[每周一问]NO.4之周中问：阿片药物
A 52 year woman who is s/p a total hip replacement under spinal anesthesia is now complaining of burning in her eyes. She received 0.2 mg of preservative-free morphine intrathecally at the time of her lumbar spinal placement and is questioning whether the morphine could be causing her ocular symptoms.
1. Where do intrathecal opioids work?
2. What are the common side effects of intrathecal morphine?
3. Can intrathecal morphine cause ocular burning?
患者女，52岁，脊麻下全髋关节置换术后主诉眼睛烧灼感。该患者在接受腰麻时通过穿刺部位给与了0.2mg吗啡鞘内注射，患者询问是否是因为吗啡导致的视觉症状。
1. 鞘内注射阿片药物作用部位是哪儿？
2. 鞘内注射吗啡通常的副作用有哪些？
3. 鞘内注射吗啡可导致视觉上的烧灼感吗？
[每周一问]NO.4之周中问：阿片药物（结合病例讨论
1.鞘内注射阿片药物作用部位是哪儿？
鞘内注射阿片药物是通过与脊髓灰质的阿片受体（主要是μ受体）结合而发挥作用。已经证实阿片药物也与存在于蛛网膜下腔的脊髓背根神经节和沿神经轴索分布的外周神经节相结合发挥作用。
阿片药物通过脑脊液在蛛网膜下腔运动。CSF中吗啡运动速度的增加更大程度上取决于其相对的亲水性。吗啡的扩散可以极大程度地提高和延长其作用持续时间，通过更多的与头侧区域的脊髓相结合而发挥此作用，而不是在最初的注射部位。相反，脂溶性药物（如舒芬太尼、芬太尼等）的扩散局限在其注射部位，通过快速扩散到脊髓及其周围组织而发挥作用。
2.鞘内注射吗啡通常的副作用有哪些？
鞘内注射吗啡通常的副作用有：
皮肤搔痒
恶心，伴或不伴有呕吐
呼吸抑制
嗜睡或定向障碍
尿储留
胃肠蠕动减慢
皮肤搔痒可能是鞘内注射吗啡最常见的副作用。发生在45~60%的患者，但是需要进行药物治疗的很少。搔痒可以使全身性的，但是更常见发生在鼻部、颜面或上胸部。虽然吗啡对全身的反应为组胺释放，但是这儿的原因更可能是因为吗啡扩散到颅内后与第五对颅神经的相互作用所致。胃肠外给予纳洛酮或纳布啡可有效地治疗这种副作用。抗组织胺药物比如苯海拉明也常被应用，但很可能是因为其镇静作用，而不是与阿片药物的相互作用。
恶心（伴或不伴有呕吐）发生率为10~25%。这也是因为吗啡向头侧的转移，并与导致恶心呕吐等趋化触发区相互作用有关。通过纳洛酮对阿片物质的直接逆转在这种情况并非有效，而使用氟哌利多或昂丹司琼（奥坦西隆,枢复宁）可以更为有效的治疗。
呼吸抑制非常罕见，但是是鞘内注射吗啡最危险的并发症，是因为吗啡向大脑髓质的呼吸中枢扩散所致。最近数据表明其发生率低于1%，呼吸频率小于8次作为标准。通气功能降低常发生于给予吗啡后的6~12小时，伴随着呼吸频率的缓慢降低。没有在给予鞘内吗啡后20小时更易发生呼吸抑制的报道。接受鞘内注射吗啡的患者至少在给药后的12小时内应该观察每小时的呼吸情况，必要时根据临床情况延长观察时间。
鞘内注射吗啡后发生呼吸抑制的危险因素包括：
老年患者
病理性肥胖
胸科手术
复杂系统性疾患
吗啡剂量大
同时给予安泰乐（羟嗪,安他乐,阿太勒克司,海特洛辛[弱安定药]）或口服阿片药物治疗Opioid naivety
呼吸抑制可以通过纳洛酮而逆转。
尿潴留，关于其发生率报道的范围较大，为0~80%。研究结果比较混乱，因为许多因素包括术中阿片药物的使用、术后其他阿片药物的使用、手术类型、尿潴留的定义界定以及导尿术的使用均可影响其判断。似乎在鞘内给予阿片类药物的年轻女性最容易出现。其作用可以通过纳洛酮而逆转。
嗜睡和胃肠抑制很少见，似乎比安泰乐阿片药物更罕见。
3.鞘内注射吗啡可导致视觉上的烧灼感吗？
类似于全身给药一样，椎管内给予吗啡可以导致瞳孔缩小，但是没有因为鞘内注射吗啡导致视觉烧灼感的报道，因此，该患者出现视觉烧灼感应该寻求于其他原因。
英文参考答案：
Where do intrathecal opioids work?
Intrathecally placed opioids work by binding to opioid receptors (primarily mu receptors) in the substantia gelatinosa of the spinal cord. There is also evidence that opioids bind at the dorsal root ganglia and more peripherally along the nerve cell axon while still in the subarachnoid space.
Opioids move within the subarachnoid space by bulk flow. The increased spread of morphine within the CSF is largely determined by its relative hydrophilicity. This spread of morphine greatly enhances and prolongs the duration of its effects by allowing binding to the spinal cord at much more cephalic locations than were directly exposed at initial injection. In contrast, the spread of lipid soluble agents like sufentanil or fentanyl is limited to the areas of placement by rapid reabsorption into the surrounding tissues and spinal cord.
What are the common side effects of intrathecal morphine?
Common side effects of neuraxial morphine include the following:
• Pruritus
• Nausea with or without vomiting
• Respiratory depression
• Sedation/disorientation
• Urinary retention
• Decreased gastrointestinal motility
Pruritus is probably the most common side effect of spinal morphine. It occurs in 45-60% of patients, although far fewer will require pharmacologic treatment. It can be generalized but is more commonly found to occur on the nose, face, or upper chest. Although systemic morphine causes histamine release, the cause here is most likely due to interaction with the 5th cranial nerve as the morphine diffuses cranially. Naloxone or nalbuphine parenterally administered effectively treats this side effect. Antihistamines like diphenhydramine are commonly used and are probably due to their sedative actions rather than by any interaction with the opioid.
Nausea and/or vomiting occur in 10-25% of patients. This is again due cephalad migration of morphine and interaction with chemotactic trigger zone leading to nausea and vomiting. Direct reversal of opioid with naloxone is not effective in these situations and is much better treated with either droperidol or ondansetron.
Respiratory depression is a very rare but dangerous side effect of intrathecal morphine due to cephalad spread of to the respiratory centers of the brain in the medulla. Latest numbers indicate this occurs much less than 1% of administration when respiratory rate less than 8 is used as the endpoint. Decreased ventilation classically occurs 6-12 hours after administration of morphine with a slowly declining respiratory rate over the same time period. There have been no reports of respiratory depression greater than 20 hours after administration of intrathecal morphine. The respiratory rate of patients who have received subarachnoid morphine should be observed hourly for at least 12 hours after administration, and longer if clinically dictated.
Risk factors for respiratory depression after intrathecal administration of morphine include the following:
• Advanced age
• Morbid obesity
• Thoracic surgery
• Multiple systemic illnesses
• High morphine dose
• Concomitant parenteral or oral opioid use
• Opioid naivety
Respiratory depression can be reversed by administration of naloxone.
Urinary retention has been reported to have a wide-ranging incidence from 0-80%. These studies have been confounded by a variety of factors including intraoperative use of opioids, postoperative use of other opioids, variety of surgeries, variety of definitions of urinary retention and variable length of use of bladder catheters. It appears that urinary retention is most common in young males receiving intrathecal opioids. Urinary retention is also reversible with use of naloxone.
Sedation and gastrointestinal dysmotility are rare and seen much less frequently than with parenteral opioids.
Can intrathecal morphine cause ocular burning?
Although spinal administration, like systemic administration, of morphine can cause miosis, there are no reports of ocular burning due to intrathecal morphine. Therefore, other causes of ocular burning will have to be sought for this patient.
References:
1. Dahl JB, Jeppesen IS, Horgensen H, Wetterslev J, and Moiniche S. Intraoperative and postoperative analgesic efficacy and adverse effects of intrathecal opioids in patients undergoing cesarean section with spinal anesthesia. Anesthesiology 91:1919-27, 1999.
2. Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anesth 42:891-103, 1995.
3. Rawal N, Schott U, and Dahlstrom B. Influence of naloxone infusion on analgesia nad respiratory depression following epidural morphine. Anesthesiology 64:194-201, 1986.
Site Editor: Sunil Eappen, M.D.
Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School
