Center for Pain and Supportive Care, Scottsdale, Arizona 85258, USA.
J Palliat Med. 2011 Sep;14(9):1029-33. doi: 10.1089/jpm.2011.0103. Epub 2011 Aug 8.
Pain is one the most common symptoms experienced by palliative care patients. The treatment of pain involves the use of strong opioids such as hydromorphone, morphine, methadone, fentanyl, oxycodone, oxymorphone, or levorphanol for moderate to severe pain. Hydromorphone is metabolized by the liver to hydromorphone-3-glucuronide (H3G), a compound that can potentially cause neuroexcitatory phenomena with accumulation. Pharmacokinetic studies have shown that H3G levels in patients with renal insufficiency are 4 times as high as those with normal renal function; however, reports have been conflicting as to whether or not it is safe to use hydromorphone in renal insufficiency.
In this study we sought to determine the prevalence of neuroexcitation in patients with renal insufficiency who were given hydromorphone, as measured by the glomerular filtration rate (GFR), and to investigate factors associated with increased risk of neuroexcitation in this patient group. For the 12- month period from June 2007 through June 2008, charts of inpatient hospice patients that showed a glomerular filtration rate of <60 (mL/min/1.73 m(2)) and hydromorphone administration for pain control via continuous infusion were reviewed for the occurrence of neuroexcitatory effects, including tremor, myoclonus, agitation, cognitive dysfunction, and seizures.
Overall prevalence of neuroexcitatory effects were: tremor 11 (20%), myoclonus 11 (20%), agitation 26 (48%), and cognitive dysfunction 21 (39%). No seizures were observed. No neuroexcitatory effects were observed for the lowest quartile of dose or duration of hydromorphone. There was a strong and graded increase in neuroexcitatory effects with increasing quartile of dose or duration of hydromorphone for agitation (dose, p<0.0001; duration, p<0.0001) and cognitive dysfunction (dose, p<0.0002; duration, p<0.002). Consistent but weaker trends were observed for tremor and myoclonus.
Parenteral hydromorphone has few neuroexcitatory symptoms until H3G accumulates past a neurotoxic threshold, such as might occur with increasing dose or duration, which, when exceeded, causes neuroexcitatory symptoms to manifest.
疼痛是姑息治疗患者最常见的症状之一。疼痛的治疗包括使用氢吗啡酮、吗啡、美沙酮、芬太尼、羟考酮、奥昔康定或左啡诺等强阿片类药物来治疗中重度疼痛。氢吗啡酮在肝脏中代谢为氢吗啡酮-3-葡糖苷酸（H3G），这种化合物可能会导致神经兴奋现象并发生蓄积。药代动力学研究表明，肾功能不全患者的 H3G 水平是肾功能正常患者的 4 倍；然而，关于在肾功能不全患者中使用氢吗啡酮是否安全的报告一直存在争议。
在这项研究中，我们试图通过肾小球滤过率（GFR）来确定接受氢吗啡酮治疗的肾功能不全患者中神经兴奋的发生率，并研究与该患者群体中神经兴奋风险增加相关的因素。在 2007 年 6 月至 2008 年 6 月的 12 个月期间，我们回顾了住院临终关怀患者的病历，这些患者的肾小球滤过率<60（mL/min/1.73m²），并通过持续输注氢吗啡酮来控制疼痛，以评估神经兴奋作用的发生情况，包括震颤、肌阵挛、激越、认知功能障碍和癫痫发作。
神经兴奋作用的总体发生率为：震颤 11 例（20%）、肌阵挛 11 例（20%）、激越 26 例（48%）和认知功能障碍 21 例（39%）。未观察到癫痫发作。在氢吗啡酮剂量或持续时间的最低四分位数时，未观察到神经兴奋作用。随着氢吗啡酮剂量或持续时间的四分位增加，激越（剂量，p<0.0001；持续时间，p<0.0001）和认知功能障碍（剂量，p<0.0002；持续时间，p<0.002）的神经兴奋作用呈强烈且分级增加。震颤和肌阵挛也观察到一致但较弱的趋势。
在 H3G 蓄积超过神经毒性阈值（例如，随着剂量或持续时间的增加）之前，氢吗啡酮的肠胃外给药很少引起神经兴奋症状，而超过该阈值则会导致神经兴奋症状表现。
