Gerra G, Fantoma A, Zaimovic A
National Department on Drug Policy, Rome, Italy.
J Psychopharmacol. 2006 Nov;20(6):806-14. doi: 10.1177/0269881106060835. Epub 2006 Jan 9.
Naltrexone treatment has demonstrated some advantages for special populations of heroin addicted individuals, but patients' compliance seems to be very poor, with a low adherence and low retention rate. Kappa-opioid system overdrive seems to contribute to opioid protracted abstinence syndrome, with dysphoria and psychosomatic symptoms during naltrexone treatment. The objective of this observational study was to determine the effectiveness of a functional k antagonist in improving naltrexone treatment outcome. A partial mu agonist/kappa antagonist (buprenorphine) and a mu antagonist (naltrexone) were combined during a 12 weeks protocol, theoretically leaving k antagonism as the major medication effect. Sixty patients were submitted to outpatient rapid detoxification utilizing buprenorphine and opioid antagonists. Starting on the fifth day, 30 patients (group A) received naltrexone alone. Alternatively, 30 patients (group B) received naltrexone (50mg oral dose) plus buprenorphine (4 mg sublingual) for the 12 weeks of the observational study. The endpoints of the study were: retention in treatment, negative urinalyses, changes in psychological symptoms (Symptom Checklist-90 Revised: SCL-90) and craving scores (visual analysis scale (VAS)). Thirty-four subjects (56.67%) completed the 12 weeks study. Twenty-one patients (35.0%) had all urine samples negative for opiates and cocaine. nine subjects (15.0%) had urine samples negative for cocaine and opiates for the last 4 weeks of the study. five subjects (8.3%) continued to use cocaine during the 12 weeks of the study. No significant change in pupillary diameter after buprenorphine administration was evidenced during clinical observations from baseline across the weekly measurements. Retention rates in group A (naltrexone) and group B (naltrexone + buprenorphine) at week 12 were respectively 40% (12 patients) and 73.33% (22 patients), with a significant difference in favour of group B (p= 0.018). Patients treated with naltrexone in combination with buprenorphine (B patients) showed a significantly lower rate of positive urines for morphine (4.45%) and cocaine metabolites (9.09%) than those treated with naltrexone alone (A) (25%, morphine; 33.33% cocaine) (p< 0.05; p< 0.05). Irritability, depression, tiredness, psychosomatic symptoms and craving scores decreased significantly less in Group A patients than in group B patients. The dysfunction of opioid system with kappa receptors hyper-activation provoked by heroin exposure, probably underlying dysphoric and psychosomatic symptoms during naltrexone treatment, seems to be counteracted, at least in part, by buprenorphine. The combination of buprenorphine and naltrexone may significantly improve the outcome of opioid antagonists treatment in terms of retention, negative urinalyses, and reduced dysphoria, mood symptoms and craving.
纳曲酮治疗已在特定人群的海洛因成瘾个体中显示出一些优势，但患者的依从性似乎很差，坚持治疗率和留用率都很低。κ-阿片系统超速驱动似乎导致阿片类药物戒断后综合征，在纳曲酮治疗期间会出现烦躁不安和身心症状。这项观察性研究的目的是确定一种功能性κ拮抗剂在改善纳曲酮治疗效果方面的有效性。在一个为期12周的方案中，将一种部分μ激动剂/κ拮抗剂（丁丙诺啡）和一种μ拮抗剂（纳曲酮）联合使用，理论上使κ拮抗作用成为主要的药物效应。60名患者接受了使用丁丙诺啡和阿片类拮抗剂的门诊快速戒毒治疗。从第5天开始，30名患者（A组）仅接受纳曲酮治疗。另外，30名患者（B组）在为期12周的观察性研究中接受纳曲酮（口服剂量50mg）加丁丙诺啡（舌下含服4mg）治疗。该研究的终点指标为：治疗留用率、尿样检测阴性、心理症状变化（症状自评量表-90修订版：SCL-90）和渴求评分（视觉模拟量表（VAS））。34名受试者（56.67%）完成了为期12周的研究。21名患者（35.0%）所有尿样的阿片类药物和可卡因检测均为阴性。9名受试者（15.0%）在研究的最后4周尿样的可卡因和阿片类药物检测为阴性。5名受试者（8.3%）在为期12周的研究期间继续使用可卡因。在临床观察中，从基线到每周测量期间，未发现给予丁丙诺啡后瞳孔直径有显著变化。第12周时，A组（纳曲酮组）和B组（纳曲酮+丁丙诺啡组）的留用率分别为40%（12名患者）和73.33%（22名患者），B组有显著优势（p=0.018）。与仅接受纳曲酮治疗的患者（A组）相比，接受纳曲酮联合丁丙诺啡治疗的患者（B组）吗啡阳性尿样率（4.45%）和可卡因代谢物阳性尿样率（9.09%）显著更低（A组吗啡为25%；可卡因为33.33%）（p<0.05；p<0.05）。A组患者的易怒、抑郁、疲劳、身心症状和渴求评分的下降幅度明显小于B组患者。海洛因暴露引起的κ受体过度激活导致的阿片系统功能障碍，可能是纳曲酮治疗期间烦躁不安和身心症状的潜在原因，而丁丙诺啡似乎至少部分地抵消了这种功能障碍。丁丙诺啡和纳曲酮联合使用在治疗留用率、尿样检测阴性以及减轻烦躁不安、情绪症状和渴求方面可能显著改善阿片类拮抗剂的治疗效果。
