Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiate-dependent volunteers

Sublingual buprenorphine is a promising new treatment for opiate dependence, but its opioid agonist effects pose a risk for parenteral abuse. A formulation combining buprenorphine with the opiate antagonist naloxone could discourage such abuse. The effects of three intravenous (IV) buprenorphine and naloxone combinations on agonist effects and withdrawal signs and symptoms were examined in 12 opiate-dependent subjects. Following stabilization on a daily dose of 60 mg morphine intramuscularly, subjects were challenged with IV doses of buprenorphine alone (2 mg) or in combination with naloxone in ratios of 2:1, 4:1, and 8:1 (1, 0.5, or 0.25 mg naloxone), morphine alone (15 mg) or placebo. Buprenorphine alone did not precipitate withdrawal and had agonist effects similar to morphine. A naloxone dose-dependent increase in opiate withdrawal signs and symptoms and a decrease in opioid agonist effects occurred after all drug combinations. Buprenorphine with naloxone in ratios of 2:1 and 4:1 produced moderate to high increases in global opiate withdrawal, bad drug effect, and sickness. These dose ratios also decreased the pleasurable effects and estimated street value of buprenorphine, thereby suggesting a low abuse liability. The dose ratio of 8:1 produced only mild withdrawal symptoms. Dose combinations at 2:1 and 4:1 ratios may be useful in treating opiate dependence. Received: 9 February 1998/Final version: 8 May 1998     

Buprenorphine alone and in combination with naloxone in non-dependent humans

This study evaluated the effects of concurrent naloxone on the opioid agonist effects of buprenorphine, a mixed agonistantagonist marketed as an analgesic and under development as a treatment for drug abuse. In a residential laboratory seven non-physically-dependent opioid abuser volunteers received intramuscular buprenorphine (0.4 mg or 0.8 mg/70 kg) alone and in combination with naloxone (0.4 mg or 0.8 mg/70 kg) versus placebo. Buprenorphine produced dose-related opioid agonist effects on physiological and subjective measures. Concurrent naloxone attenuated the opioid agonist effects of buprenorphine. Thus, a combination product of buprenorphine and naloxone may have lower abuse liability than buprenorphine alone.     

阿片类药物替代疗法:安全性和滥用倾向的比较研究

阿片类药物维持疗法是治疗阿片、海洛因和阿片类制剂依赖的有效方法。美沙酮和丁丙诺啡是世界范围内最常用于替代治疗的阿片类药物,纳曲酮作为一种阿片受体的拮抗剂用于阻断治疗。研究数据显示维持疗法比脱毒疗法疗效更好,但是,存在长期用药剂量的安全性问题,包括对药物的直接反应和滥用风险。对美沙酮和丁丙诺啡(单独使用或与纳曲酮合用)的研究揭示了剂量与效应的关系,以及最佳的用药方案。研究数据提示,在呼吸抑制(过量)和对心血管的直接作用方面丁丙诺啡较美沙酮风险更低。丁丙诺啡,作为一种部分激动剂,可能比美沙酮或者海洛因等完全激动剂的滥用倾向更小。本文提供的数据说明在阿片依赖的个体上丁丙诺啡的滥用风险较美沙酮的更低。最近的数据提示,在阿片依赖和非依赖的使用者中,丁丙诺啡/纳曲酮合用的滥用潜力低于丁丙诺啡单独使用。     

Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers

Rationale: Buprenorphine is an opioid agonist-antagonist under development in the United States as a sublingual medication for treatment of opioid dependence. Buprenorphine may be abused; therefore, tablets combining buprenorphine with naloxone have been developed with the intent of reducing the abuse risk in people physically dependent upon opioids. The characteristics and abuse potential of buprenorphine and buprenorphine/naloxone tablets in non-dependent opioid abusers have not been determined. Non-parenteral abuse of opioids such as buprenorphine may be more likely in people who have less severe substance abuse disorders (e.g., are not physically dependent upon opioids). Objectives: To assess the abuse potential of sublingual buprenorphine and buprenorphine/naloxone tablets in non-dependent opioid abusers. Methods: Subjects (n=7) were tested with sublingual buprenorphine (4, 8, 16 mg), sublingual buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg), as well as intramuscular hydromorphone as an opioid agonist control (2, 4 mg) and placebo in laboratory sessions conducted twice per week. Dosing was double-blind and double-dummy. Results: The higher doses of both buprenorphine and buprenorphine/naloxone produced similar opioid agonist-like effects. The onset of these effects was slowed, consistent with the sublingual route of administration, and the magnitude of effects was moderate. There was no evidence to suggest the addition of naloxone attenuated buprenorphine’s opioid agonist effects in this population when buprenorphine was delivered by the sublingual route. Conclusions: These results suggest that sublingual buprenorphine and buprenorphine/naloxone may both be abused by opioid users who are not physically dependent upon opioids. Received: 15 April 1999 / Final version: 11 September 1999     

Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine

RATIONALE: Buprenorphine is an opioid agonist-antagonist used in the treatment of opioid dependence. Naloxone has been combined with buprenorphine to decrease the parenteral abuse potential of buprenorphine. This addition of naloxone may also confer further opioid blockade efficacy. OBJECTIVES: To test the opioid blockade efficacy of sublingual buprenorphine/naloxone versus buprenorphine alone and determine whether: (1) the blockade efficacy of buprenorphine/naloxone varies between the time of expected maximal and minimal effects of naloxone, (2) the blockade efficacy of buprenorphine/naloxone and buprenorphine varies as a function of maintenance dose level, and (3) there are adaptive changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine. METHODS: Residential subjects ( n=6) were maintained on different double-blind dose levels of buprenorphine/naloxone (4/1, 8/2, 16/4, 32/8 mg) and buprenorphine (32 mg) for 6-day periods and challenged with parenteral doses of hydromorphone (12 mg) in laboratory sessions. RESULTS: There was no evidence of additional opioid blockade efficacy conferred by combining naloxone with buprenorphine. Higher doses of buprenorphine/naloxone provided greater blockade of hydromorphone effects. Changes over time associated with repeated daily dosing of buprenorphine/naloxone and buprenorphine were minimal. CONCLUSIONS: The addition of naloxone to buprenorphine may deter the parenteral abuse of buprenorphine/naloxone, but it does not enhance the therapeutic efficacy of buprenorphine. The blockade efficacy of buprenorphine/naloxone is dose related; however, doses up to 32/8 mg buprenorphine/naloxone provide only partial blockade when subjects receive a high dose of an opioid agonist.     

A Case Series of Buprenorphine/Naloxone Treatment in a Primary Care Practice

ABSTRACT

Physicians’ adoption of buprenorphine/naloxone treatment is hindered by concerns over feasibility, cost, and lack of comfort treating patients with addiction. We examined the use of buprenorphine/naloxone in a community practice by two generalist physicians without addiction training, employing a retrospective chart review. From 2006–2010, 228 patients with opiate abuse/dependence were treated with buprenorphine/naloxone using a home-induction protocol. Multiple co-morbidities including diabetes (23% of patients), hypertension (36%), Hepatitis C (43%), and depression (74%) were concurrently managed. In this diverse sample, 1/228 experienced precipitated withdrawal during induction. Of the convenience subsample analyzed (n = 28), 82% (+/?10%) had negative urine drug tests for opioids; 92% (+/?11%) were negative for cocaine; 88% (+/?12%) were positive for buprenorphine. This case series demonstrated feasibility and safety of a low-cost buprenorphine/naloxone home induction protocol employed by generalists. Concurrent treatment of multiple comorbidities conforms with the patient-centered medical home ideal. Randomized trials of this promising approach are needed.     

Buprenorphine and naloxone alone and in combination in opioid-dependent humans

Subjective, physiological and behavioral effects of subcutaneously administered hydromorphone (6 mg), naloxone (0.2 mg), buprenorphine (0.2 and 0.3 mg), and two buprenorphine-naloxone combinations (buprenorphine 0.2 mg plus naloxone 0.2 mg and buprenorphine 0.3 mg plus naloxone 0.2 mg) were assessed under double-blind conditions in six opioid-dependent volunteers. Physiologic measures and subject- and observer-rated behavioral responses were measured before dosing and for 120 min after drug administration. Hydromorphone decreased pupil diameter and respiration, increased blood pressure and increased scores on subjective measures indicating opioid-like effects. Buprenorphine given alone had no significant effect on any variable measured. Naloxone given alone produced opioid abstinence-like effects which were measurable on subject- and observer-rated behavioral measures and physiological measures. Buprenorphine in combination with naloxone somewhat attenuated the naloxone-precipitated withdrawal response. Overall, the naloxone-buprenorphine combinations produced effects which were qualitatively similar to the effects of naloxone alone, suggesting a low potential for abuse of the combination product by opioid-dependent individuals.Supported by a grant from Reckitt and Colman Pharmaceutical Division and USPHS Grants DA-00050 and DA-04089 from the National Institute on Drug Abuse     

Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine

Buprenorphine and naloxone sublingual (s.l.) dose formulations may decrease parenteral buprenorphine abuse. We evaluated pharmacologic interactions between 8 mg s.l. buprenorphine combined with 0, 4, or 8 mg of naloxone in nine opiate-dependent volunteers stabilized on 8 mg s.l. buprenorphine for 7 days. Combined naloxone and buprenorphine did not diminish buprenorphine's effects on opiate withdrawal nor alter buprenorphine bioavailability. Opiate addicts stabilized on buprenorphine showed no evidence of precipitated opiate withdrawal after s.l. buprenorphine-naloxone combinations. Buprenorphine and naloxone bioavailability was approximately 40 and 10%, respectively. Intravenous buprenorphine and naloxone produced subjective effects similar to those of s.l. buprenorphine and did not precipitate opiate withdrawal.     

Buprenorphine + naloxone: new combination. Opiate dependence: no proof of reduced risk of self-administered injection

(1) Two drugs with similar efficacy are available in France for heroin replacement therapy: methadone and buprenorphine. (2) Buprenorphine is sold in the form of sublingual tablets, but some patients dissolve and inject them. Methadone is the main alternative for these patients. Other intravenous opiate derivatives can also be tried, although they have not been approved for this indication. (3) In order to help prevent patients from injecting themselves with buprenorphine, a sublingual combination of buprenorphine + naloxone is to be marketed in France. (4) From a pharmacological point of view, this combination makes sense. Naloxone, an opiate antagonist, is very poorly absorbed with sublingual administration, but if it is injected intravenously, it will antagonise the effects of buprenorphine. However, clinical studies are needed to determine whether or not this prevents injection. (5) A double-blind trial in 326 patients compared replacement therapy with buprenorphine 16 mg + naloxone 4 mg/day versus buprenorphine 16 mg + placebo. The addition of naloxone did not reduce the efficacy of sublingual buprenorphine, but the frequency with which patients injected the drugs was not studied in this trial. (6) This combination of buprenorphine + naloxone has not been directly compared with methadone. (7) In addition to the classical adverse effects of opiates, buprenorphine can cause hepatic adverse effects. (8) Little evidence is available on the effects of intravenous injection of buprenorphine + naloxone. According to an epidemiological survey conducted in Finland, where the combination is also marketed, about 8% of patients regularly inject it intravenously. (9) Patients who are likely to inject buprenorphine should be switched to methadone.     

Acute effects of intramuscular and sublingual buprenorphine and buprenorphine/naloxone in non-dependent opioid abusers

Rationale  

Buprenorphine is a partial mu opioid receptor agonist with clinical efficacy as a pharmacotherapy for opioid dependence. A sublingual combination formulation was developed containing buprenorphine and naloxone with the intent of decreasing abuse liability in opioid-dependent individuals. However, the addition of naloxone may not limit abuse potential of this medication when taken by individuals without opioid physical dependence.     

Behavioral pharmacology of buprenorphine

Buprenorphine is an opioid mixed agonist-antagonist that has potential usefulness as a pharmacotherapy for opiate addiction. Buprenorphine significantly suppressed opiate self-administration by heroin addicts. Buprenorphine also suppressed opiate self-administration in a primate model. Although buprenorphine is a positive reinforcer in rhesus monkey, it is less reinforcing than other opioids and some opioid mixed agonist-antagonists as evaluated in progressive ratio and drug substitution procedures. These data suggest that the abuse liability of buprenorphine should be less than that of other opioid drugs. The safety and potential therapeutic benefits of buprenorphine relative to other currently available pharmacotherapies probably overweigh the possible risks of abuse.     

Buprenorphine-containing treatments: place in the management of opioid addiction

Although the synthetic opioid buprenorphine has been available clinically for almost 30 years, its use has only recently become much more widespread for the treatment of opioid addiction.The pharmacodynamic and pharmacokinetic profiles of buprenorphine make it unique in the armamentarium of drugs for the treatment of opioid addiction. Buprenorphine has partial mu-opioid receptor agonist activity and is a kappa-opioid receptor antagonist; hence, it can substitute for other micro-opioid receptor agonists, yet is less apt to produce overdose reactions or dysphoria. On the other hand, buprenorphine can block the effects of opioids such as heroin (diamorphine) and morphine, and can even precipitate withdrawal in individuals physically dependent upon these drugs. Buprenorphine has significant sublingual bioavailability and a long half-life, making administration on a less than daily basis possible. Furthermore, its discontinuation is associated with only a mild withdrawal syndrome.Clinical trials have demonstrated that sublingual buprenorphine is effective in both maintenance therapy and detoxification of individuals addicted to opioids. The introduction of a sublingual formulation combining naloxone with buprenorphine further reduces the risk of diversion to illicit intravenous use. Because of its relative safety and lower risk of illegal diversion, buprenorphine has been made available in several countries for treating opioid addiction in the private office setting, greatly enhancing treatment options for this condition.     

Preference for buprenorphine/naloxone and buprenorphine among patients receiving buprenorphine maintenance therapy in France: A prospective,multicenter study

Maintenance treatment with buprenorphine tablets (Subutex) has been associated with reductions in heroin use; however, concerns for intravenous misuse exist. A buprenorphine/naloxone formulation (Suboxone) was designed to reduce this misuse risk while retaining buprenorphine's efficacy and safety. This prospective, open-label, multicenter trial compared preferences for buprenorphine and buprenorphine/naloxone in 53 opioid-dependent patients stabilized on buprenorphine. Buprenorphine was first administered at the patient's current dose (Days 1–2), followed by a direct switch to buprenorphine/naloxone (Days 3–5). Global satisfaction rates were high and similar between buprenorphine and buprenorphine/naloxone; however, patients preferred the tablet taste, size, and sublingual dissolution time of buprenorphine/naloxone. At the end of the study, 54% of patients preferred buprenorphine/naloxone, 31% preferred buprenorphine, and 15% had no preference; most patients (71%) wished to continue treatment with buprenorphine/naloxone. This study did not identify any impediments to a direct buprenorphine-to-buprenorphine/naloxone switch and revealed some characteristics that may facilitate treatment with buprenorphine/naloxone.     

Effects of buprenorphine/naloxone in opioid-dependent humans

RATIONALE: Buprenorphine is a partial mu opioid agonist under development as a sublingual (SL) medication for opioid dependence treatment in the United States. Because buprenorphine may be abused, tablets combining buprenorphine with naloxone in a 4:1 ratio have been developed to reduce that risk. Low doses of injected buprenorphine/naloxone have been tested in opioid-dependent subjects, but higher doses (more than 2 mg of either medication) and direct comparisons to SL buprenorphine/naloxone have not been examined. OBJECTIVES: To assess and compare the effects of intramuscular (i.m.) versus SL buprenorphine/naloxone in opioid-dependent volunteers. METHODS: Opioid-dependent volunteers were maintained on 40 mg per day of oral hydromorphone while on a residential research ward. After safety testing in two pilot subjects, participants (n = 8) were tested with both i.m. and SL buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg); i.m. hydromorphone (10 mg) and naloxone (0.25 mg); both i.m. and SL buprenorphine alone (8 mg); and placebo. Test sessions were twice per week; dosing was double-blind. RESULTS: Intramuscular buprenorphine/naloxone produced dose-related increases on indices of opioid antagonist effects. Effects were consistent with naloxone-precipitated withdrawal, and were short-lived. As withdrawal effects dissipated, euphoric opioid agonist effects from buprenorphine did not appear. Sublingual buprenorphine/naloxone produced neither opioid agonist nor antagonist effects. CONCLUSIONS: Intramuscular injection of buprenorphine/naloxone precipitates withdrawal in opioid dependent persons; therefore, the combination has a low abuse potential by the injection route in this population. Sublingual buprenorphine/naloxone by tablet is well tolerated in opioid dependent subjects, and shows neither adverse effects (i.e., precipitated withdrawal) nor a high abuse potential (i.e., opioid agonist effects).     

四省市吸毒人群中丁丙诺啡药物滥用/使用的现况调查

目的:调查丁丙诺啡(buprenorphine,Bup)在吸毒人群中滥用/使用的一般情况,评价其药物滥用与药物依赖性潜力。方法:自拟调查表,采取回顾性调查方法,于2006年1月-2006年7月在北京、云南、湖北和广东四地区的六所公安、司法强制戒毒机构,以戒毒所为单位,对符合调查对象条件的全体戒毒人员进行整群调查。结果:(1)使用率:在3254例被调查者中,27.4%(892例)不同程度、不同目的使用过Bup。使用率以云南个旧最高,北京地区次之。(2)使用目的及场所:用于"戒毒或临时替代"及"治疗戒毒后稽延性症状"分别占55.8%和40.6%;82例(9.2%)为"体验特殊精神效应(如欣快、飘等)"。使用场所:主要是在"自己家中"(74.4%)和"戒毒所"(32.1%)。(3)使用方式:47.7%的人有多药使用的经历。在有多药使用者中,采用Bup加镇静催眠药(三唑仑、安定)、氯丙嗪、东莨菪碱和异丙嗪分别占47.6%、5.8%、1.2%和10.1%。(4)使用频率:连续3 d以上使用经历者占36.1%,偶尔使用/间断使用占34.3%,有时连续、有时间断使用占29.5%。(5)主要来源:"医院或诊所"、"戒毒机构"(或在戒毒机构中使用)、"药店"、"非正常渠道"(黑市)、"亲朋"分别占24.7%、38.7%、29.0%、18.4%,4.9%。(6)获得的难易程度:34.0%表示很容易得到,23.4%表示比较容易得到,12.5%表示比较困难得到,7.2%表示非常困难得到,22.8%表示不知道或不便回答。(7)使用后的感觉:46.0%应答者主诉使用后"有感觉",其中"快感"占33.8%,"幻觉"占26.6%,"飘感"占34.8%。这种特殊感觉"同海洛因不一样"占67.6%;"同海洛因一样,但比海洛因作用小"占25.8%;"同海洛因一样,但比海洛因作用强"占4.5%。以上主观效应是单一使用丁丙诺啡产生的占63.8%,合并用药产生的占36.2%。结论:本次调查有近30%的人不同程度和不同目的使用过丁丙诺啡;大多数Bup使用者属于医疗目的使用,但也有少数为"体验Bup特殊精神效应";Bup滥用/使用群体中近一半的人有多药使用的经历;大多数药品来源正常。对非医疗目的使用、多药使用、使用频率高、从非正常渠道获得、使用后有特殊感觉、容易获得的情况有必要进行进一步调查。     

Does high-dose buprenorphine cause respiratory depression?: possible mechanisms and therapeutic consequences

Buprenorphine is an opioid agonist-antagonist with a 'ceiling effect' for respiratory depression. Compared with methadone, its unique pharmacology offers practical advantages and enhanced safety when prescribed as recommended and supervised by a physician. Buprenorphine has been approved in several countries as an efficient and safe maintenance therapy for heroin addiction. Its use resulted in a salutary effect with a reduction in heroin overdose-related deaths in countries that implemented office-based buprenorphine maintenance. In France, however, where high-dose buprenorphine has been marketed since 1996, several cases of asphyxic deaths were reported among addicts treated with buprenorphine. Death resulted from buprenorphine intravenous misuse or concomitant sedative drug ingestion, such as benzodiazepines. In these situations of abuse, misuse, or in association with elevated doses of psychotropic drugs, buprenorphine may cause severe respiratory depression. Unlike other opiates, the respiratory effects from buprenorphine are not responsive to naloxone. However, the exact mechanism of buprenorphine-induced effects on ventilation is still unknown. The role of norbuprenorphine, the main N-dealkylated buprenorphine metabolite with potent respiratory depressor activity, also remains unclear. Experimental studies investigating the respiratory effects of combinations of high doses of buprenorphine and benzodiazepines suggested that this drug-drug interaction may result from a pharmacodynamic interaction. A pharmacokinetic interaction between buprenorphine and flunitrazepam is also considered. As there are many questions regarding the possible dangers of death or respiratory depression associated with buprenorphine use, we aimed to present a comprehensive critical review of the published clinical and experimental studies on buprenorphine respiratory effects.     

Groin tissue necrosis requiring skin graft following parenteral abuse of buprenorphine tablets

In May 2002 Buprenorphine (Subutex®) was listed on the Australian Pharmaceutical Benefits Schedule for treatment in opioid dependence. In addition to broadening treatment options, buprenorphine has the advantage of an improved safety profile. The risk of overdose is lessened but other risks remain due to diversion. French experience reports widespread deviation of buprenorphine sublingual tablets to intravenous injection. We report a case of attempted parenteral administration of buprenorphine tablets. Stringent protocols for dispensing are appropriate. [Feeney GFX, Fairweather P. Groin tissue necrosis requiring skin graft following parenteral abuse of buprenorphine tablets. Drug Alcohol Rev 2003;22:359 - 361]     

Does High-Dose Buprenorphine Cause Respiratory Depression?

Buprenorphine is an opioid agonist-antagonist with a ‘ceiling effect’ for respiratory depression. Compared with methadone, its unique pharmacology offers practical advantages and enhanced safety when prescribed as recommended and supervised by a physician. Buprenorphine has been approved in several countries as an efficient and safe maintenance therapy for heroin addiction. Its use resulted in a salutary effect with a reduction in heroin overdose-related deaths in countries that implemented office-based buprenorphine maintenance. In France, however, where high-dose buprenorphine has been marketed since 1996, several cases of asphyxic deaths were reported among addicts treated with buprenorphine. Death resulted from buprenorphine intravenous misuse or concomitant sedative drug ingestion, such as benzodiazepines. In these situations of abuse, misuse, or in association with elevated doses of psychotropic drugs, buprenorphine may cause severe respiratory depression. Unlike other opiates, the respiratory effects from buprenorphine are not responsive to naloxone. However, the exact mechanism of buprenorphine-induced effects on ventilation is still unknown. The role of norbuprenorphine, the main N-dealkylated buprenorphine metabolite with potent respiratory depressor activity, also remains unclear. Experimental studies investigating the respiratory effects of combinations of high doses of buprenorphine and benzodiazepines suggested that this drug-drug interaction may result from a pharmacodynamic interaction. A pharmacokinetic interaction between buprenorphine and flunitrazepam is also considered. As there are many questions regarding the possible dangers of death or respiratory depression associated with buprenorphine use, we aimed to present a comprehensive critical review of the published clinical and experimental studies on buprenorphine respiratory effects.     

云南省丁丙诺啡片与安定、盐酸异丙嗪等多种药物混合滥用的潜力分析

目的:分析云南省丁丙诺啡舌下片(简称丁丙诺啡片)与安定注射液、盐酸异丙嗪注射液等多种药物混合注射滥用(简称丁丙诺啡片多药滥用)的潜力,为政府主管部门的防治工作提供参考依据。方法:采用自行设计的《丁丙诺啡使用情况调查问卷》收集丁丙诺啡片多药滥用者的基本情况和多药滥用情况;采用《视觉类比量表》调查滥用者滥用的主观感受等,并将结果与单独海洛因滥用者和单独丁丙诺啡片滥用者进行比较。结果:丁丙诺啡片与安定注射液、盐酸异丙嗪注射液混合注射滥用者开始使用频率比较与经常使用频率有统计学意义(P=0.001),随着滥用时间的延长,丁丙诺啡片每日使用次数及每次使用量在增加;丁丙诺啡片多药滥用可以减少丁丙诺啡片的用量。66.9%的丁丙诺啡片多药滥用者在减少或停止使用后出现过戒断症状。海洛因滥用者、丁丙诺啡片单一滥用者、丁丙诺啡片多药滥用者的视觉类比量表(VAS)测量分值存在差异(P<0.01)。丁丙诺啡片多药滥用自1992年开始出现以来,滥用人数逐年增多。结论:丁丙诺啡片与安定、盐酸异丙嗪等混合滥用具有滥用潜力,存在流行趋势。建议相关部门进一步加强对丁丙诺啡片、安定等精神药物的处方管理及监管,以防止这些药品的流弊或非法销售,造成更大范围的滥用。