Freye E, Baranowski J, Latasch L
Clinics of Vascular Surgery, Heinrich-Heine University of Düsseldorf, Germany.
Arzneimittelforschung. 2001 Jan;51(1):60-6. doi: 10.1055/s-0031-1300003.
It is well accepted that long-term administration of opioids results in a dose-related constipation. No data so far have demonstrated conclusively whether such constipation is also seen after intake of a controlled release formulation. It was therefore of interest to evaluate whether increasing doses of a controlled release formulation of dihydrocodeine (DHC, CAS 125-28-0) after oral administration also induces a dose-related increase in constipation. Additionally, it was of interest to study whether such a peripheral opioid-related side effect is also seen in another, central receptor-mediated effect, the constriction of the pupil, at clinically relevant doses. Twelve volunteers were given controlled release DHC (60 and 120 mg, respectively) or placebo orally within a randomized, double-blind cross-over study. In order to determine the degree of constipation, oro-cecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripherally and centrally mediated effects were compared to placebo. DHC at both dosages induced a significant (p < 0.01) prolongation of oro-cecal transit time when compared to placebo. However, prolongation of oro-cecal transit was not significantly longer when comparing the lower (60 mg) with the higher dose (120 mg). DHC also induced a significant (p < 0.005) depression of the pupillary light reflex from 53.9 mm (control) to 8.3 and 7.4 mm, respectively. Similar to intestinal transit, the pupillary light reflex was not significantly different among the two doses of DHC. Also, both dosages induced a similar amount of side effects. Tiredness and dry mouth were reported in 80% after both doses while vertigo was reported in 5% and 1% complained of headache. None of the volunteers reported nausea or emesis. It is concluded that opioid receptor sites, which are located in the plexus myentericus of the intestinal wall, are responsible for the delay in propulsion. Because of the controlled release of a fixed amount of DHC over time there is constant binding of the ligand followed by a constant conformational change of peripheral and central receptor sites. Thus constant release induces no dose-related increase in oro-cecal transit and inhibition of the pupillary light reflex.
长期服用阿片类药物会导致剂量相关的便秘，这一点已被广泛接受。目前尚无数据能确凿证明服用控释制剂后是否也会出现这种便秘情况。因此，评估口服不同剂量的二氢可待因控释制剂（DHC，化学物质登记号125 - 28 - 0）是否也会导致便秘剂量相关的增加很有意义。此外，研究在临床相关剂量下，这种外周阿片类药物相关的副作用在另一种由中枢受体介导的效应（瞳孔收缩）中是否也会出现也很有意义。在一项随机、双盲交叉研究中，12名志愿者分别口服控释DHC（分别为60毫克和120毫克）或安慰剂。为了确定便秘程度，使用氢气呼气试验测量口盲肠转运时间。此外，为了评估中枢介导的效应，使用瞳孔对光反射技术量化瞳孔对光的反应。将外周和中枢介导的效应与安慰剂进行比较。与安慰剂相比，两种剂量的DHC均显著（p < 0.01）延长了口盲肠转运时间。然而，比较低剂量（60毫克）和高剂量（120毫克）时，口盲肠转运时间的延长并无显著差异。DHC还显著（p < 0.005）抑制了瞳孔对光反射，从53.9毫米（对照）分别降至8.3毫米和7.4毫米。与肠道转运情况类似，两种剂量的DHC之间瞳孔对光反射并无显著差异。而且，两种剂量引起的副作用数量相似。两种剂量后均有80%的人报告感到疲倦和口干，5%的人报告眩晕，1%的人抱怨头痛。没有志愿者报告恶心或呕吐。结论是，位于肠壁肌间神经丛的阿片受体部位是导致推进延迟的原因。由于DHC随时间固定量的控释，配体持续结合，随后外周和中枢受体部位持续发生构象变化。因此，持续释放不会导致口盲肠转运时间剂量相关的增加以及瞳孔对光反射的抑制。
