcohol use in two hundred and eighteen heroin addicts with alcohol dependence. Daily maintenance doses of methadone were 80, 120, 160, and 200 mg/day, while doses of buprenorphine were 8, 16, 24, and 32 mg/day.As expected, both treatments were able to reduce both heroin use and addiction severity (measured with ASI interview). However, although both medications were able to suppress alcohol use, the highest dose of buprenorphine was better than the highest dose of methadone, in reducing alcohol craving, ethanol intake (measured as daily number of drinks), and the ASI subscale of alcohol use.The mechanism underlying the effects of the opioid maintenance therapy on the reduction of alcohol intake is still unclear.The results of the present study may represent the first clinical evidence of the potential effective use of the highest doses of buprenorphine for the suppression of ethanol intake in heroin addicts with alcohol dependence.     

Aftercare of schizophrenic patients: pharmacotherapy and consistency of therapists

Fifty-seven chronic schizophrenic patients were followed an average of six years after index mental hospital admission and compared on the variables of depot fluphenazine (N = 26) versus oral antipsychotic medications (N = 31), and of consistent aftercare with one therapist (N = 17) versus aftercare with multiple therapists or caregivers (N = 40). The patients who had been maintained on depot fluphenazine scored significantly better on measures of mental status than did those on oral medications, but had a significantly lower score on work performance. The group with consistent aftercare scored better on self-ratings and time without serious psychotic symptoms, but showed no difference on objective mental status when compared with the multiple-therapist aftercare group. The authors conclude that consistent aftercare and provision of medications that do not require a major commitment by the patient to remain well may make a small but significant contribution to the welfare of the chronic schizophrenic patient.     

Improving treatment adherence in patients with schizophrenia

Nonadherence to antipsychotic medications is an enormous challenge for clinicians and patients in the treatment of schizophrenia. Nonadherence and partial adherence are associated with high rates of relapse, rehospitalization, and suicide attempts. Assessing adherence can be difficult because patients are likely to overestimate their medication adherence and may not report skipping doses or discontinuing medication. Strategies for assessing and improving adherence rates among patients with schizophrenia, including the use of long-acting depot antipsychotic medications, are discussed.     

Depot neuroleptic usage in adults with learning disabilities

Most previous surveys of depot neuroleptic usage have monitored the consumption of oral psychoactive medications by heterogeneous mental handicap hospital populations. The present study assessed the prevalence, patient, practice and service delivery factors associated with depot neuroleptic usage in community learning disabilities services. The total of 79 adult subjects receiving depot neuroleptics roughly represented 0–5% of local service users. Several significant differences emerged between the factors associated with usage in the 61 (77%) subjects with psychotic disorders and 18 (23%) other subjects. Fitting backward elimination regression models accounted for 67–75% of the depot dosage variance. Comparison of these results with data from previous depot research studies suggested several methodological, clinical, ethical and research issues for future consideration.     

Pharmacological characterization of buprenorphine, a mixed agonist–antagonist with κ3 analgesia

Buprenorphine is a mixed opioid agonist/antagonist analgesic. This study was designed to determine the role of opioid receptor subtypes, especially κ₃, in buprenorphine-induced analgesia in mice. Buprenorphine, when injected systemically, revealed a potent analgesic effect by tailflick assay, with a biphasic dose–response curve, which was reversed by naloxone. The presence of analgesic cross-tolerance between buprenorphine and naloxone benzoylhydrazone (NalBzoH) and morphine indicated a role for κ₃ and μ receptor subtype in buprenorphine analgesia. Additional studies with selective opioid antagonists indicated κ₁ mechanisms of action. We did not detect any involvement of the δ receptor subtype. Low doses of buprenorphine antagonized morphine analgesia, while high doses of buprenorphine coadministered with morphine elicited increasing analgesia in a dose-dependent manner. These findings suggest that buprenorphine elicits analgesia through an interaction with κ₃ receptors and to a lesser extent with κ₁ as well as its activity as partial μ receptor agonist.     

Substance use disorders among older adults: A review of randomized controlled pharmacotherapy trials

Substance use disorders (SUDs) are a growing problem among older adults. Acamprosate, disulfiram, and naltrexone are United States Food and Drug Administration (referred to as FDA) approved for the treatment of alcohol use disorder, and buprenorphine is approved for the treatment of opiate use disorder among adults. However, the data on the use of these medications for the treatment of SUDs among older adults are unclear from randomized controlled trials (referred to as RCTs). A review of the literature indicates that there are only two RCTs that evaluated the use of pharmacologic agents for SUDs among older adults (≥ 50 years). One trial evaluated the use of naltrexone when compared to placebo for the treatment of alcohol use disorder among individuals, 50-70 years in age. The other trial evaluated the use of naltrexone or placebo as adjuncts with sertraline in the treatment of alcohol use disorder among individuals older than 55 years in age. Both trials indicated that the use of naltrexone reduced the rates of relapse among older adults with alcohol use disorder. However, we did not identify any RCTs that studied the use of buprenorphine, acamprosate, or disulfiram for SUDs among older adults. Based on available evidence, it would be safe to conclude that limited data indicate some efficacy for naltrexone in the treatment of alcohol use disorder among older adults. However, data from controlled trials on the use of other medications that are FDA approved for the treatment of SUDs among younger adults are nonexistent among older adults with SUDs.     

Characteristics and use patterns of patients taking first-generation depot antipsychotics or oral antipsychotics for schizophrenia

OBJECTIVE: Investigators compared patient characteristics and antipsychotic use patterns between individuals with schizophrenia treated in usual care with first-generation depot antipsychotics and those treated with oral antipsychotics (first- or second-generation or both). METHODS: Analyses used data from the U.S. Schizophrenia Care and Assessment Program, a large, prospective study of treatment for schizophrenia conducted July 1997 through September 2003. Participants were assessed at enrollment and every six months thereafter with patient self-report, validated psychiatric measures, and systematic extraction of medical records. Individuals treated with a first-generation depot antipsychotic at any time during the three-year study (N=569) were compared with those treated with only oral antipsychotics (N=1,617) on characteristics at enrollment and medication use pattern during the year after enrollment. RESULTS: Compared with patients receiving only oral antipsychotics, participants treated with depot medications (haloperidol or fluphenazine decanoate) were more likely to be African American (p<.001); less likely to be a veteran (p=.005); had more psychiatric hospitalizations in the year before enrollment (p<.001); and were more likely to have been arrested (p<.001), to use alcohol and illicit substances (p<.001), and to show higher psychopathology, particularly psychotic symptoms and disorganized thinking (p<.01 for both). In the year after enrollment, participants treated with depot medications had a high mean medication possession ratio (91%), and most of the medication regimens (68%) were augmented with oral antipsychotics for prolonged durations (median of 144 days). CONCLUSIONS: Patients with schizophrenia treated with first-generation depot antipsychotics differed from those treated with only oral antipsychotics. Findings suggest that first-generation depot antipsychotics might address some unmet needs of a unique subgroup of patients with schizophrenia.     

Depot antipsychotic medications in bipolar disorder: a review of the literature

OBJECTIVE: To review the literature on the efficacy and safety of depot formulations of first- and second-generation antipsychotic medications (FGAs and SGAs) in patients with bipolar disorder. METHOD: We conducted a computer-aided MEDLINE search using the search terms 'depot antipsychotic', 'bipolar disorder' and 'compliance.' RESULTS: We identified eight published reports in bipolar patients regarding the use of depot FGAs, and six preliminary reports on the use of depot SGAs. These studies suggest that depots FGAs are efficacious in preventing manic episodes during the maintenance treatment of bipolar disorder. Several studies, however, indicate that depot FGAs may be associated with increased time with depressive symptoms, particularly in patients with a predominantly depressive course of illness. Preliminary data on the role of depot formulations of SGAs suggest that they reduce the frequency of both manic and depressive episodes during maintenance treatment, and are well tolerated by patients. CONCLUSION: After a careful risk-benefit analysis, depot antipsychotics may be considered for the long-term control of mood episodes in bipolar patients who have relapsed due to medication non-adherence or who have failed to respond to standard therapies. Depot FGAs should be avoided in patients with a high burden of illness from depressive symptoms and particularly in those judged to be at high risk of suicide. The available data on depot formulations of SGAs indicate that they are efficacious in the maintenance treatment of bipolar illness without increasing the burden of the depressive pole of the illness, but further systematic studies are required to definitively assess this.     

A 15-year open study on a cohort of West-African out-patients with a chronic psychosis

BACKGROUND: We wanted to find out if the additional costs of depot neuroleptic in comparison to oral medication was justified by a decrease in admission days. METHODS: An open study on a cohort of chronic psychotic out-patients (n=45) consisting of a retrospective 10-year period on oral medication followed by a prospective 5-year period of treatment with haloperidol decanoate. After recording socio-demographic characteristics and a DSM-III-R diagnosis, patients were assessed before and after the administration of depot neuroleptic with the BPRS, the NOSIE, the SDRS and a list of side effects. A semi-structured interview was conducted with the patients and their families to ask about the change in social relationships with family members and other people after starting the depot treatment. Social intervention was limited to involvement of the family in the monthly depot medication outpatient clinic and to an explanation of the rationale of follow-up treatment and deinstitutionalisation of psychiatric care in the village of origin. RESULTS: The number of admission days decreased from an average of 100 days a year on oral medication to 5 days a year on depot neuroleptic. Patients report a sharp decrease in symptoms paralleled by an increase in social functioning over the first 3 months. After 6-9 months this pattern stabilised and was maintained over the period from 1 to 5 years whereas the dosage was further decreased to an average of 1 cc decanoate or 20 haldol equivalents monthly. CONCLUSIONS: This study suggests that depot neuroleptic in the context of a public mental health approach is a highly effective and feasible treatment for West African patients suffering from a chronic functional psychosis.