Terra S G, Tsunoda S M
Duke University Medical Center, Durham, NC, USA.
Ann Pharmacother. 1998 Nov;32(11):1228-30. doi: 10.1345/aph.18115.
The theory that pruritus from cholestasis is due to increased opiate tone appears to have merit, based on the results of the clinical trials presented above. However, although opioid antagonists relieve itching to a large extent, the itching usually is not abolished completely. Several factors may explain this lack of complete relief. The doses used in the clinical trials may have been insufficient, or duration of therapy may have been short. It is also possible that nonopioid mechanisms contribute to pruritus from cholestasis. Although effective, naloxone therapy has several limitations for long-term use, including a short half-life and large first-pass metabolism, which necessitates parenteral administration. Intravenous administration is clearly not practical for a chronic disease. Nalmefene treatment has several advantages over naloxone, with both prolonged duration of action and increased potency at the opioid receptor level. However, nalmefene is available only as a parenteral product in the US. The nalmefene studies are limited by their small sample size and short follow-up periods. Additionally, two of the studies are available in abstract form only. Based on two clinical studies, naltrexone therapy appears promising. Gradual dose titration from 25 mg/d up to a maximum of 50 mg/d may minimize withdrawal reactions. Further long-term clinical trials using objective measures that compare opioid antagonists with other therapies are needed to clearly establish the role of these agents. Potential tachyphylaxis from long-term use of opioid antagonists requires further investigation. Combination therapy may also be required, since monotherapy with either opioid antagonists or other therapies have failed to completely relieve the pruritus caused by cholestasis. Given the potential for severe withdrawal reactions, opioid antagonists should be reserved for patients refractory to other treatments.
基于上述临床试验结果，胆汁淤积性瘙痒是由于阿片类物质张力增加这一理论似乎有其合理性。然而，尽管阿片类拮抗剂在很大程度上能缓解瘙痒，但瘙痒通常并不能完全消除。有几个因素可以解释这种未能完全缓解的情况。临床试验中使用的剂量可能不足，或者治疗持续时间可能较短。非阿片类机制也有可能导致胆汁淤积性瘙痒。虽然纳洛酮治疗有效，但长期使用有几个局限性，包括半衰期短和首过代谢大，这就需要胃肠外给药。静脉给药对于慢性病显然不实用。与纳洛酮相比，纳美芬治疗有几个优点，作用持续时间延长且在阿片受体水平上效力增加。然而，在美国纳美芬仅有一种胃肠外制剂。纳美芬的研究受样本量小和随访期短的限制。此外，其中两项研究仅有摘要形式。基于两项临床研究，纳曲酮治疗似乎很有前景。从25毫克/天逐渐滴定至最大50毫克/天的剂量可能会使戒断反应最小化。需要进一步进行长期临床试验，采用客观指标比较阿片类拮抗剂与其他疗法，以明确确定这些药物的作用。长期使用阿片类拮抗剂可能出现的快速耐受性需要进一步研究。可能还需要联合治疗，因为单独使用阿片类拮抗剂或其他疗法都未能完全缓解胆汁淤积引起的瘙痒。鉴于有发生严重戒断反应的可能性，阿片类拮抗剂应仅用于对其他治疗无效的患者。
