Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Representativeness of initial skin biopsies showing pure desmoplastic melanoma: implications for management.

Desmoplastic melanoma (DM) is an uncommon subtype of melanoma with distinct clinicopathological features. It is classified into pure desmoplastic melanoma (PDM) when the proportion of desmoplastic melanoma is ≥90% of the dermally-invasive component, and mixed desmoplastic melanoma (MDM) when the proportion of desmoplastic melanoma is <90%. Studies have reported a lower sentinel lymph node biopsy (SLNB)-positivity rate in PDM compared to MDM and non-DM. As a result, some have recommended not performing SLNB in PDM patients. When PDM is identified in a partial biopsy of a melanoma, there is a risk that sampling bias may under-recognise MDM, but to the best of our knowledge this has not been previously assessed or quantified. The aim of this study was to assess the concordance of the proportion of desmoplastic melanoma in an initial partial biopsy of PDM with the proportion in the entire tumour following complete excision, in patients with cutaneous melanoma. A secondary aim was to determine how frequently this potentially resulted in a patient not receiving a SLNB. Seventy-eight cases of cutaneous melanoma were identified from the Melanoma Institute Australia (MIA) database and 23 cases from the Memorial Sloan Kettering Cancer Centre (MSKCC), where an initial biopsy contained PDM and a subsequent wide excision had residual invasive melanoma. Clinicopathological features were analysed in all patients, including whether a SLNB was performed, the results of SLNB, and any subsequent recurrence. Ninety percent (91/101) of cases were still classified as PDM in the complete wide excision specimen while 10% (10/101) of cases were reclassified as MDM, which was a significant change in classification of final desmoplastic melanoma subtype (p<0.001). The proportion of desmoplastic melanoma was also significantly different between the initial and excisional biopsies (p=0.004). Forty-eight (48/101) patients had a SLNB, of which two (4.5%) were positive for metastatic melanoma; both cases were PDM in the excision specimen. Of the 10 cases demonstrating MDM in the excision specimen, the initial biopsy was a punch biopsy in six cases, shave biopsy in two cases and subcutaneous tissue was sampled in two patients (one punch biopsy, one incisional biopsy). Four of these 10 patients underwent SLNB which was negative in all cases. Twenty-two patients developed recurrence in the follow-up period (median 30 months, range 1-192 months), three with MDM in their excision specimen. One patient did not have a SLNB and developed regional lymph node recurrence. In this study there was a 10% risk that the percentage of desmoplastic melanoma in an initial biopsy of PDM was not representative of the entire lesion, resulting in reclassification as MDM in the excision specimen. If a SLNB is not performed in such cases, a positive SLNB may be missed (one patient in our study) which could impact treatment options for the patient. We recommend caution in not offering a SLNB in the setting of an initial biopsy of PDM if the biopsy is small compared with the overall lesion. If a SLNB is not procured at the time of wide excision in such cases, the SLNs should still be mapped by lymphoscintigraphy to facilitate careful follow up and to enable earlier detection and treatment of nodal disease.

Lentigo maligna: defining margins and predictors of recurrence utilizing clinical, dermoscopic, confocal microscopy and histopathology features.

BACKGROUND: Lentigo maligna (LM) is a subtype of melanoma in situ with poorly defined margins and a high recurrence rate. The biological behaviour of LM appears to differ widely between cases, from biologically indolent to biologically active variants, with some patients experiencing multiple recurrences. It is not known whether this is secondary to inadequate margins, field cancerization or the innate biology of the lesion itself. OBJECTIVES: (a) Describe the margins of LM in detail by analysing LM in three zones, that is centre, edge and surround using reflectance confocal microscopy (RCM) and histopathology; (b) ascertain association of histological distance of LM and atypical melanocytic hyperplasia from the surgical margin with multi-recurrent (MR) disease and (c) identify features (clinical, dermoscopy, RCM and histopathology) associated with MR LM. METHODS: (1) Descriptive observational study comparing the centre, edge and surround of LM on histopathology and RCM; (2) retrospective cohort study comparing parameters associated with MR and non-recurrent (NR) LM. RESULTS: 30 patients (median follow-up time 6.2 years) were included. On histopathology, confluent or near confluent lentiginous proliferation, melanocyte density >15 per 0.5 mm and adnexal spread were best for distinguishing surround from edge of LM. On RCM, predominant melanocytes, lentiginous proliferation and pleomorphism distinguished surround from centre/edge. MR patients had a median histological distance of LM from the surgical margin of 2mm (versus NR patients with an average distance of 4mm). MR patients had a greater proportion of more florid features, compared with NR on histopathology at both the centre and the edge but were similar in the surround. CONCLUSION: These data may help pathologists and confocalists better define margins of LM. More florid features in MR patients, despite a similar background of sun-damaged skin, suggest the innate biology of the lesion rather than the field of cancerization may explain MR LM.

Not all melanomas are created equal: a review and call for more research into nodular melanoma.

Among the histogenic subtypes of melanoma, nodular melanoma (NM) is the major contributor for thicker and fatal melanomas and it has been associated with melanoma-specific death in thin tumours, highlighting an important subgroup of 'aggressive thin' melanomas. This review provides a synthesis of the distinct characteristics of NM, with respect to epidemiology and risk factors, clinical presentation, histopathology, molecular and dermoscopic aspects, and screening practices. The real challenges are to find better biomarkers of aggressiveness and to know whether the control of such aggressive melanomas can be influenced by targeted interventions such as early detection, drug interventions and preventive strategies.

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.

BACKGROUND: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS. PATIENTS AND METHODS: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry. RESULTS: There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had ≥70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P ≤ 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046). CONCLUSIONS: There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of ≥70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.

Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma.

BACKGROUND: Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. METHODS: Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. RESULTS: Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035). CONCLUSIONS: The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.

TGFß1 single-nucleotide polymorphism C-509T alters mucosal cell function in pediatric eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic Th2 antigen-driven disorder associated with tissue remodeling. Inflammation and remodeling lead to esophageal rigidity, strictures, and dysphagia. TGFß1 drives esophageal remodeling including epithelial barrier dysfunction and subepithelial fibrosis. A functional SNP in the TGFß1 gene that increases its transcription (C-509T) is associated with elevated numbers of esophageal TGFß1-expressing cells. We utilized esophageal biopsies and fibroblasts from TT-genotype EoE children to understand if TGFß1 influenced fibroblast and epithelial cell function in vivo. Genotype TT EoE esophageal fibroblasts had higher baseline TGFß1, collagen1α1, periostin, and MMP2 (p < 0.05) gene expression and distinct contractile properties compared with CC genotype (n = 6 subjects per genotype). In vitro TGFß1 exposure caused greater induction of target gene expression in genotype CC fibroblasts (p < 0.05). Esophageal biopsies from TT-genotype subjects had significantly less epithelial membrane-bound E-cadherin (p < 0.01) and wider cluster distribution at nanometer resolution. TGFß1 treatment of stratified primary human esophageal epithelial cells and spheroids disrupted transepithelial resistance (p < 0.001) and E-cadherin localization (p < 0.0001). A TGFß1-receptor-I inhibitor improved TGFß1-mediated E-cadherin mislocalization. These data suggest that EoE severity can depend on genotypic differences that increase in vivo exposure to TGFß1. TGFß1 inhibition may be a useful therapy in subsets of EoE patients.

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma.

Background: Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods: The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. Results: Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. Conclusions: Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.

The smart approach: feasibility of lentigo maligna superficial margin assessment with hand-held reflectance confocal microscopy technology.

BACKGROUND: Lentigo maligna may be challenging to clear surgically. OBJECTIVE: To evaluate feasibility of using superficial skin cuts as RCM imaging anchors for attaining negative surgical margins in lentigo maligna. METHODS: Included patients presented with lentigo maligna near cosmetically sensitive facial structures. We evaluated, with hand-held-RCM, microscopic clearance of melanoma beyond its dermoscopically detected edges. Evaluated margins were annotated using shallow skin cuts. If a margin was positive at 'first-step' RCM evaluation, we sequentially advanced the margin radially outward at that segment by 2-mm intervals until an RCM-negative margin was identified. Prior to final surgical excision, we placed sutures at the outmost skin cuts to allow comparison of RCM and histopathological margin assessments. Primary outcome measure was histopathological verification that RCM-negative margins were clear of melanoma. RESULTS: The study included 126 first-step margin evaluations in 23 patients, median age 70 years (range: 43-91). Seventeen patients (74%) had primary in-situ melanoma and six (26%) invasive melanoma, mean thickness 0.3 mm (range 0.2-0.4 mm). Six cases (26%) showed complete negative RCM margins on 'first-step', 11 (48%) were negative at 'second-step', and four (17%) at 'third-step'. In two additional cases (9%), margins clearance could not be determined via RCM due to widespread dendritic cells proliferation. The RCM-negative margins in all 21 cases proved clear of melanoma on histopathology. Of the 15 cases that returned at 1-year follow-up, none showed any residual melanoma on dermoscopic and RCM examinations. Interobserver reproducibility showed fair agreement between bedside RCM reader and blinded remote-site reader, with Spearman's rho of 0.48 and Cohen's kappa of 0.43; using bedside reader as reference, the remote reader's sensitivity was 92% and specificity 57% in positive margin detection. CONCLUSIONS: Margin mapping of lentigo maligna with hand-held-RCM, using superficial skin cuts, appears feasible. This approach needs validation by larger studies.

Providing a community-based cancer risk assessment service for a socially and ethnically diverse population.

BACKGROUND: Patients from ethnic minorities are under-represented in referrals to cancer genetics services. In a regional genetics centre that serves two London boroughs, the existing service attracts 3% of its referrals from Black and Minority Ethnic (BME) and other ethnic groups, despite the fact that these groups make up 34% of the population. OBJECTIVES: To improve access to familial cancer risk assessment in a socially and ethnically diverse population. SETTING: The London boroughs of Lambeth and Southwark. DESIGN: Community-based, nurse-led clinics were established for people who were concerned about their familial cancer risk. Patients were asked to triage themselves by answering three questions. Self-referral was encouraged. MAIN OUTCOME MEASURES: Data were gathered on ethnicity of clients, cancer risk, source of referral and patient and health professional satisfaction with the service. RESULTS: Of the 415 people who have accessed the service, 46% were from not White British groups and 67% referred themselves to the service, demonstrating the success of this model in reaching 'hard to reach' groups. Thirty-seven percent of patients were assessed as being at population risk and 63% were assessed as being at moderate risk or higher, showing that the clinics were meeting an unmet need in the community.

Arterial blood gas tensions during exercise in neonatal lambs.

At the onset of exercise, adult animals increase ventilation to match or exceed the metabolic requirement. This error-free regulation of arterial blood gas tensions may be attributable to 'adaptive feed-forward control'--respiratory control based on experience gained in infancy. This hypothesis predicts that neonates exhibit hypercapnia at the onset of exercise. To test this prediction, seven lambs were exercised on a treadmill at 0.8 m/sec at the ages of 2-5 days, and again at 9-12 days. Arterial blood samples were drawn pre-exercise and at 0.5, 1, 2, 5, 7 and 10 min of exercise. Seven adult sheep were similarly tested for comparison. The lambs had significantly higher arterial CO2 tensions (PaCO2) and lower arterial O2 tensions (PaO2) than adult sheep both at rest and during exercise. Nonetheless, the lambs maintained PaCO2 at or below the resting level throughout exercise. PaO2 rose significantly during exercise in the sheep and lambs. The results do not support the hypothesis since hypercapnia was not observed in the exercising neonatal lambs.

Interest in smoking cessation among methadone maintained outpatients.

The prevalence of cigarette smoking among opiate abusers is extremely high and tobacco related diseases are a major factor associated with morbidity and mortality for this group. Yet, many treatment providers remain reluctant to address smoking cessation with their clients due in part to the belief that substance abusers are not interested in quitting smoking. The present study examined self-reported interest in smoking cessation among methadone maintenance clients (N = 120) in four clinics in Los Angeles. Fifty-eight percent of subjects rated themselves as 'Somewhat' or 'Very Interested' in a smoking cessation program. Overall subjects appeared to accurately perceive the personal risks from tobacco smoking. In conclusion we find that clients in methadone maintenance treatment programs evidence a high level of interest in quitting smoking and may well be suited for a highly structured smoking cessation intervention.

UbcD1, a Drosophila ubiquitin-conjugating enzyme required for proper telomere behavior.

The end-to-end association of chromosomes through their telomeres has been observed in normal cells of certain organisms, as well as in senescent and tumor cells. The molecular mechanisms underlying this phenomenon are currently unknown. We show here that five independent mutant alleles in the Drosophila UbcD1 gene cause frequent telomere-telomere attachments during both mitosis and male meiosis that are not seen in wild type. These telomeric associations involve all the telomeres of the D. melanogaster chromosome complement, albeit with different frequencies. The pattern of telomeric associations observed in UbcD1 mutants suggests strongly that the interphase chromosomes of wild-type larval brain cells maintain a Rab1 orientation within the nucleus, with the telomeres and centromeres segregated to opposite sides of the nucleus. The UbcD1 gene encodes a class I ubiquitin-conjugating (E2) enzyme. This indicates that ubiquitin-mediated proteolysis is normally needed to ensure proper telomere behavior during Drosophila cell division. We therefore suggest that at least one of the targets of UbcD1 ubiquitination is a telomere-associated polypeptide that may help maintain proper chromosomal orientation during interphase.

Contingency management for tobacco smoking in methadone-maintained opiate addicts.

Seventeen methadone-maintained cigarette smokers received 4 weeks of contingency management (CM) as a stop-smoking intervention. Results indicated that CM patients significantly reduced breath CO levels from baseline to completion of treatment and that 23.4% of patients maintained 1 week or more of continued smoking abstinence. Results indicated a link between smoking abstinence and reduced cocaine use, although not reduced opiate use, which raised questions about possible shared biological and psychological mechanisms for tobacco and cocaine use.

What happens when a demonstration project ends. Consequences for a clinic and its clients.

The Los Angeles Enhanced Methadone Maintenance Project was a 5-year research demonstration project funded by the National Institute on Drug Abuse with the goal of reducing high-risk behavior for human immunodeficiency virus (HIV) among heroin users. A clinic was established for the purposes of the study and 500 clients with high-risk profiles were recruited into treatment. Follow-up assessments demonstrated that clients had reduced their drug use, criminal behavior, and HIV-risk behaviors after entering treatment. At the end of the project clients were given the option of continuing treatment at the clinic on a fee-for-service basis, transferring to another treatment provider, or undergoing detoxification. Clients who were eligible for Medicaid were likely to continue receiving methadone treatment, but those without Medicaid funding were not. The implications of terminating treatment among a high-risk population recruited into a research demonstration project are discussed.

Reasons for discharge from methadone maintenance for addicts at high risk of HIV infection or transmission.

This article reports on a methadone maintenance program that had the goal of retaining in treatment heroin addicts at high risk of HIV infection and/or transmission. Subjects were recruited from four-high-risk target groups and randomly assigned to either an enhanced or standard methadone maintenance group. The analysis examined predictors of any type of discharge, negative discharge, and circumstantial discharge. Discharge for any reason was more likely for younger individuals, sex industry workers, and high-risk sex partners. Legal supervision at intake and coercion into treatment reduced the probability of discharge for any reason. HIV-positive individuals were more likely to discharge for circumstantial reasons than negative reasons. The probability of circumstantial discharge was increased for males, individuals reporting suicidal ideation, and those scoring higher on an impulse expression scale. The likelihood of circumstantial discharge was decreased for individuals who reported more sources of legal income or who lived someone using illegal drugs. Participation in the enhanced treatment group appeared to reduce the probability of negative, compared with circumstantial, discharge. The findings should assist methadone treatment providers in targeting individuals at high probability of discharge for special efforts to increase treatment retention and to reengage them back into treatment after discharge, as part of a harm-reduction strategy to minimize risks of HIV infection and/or transmission.

Clinical experiences with 959 opioid-dependent patients treated with levo-alpha-acetylmethadol (LAAM).

Levo-alpha-acetylmethadol (LAAM) is an orphan drug that will soon be generally available to treatment facilities. We have recently treated 959 opioid addicts with LAAM for periods up to 36 consecutive months. Three times per week dosing of LAAM proved to be a safe and effective treatment agent for the majority of subjects. During LAAM induction there is a delay in opioid activity as LAAM forms its long-acting metabolites, therefore, symptomatic withdrawal medication must usually be administered during the first 96 hours of treatment to adequately suppress opioid withdrawal symptoms and prevent self-administration of drugs by the patient. No long-term hepatic toxicity or tumor formation could be demonstrated by liver function studies and liver-spleen imaging in a subgroup of patients. Some opioid addicts report that they prefer LAAM over methadone, but the reverse was reported by about 40% of our patients which suggests that both drugs are needed for adequate maintenance treatment of the opioid-addicted population.

Vascular penetration following intraligamental injection.

The potential for inadvertant intravascular injection of a local anesthetic solution with the intraligament injection syringe is described. The spread of solution is radiographically demonstrated, and precautions during the use of the procedure are suggested.

Clinical experience with naltrexone in suburban opioid addicts.

In a study of 160 patients (including 114 active heroin addicts and 42 former heroin addicts maintained on methadone, propoxyphene napsylate, or LAAM), subjects were retained on treatment with naltrexone for a mean of 50.7 days (range, 1-635). Clonidine or guanabenz acetate was used to detoxify subjects who received naltrexone within 10 days of their last dose of opioid. Because of the number of subjects dropping out of treatment after only a few days, it is recommended that there be an opioid-free period of 5 or more days for heroin-dependent subjects and 10 or more days for those on medical maintenance. A naloxone challenge should be administered at a dosage of 0.8 mg. Use of naltrexone combined with psychotherapy appears to promote long periods of opioid abstinence but does not prevent relapse after treatment. Trained clinicians utilizing an appropriate induction protocol can effectively treat volunteer opioid addicts with naltrexone.

Guanabenz acetate: a new, long-acting alpha-two adrenergic agonist for opioid withdrawal.

Guanabenz Acetate (GA) is a new long-lasting alpha-two agonist. We found that it effectively suppressed opioid withdrawal in the majority of 47 opioid-dependent subjects. GA was usually given in twice per day dosages and did not appear to have as many side effects as clonidine. It may have greater acceptance among heroin addicts than clonidine.