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April 10, 2005 [每周一问]NO.4 阿片药物（结合病例讨论）

We continue our discussion of opioids.
The wife of a 32 year-old man with a history of intravenous heroine addiction presents to you for advice. The husband had previously made an attempt at heroine abstinence with the aid of methadone 20 mg/daily in conjunction with a rehab clinic and had failed. Now he is going back to the clinic, and they are offering him the option of using buprenorphine or levomethadyl.
1.  What type of drugs are buprenorphine and levomethadyl?
2.  What possible advantages and disadvantages could these drugs have in comparison with methadone as a method of curbing illicit opioid use?

患者，男性，32岁，静脉注射海洛因成瘾。以前曾经试图通过每天服用美沙酮20mg，同时辅助一些临床康复措施以寻求戒除毒瘾，但是没有成功。现在，医务人员建议其使用丁丙诺非或左旋美沙酮治疗。
1.  丁丙诺非和左旋乙酰美沙酮是什么类型的药物
2.  作为一种抑制阿片药物不正当使用的方法，与美沙酮相比，这些药物可能的优点和缺点是什么。

April 10, 2005 [每周一问]NO.4 阿片药物（结合病例讨论）

1.丁丙诺非和左旋乙酰美沙酮是什么类型的药物
左旋乙酰美沙酮与美沙酮一样均为µ-阿片受体激动剂。具有典型µ-阿片受体的全部特性，同时持续时间较美沙酮明显延长。
丁丙诺非是一来自蒂巴因的部分µ-阿片受体激动-拮抗剂，这意味着其最大效应（不考虑剂量）并非全都是激动作用。其镇痛强度是吗啡的30倍，同时持续时间更长。
左旋美沙酮和美沙酮均为FDA支持的替代阿片药物的治疗药物，而丁丙诺非最近被FDA重新审查。

2.作为一种抑制阿片药物不正当使用的方法，与美沙酮相比这些药物可能的优点和缺点是什么。
近期研究表明，丁丙诺啡、左旋美沙酮与大剂量美沙酮（>60mg/d）效果相当。这三种药物均优于早期治疗的低剂量的美沙酮方法（20mg/d）。最近Johnson及其同事证明，与低剂量美沙酮相比，左旋乙酰美沙酮具有明显的持续解除阿片成瘾的作用，而与高剂量美沙酮与丁丙诺非相当。通过大量病人证明，解除成瘾的成功标志是通过药物治疗阿片类药物的使用持续降低。

虽然左旋美沙酮和丁丙诺啡副作用相似（共同副作用包括便秘、恶心和口干），但是对于部分病人的优点仍旧有不同之处。左旋美沙酮在达到靶血浆浓度之前需要较长时间的诱导期，这可能导致患者失去继续治疗的信心导致退出治疗。另一方面，一旦诱导期过后，左旋美沙酮表现出更稳定的血浆药物浓度，而很少出现药物浓度的急剧变化。

左旋美沙酮与丁丙诺非均可每周服用三次，而美沙酮需要每天服用。

总之，该患者可以通过给与左旋美沙酮或丁丙诺非而治疗得到改善，或者给与大剂量的美沙酮代替其以前使用的每天20mg的美沙酮治疗。

英文参考答案：

What type of drugs are buprenorphine and levomethadyl?
Levomethadyl acetate is a µ-opioid agonist, like methadone. It has all of the properties of a typical µ-opioid and is significantly longer lasting than methadone.
Buprenorphine is a partial µ-opioid agonist-antagonist derived from thebaine. This means that its maximal effects (regardless of dose) are less than that of a full agonist. Its analgesic potency is about 30 times greater than morphine with a much greater duration of action
Levomethadyl and methadone are FDA approved for use as pharmacotherapy for opioid dependence, whereas buprenorphine is currently being reviewed by the FDA for this use.

What possible advantages and disadvantages could these drugs have in comparison with methadone as a method of curbing illicit opioid use?
Recent evidence suggests that buprenorphine, levomethadyl and high-dose methadone (> 60 mg/day) may be comparable. All three of these agents are superior to the low-dose methadone regimen (20 mg/day) that this patient was treated with earlier. Recently Johnson and colleagues (1) demonstrated levomethadyl acetate had a significantly higher rate of continuous abstinence from opioids compared to low-dose methadone, and comparable rates of abstinence to high-dose methadone and buprenorphine. Success was defined by the number of patients remaining in the program using the treatment drug as well as the continued decreasing self-report of illicit opioid use.
Although the side-effect profile of levomethadyl and buprenorphine is similar, (common side effects include constipation, nausea, and dry mouth), there are some differences that may be beneficial to particular groups of patients. Levomethadyl acetate has a long induction period before the target plasma concentration may be achieved, which may lead to patients dropping out of treatment programs. On the other hand, once the induction period is complete, levomethadyl has been shown to have more stable blood concentrations with less variation in the peak-to-trough levels.
Both levomethadyl and buprenorphine have the advantage of being able to be dosed three times weekly as opposed to the normal daily dosing of methadone.
In summary, this patient may benefit from either levomethadyl acetate or buprenorphine, or high-dose methadone compared to his earlier regimen of 20 mg of methadone per day.
References:
1.  Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, and Bigelow GE. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 343:1290-7, 2000.
2.  Stoelting RK. Opioid agonists and antagonists in Pharmacology and Physiology in Anesthesia Practice, 3rd edition, Lippincott-Raven, New York, 1999, pp 77-112..
3.  Strain EC, Bigelow GE, Liebson IA, and Stitzer ML. Moderate- vs. High- dose methadone in the treatment of opioid dependence: a randomized trial. JAMA 281:1000-5, 1999.
Site Editor: Sunil Eappen, M.D.
Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School