Experimental Cutaneous Pain Thresholds and Tolerance in Clinical Analgesia with Epidural Morphine

Ten patients experiencing significant analgesia from repealed low-dose morphine injections via an indwelling epidural catheter were studied. One group (n=5) with acute, postoperative pain was tested for changes in experimental cutaneous pain thresholds with and without clinical morphine analgesia. Three of these patients received intravenous naloxone. The analgesia was reversed in two. There was no significant alteration in any cutaneous modality, including pain, although the postoperative deep pain was relieved. This discrepancy might be explained by the existence of separate subpopulations of opiate receptors at the spinal cord level, which differentiate nociceptive input from the skin and from deep body structures. The other group (n = 5) of cancer pain patients with a permanent epidural catheter was monitored for long-term changes in clinical pain. Signs of tolerance were not seen with an observation period up to 6 weeks.     

Long-Term Epidural Morphine Analgesia

Long-term treatment for malignant pain with morphine epidurally poses some technical problems: infection and contamination of epidural space, fixation of the epidural cannula, personal hygiene of the patient, etc. We suggest that a solution to these problems is subcutaneous tunnelling of the epidural cannula. This paper describes our technique and presents the case histories of two patients. In one case, a single epidural cannula was used for 207 days for treatment with morphine epidurally without any complications.     

Sustained-release Morphine for Epidural Analgesia in Rats

Background: Epidural opioid analgesia often requires either continuous infusion or repeated injections, which are inconvenient for patients, increase risk of infection, and consume expensive physician and nursing time. In addition, potential respiratory depression is a major safety concern. The authors studied whether a single dose of epidurally administered, sustained-release morphine could prolong analgesia and reduce toxic effects in rats.

Methods: Sustained-release morphine (DTC401) was prepared by encapsulating morphine sulfate in DepoFoam (Dep. Tech, San Diego, CA), a lipid-based, sustained-release drug delivery system. A standard hot-plate test for analgesia, pulse oximetry for hemoglobin oxygen saturation, corneal-reflex loss, and incidence of catalepsy were used to assess efficacy and toxicities. Cerebrospinal fluid and serum pharmacokinetic studies were performed after a single epidural dose, using a commercially available radioimmunoassay kit.

Results: Single epidural doses of DTC401 resulted in equivalent onset time to peak analgesia but significantly prolonged analgesia compared with morphine sulfate. Hemoglobin oxygen saturation was decreased minimally, and the incidences of catalepsy and corneal-reflex loss were minimal, even at large doses of DTC401. In contrast, the larger doses of morphine sulfate significantly decreased hemoglobin oxygen saturation, and caused catalepsy and loss of the corneal-reflex. The Cmax for DTC401 was 32% in cerebrospinal fluid and 6% in serum, relative to morphine sulfate. The terminal half-life for DTC401 was increased 32 fold in the cerebrospinal fluid compared with morphine sulfate.     

Epidural Morphine for Postoperative Pain Relief

In a clinical, double-blind study including 45 patients, who all underwent lower abdominal or urological surgery, the analgesic effect, latency and duration of epidural application of morphine were investigated in doses of 2 and 4 mg, respectively, compared to placebo. No significant difference was found in the effect of 2 mg morphine, compared to placebo. A significant decrease in pain score was found in the group of patients who received 4 mg morphine administered epidurally; however, this effect did not occur until 60 min after epidural administration. The effect of 4 mg morphine was found to be of long duration, as eight out of 15 patients did not require any supplementary analgesics within the first 24 h, compared to two out of 14 and three out of 15 patients, respectively, in the placebo and 2-mg groups.     

Epidural Morphine for Postoperative Pain Relief

Thirty-three patients were randomly assigned to two groups to study the analgesic potency, duration of action and side effects of epidural and intramuscular morphine after hip surgery. Two milligrams of preservative-free morphine chloride in 10 ml of normal saline in the epidural space was compared to 10 mg of intramuscularly administered morphine. There was a more rapid onset of action after intramuscular morphine. However, the quality of pain relief was substantially higher and the duration of action markedly longer after epidural morphine. The total dose required in the epidural group was 3.6 mg and in the intramuscular group 41 mg during the 15-h observation period. The side effects of epidural morphine were few and mild, the most embarrassing being urinary retention (20 %). Nausea and/or vomiting was less common after epidural morphine (20% versus 55%). Pruritus or respiratory depression which have been reported previously were not encountered. However, it is recommended that preservative-free solutions are used to avoid itching and that the patients are monitored, as respiratory depression may occur long after administration of epidural opiate.     

Experimental Pain Models Reveal No Sex Differences in Pentazocine Analgesia in Humans

Background: Accumulating evidence suggests that there are sex differences in analgesic responses to opioid agonists. Several studies using an oral surgery pain model have reported more robust analgesia to [kappa]-agonist-antagonists (e.g., pentazocine, nalbuphine, butorphanol) among women than among men. However, evidence of sex differences in [kappa]-agonist-antagonist effects from studies of experimentally induced pain in humans is lacking.

Methods: Therefore, the analgesic effects of intravenous pentazocine (0.5 mg/kg) were determined in healthy women (n = 41) and men (n = 38) using three experimental pain models: heat pain, pressure pain, and ischemic pain. Each pain procedure was conducted before and after double-blind administration of both pentazocine and saline, which occurred on separate days in counterbalanced order.

Results: Compared with saline, pentazocine produced significant analgesic responses for all pain stimuli. However, no sex differences in pentazocine analgesia emerged. Effect sizes for the sex differences were computed; the magnitude of effects was small, and an equal number of measures showed greater analgesia in men than in women. Also, analgesic responses were not highly correlated across pain modalities, suggesting that different mechanisms may underlie analgesia for disparate types of pain.     

硬膜外氟哌啶,灭吐灵预防术后吗啡并发恶心呕吐的临床观察

剖宫产手术病人６０例，随机分三组，手术结束时硬膜外腔分别注入吗啡２ｍｇ（Ⅰ组）、吗啡２ｍｇ＋灭吐灵１０ｍｇ（Ⅱ组）或吗啡２ｍｇ＋氟哌啶２．５ｍｇ（Ⅲ组）进行硬膜外术后镇痛，观察病人２４ｈ内恶心，呕吐及切口明显疼痛的发生情况。结果Ⅱ，Ⅲ组病人术后２４ｈ内切口明显疼痛的发生率小于其它两组（Ｐ＜０．０５）。     

Postoperative Pain Treatment after Upper Abdominal Surgery with Epidural Morphine at Thoracic or Lumbar Level

Thirty patients undergoing upper laparotomy were entered into a randomized trial, comparing the effect of midthoracic (T) and lumbar (L) epidural morphine on postoperative pain and pulmonary function. Five mg morphine was injected through the catheter at the end of the operation, and subsequently three times a day. Six, 30 and 54 h postoperatively, the following tests were performed: linear analogue pain score, arterial gas tensions (PaO2, PaCO2 and pH), forced ventilatory capacity (FVC), forced expiratory volume in 1s (FEV1) and peak expiratory flow rate (PEF). The changes in pain score (increase of the median): T: 21, 6, 5, and L: 24, 15, 8 per cent of full scale), PaO2 (decrease of the tension: T: 1.7, 2.1, 2.4, and L: 2.0, 2.8, 2.0 kPa), PaCO2, pH, FVC (decrease of the volume: T: 1.3, 1.1, 0.9, and L: 1.3, 1.3, 1.21), FEV1 and PEF from the preoperative tests were not significantly different. It is concluded that the clinical effect of epidural morphine for postoperative pain treatment is the same or little different whether the administration takes place at the thoracic or lumbar level.     

Mood during Epidural Patient-controlled Analgesia with Morphine or Fentanyl

Background: Mood states during epidural opioids are not known. The authors studied the change in mood during the 48-h period of epidural morphine and epidural fentanyl in 47 patients after elective hip or knee joint arthroplasty.

Methods: An epidural catheter was inserted at the L2-L3 or L3-L4 interspace. Anesthesia was induced with thiopenthal and maintained with isoflurane and nitrous oxide. One hour before the conclusion of the operation, patients received an epidural bolus injection of 2 mg morphine (n = 23) or 100 micro gram fentanyl (n = 24), followed by the same opiate (125 micro gram/ml morphine or 25 micro gram/ml fentanyl) epidurally delivered by a patient-controlled analgesia (PCA) pump in the postoperative period for 48 h. Mood was assessed using the bipolar form of the Profile of Mood States before operation and 24 h, 48 h, and 72 h after operation.

Results: There was no significant difference in pain intensity between the groups during epidural PCA. Mood states became more positive over time in the patients who received morphine (P < 0.01 at 48 h) and negative in those who were given fentanyl (P < 0.01 at 24 and 48 h, respectively) compared with those before the operation, and they were more positive in the morphine than in the fentanyl group at 24 h, 48 h (P < 0.05), and 72 h (P < 0.01). Patients in the morphine group were more composed, agreeable, elated, confident, energetic, and clearheaded than were those in the fentanyl group (P < 0.05). There was no correlation between mood scores and pain scores in either group. There was an inverse correlation at 48 h between mood scores and plasma fentanyl concentrations (r = -0.58, P < 0.05).     

硬膜外注射吗啡术后镇痛最佳剂量探讨

本文报告腹部手术１１７９例硬膜外注药镇痛，根据吗啡用量随机分为四组：Ａ组０．５ｍｇ；Ｂ组１．０ｍｇ；Ｃ组１．５ｍｇ；Ｄ组２．０ｍｇ，观察各组的镇痛效果与并发症。结果：１～１．５ｍｇ剂量的吗啡不仅镇痛效果佳，且并发症少（２．６％～４．７％）；超过此剂量（如用２ｍｇ），镇痛效果未见明显增加，而并发症却明显上升（３０．９％）；相反剂量太小（０．５ｍｇ）镇痛效果欠佳。结论：使用吗啡１～１．５ｍｇ可能是硬膜外注射吗啡术后镇痛的最佳剂量     

硬膜外吗啡术后镇痛对血清皮质醇和血糖的影响

选择３０例中上腹部手术病人，随机分为镇痛组和对照组（各１５例），观察比较两组血清皮质醇、血糖和循环系统的变化。结果表明，镇痛组术后血清皮质醇升高的持续时间明显较对照组短，术后第１ｄ、第３ｄ的结果相比，两组有显著性和非常显著性差异（Ｐ＜０．０５、Ｐ＜０．０１）。血糖变化，镇痛组术后即恢复到术前水平，对照组术后第１ｄ仍较术前为高，两组相比Ｐ＜０．０５。结果提示，硬膜外吗啡术后镇痛能有效地防止机体应激性变化     

A Comparison of Epidural Morphine and Epidural Bupivacaine for Postoperative Pain Relief

In 32 patients subjected to total hip replacement, postoperative pain relief was achieved by random treatment with either 5 mg of morphine in 10 ml of saline (n = 15) or 6–8 ml of 0.5% bupivacaine with epinephrine (n = 17), both drugs administered by the lumbar epidural route. In an additional group of 10 patients, post-traumatic thoracic or post-operative abdominal pain was relieved first by 4–6 ml of 0.5% bupivacaine with epinephrine and subsequently by 5 mg of morphine in 10 ml of saline, both drugs being administered by the thoracic epidural route. The duration of analgesia was significantly longer, on average, with morphine (28 h) than with bupivacaine (4.3 h) when the drugs were given by the lumbar route. Thoracic administration of morphine also resulted in a significantly longer duration of pain relief (on average 9.8 h) than that of bupivacaine (3.8 h). Morphine gave satisfactory pain relief in all cases. It was not associated with motor block, loss of sensitivity to temperature, touch, or pin-prick, or any signs of sympathetic block, as was the case with epidural bupivacaine. Plasma concentrations of morphine were not detectable 8 h after injection, though the patients still had pain relief. One case of delayed severe respiratory depression occurred 6 h after morphine injection via the thoracic route. Epidural morphine analgesia should therefore be reserved for patients in whom continual surveillance is possible, at least until more is known about the pharmacokinetics of narcotics in the epidural and subarachnoid space.     

A Change in Practice from Epidural to Intrathecal Morphine Analgesia for Hepato-Pancreato-Biliary Surgery

Background  This study was designed to audit the change of anesthetic practice from thoracic epidural analgesia (TEA) to intrathecal morphine (ITM) combined with patient-controlled analgesia (PCA) for hepato-pancreato-biliary (HPB) surgery. Methods  All patients who underwent major HPB surgery and received TEA or ITM from March 2005 to March 2008 were identified. Patients who received PCA alone were used for comparison. Data were retrospectively collected and analyzed for success of TEA, perioperative intravenous fluid (IVF) volume administered, hypotension, complications, and hospital stay. Results  During the study period, 51 (32%) patients received TEA, 79 (49%) received ITM plus PCA opiate, and 31 (19%) received PCA alone. The incidence of postoperative hypotension was significantly higher in those who received TEA compared with those who received ITM (21/51 (41%) vs. 7/79 (9%), P < 0.001). The median (range) perioperative IVF administration was higher in the TEA group compared with the ITM group for both the first 24 h (6 (3–11) liters vs. 5 (3–11) liters, P < 0.05) and in total (15.5 (5–48.5) liters vs. 9 (3–70) liters, P < 0.001). Respiratory complications occurred in five (10%) of the TEA group compared with one (1%) in the ITM group (P < 0.05). The median (range) hospital stay was longer in the TEA group compared with the ITM group (9 (3–36) days vs. 7 (3–55) days, P < 0.01). Conclusions  In a resource-limited setting, ITM, compared with TEA, is associated with a reduced incidence of postoperative hypotension, reduced IVF requirements, shorter hospital stay, and lowers the incidence of respiratory complication.     

Opioids Inhibit Febrile Responses in Humans, Whereas Epidural Analgesia Does Not: An Explanation for Hyperthermia during Epidural Analgesia

Background: Epidural analgesia is frequently associated with hyperthermia during labor and in the postoperative period. The conventional assumption is that hyperthermia is caused by the technique, although no convincing mechanism has been proposed. However, pain in the "control" patients is inevitably treated with opioids, which themselves attenuate fever. Fever associated with infection or tissue injury may then be suppressed by opioids in the "control" patients while being expressed normally in patients given epidural analgesia. The authors therefore tested the hypothesis that fever in humans is manifested normally during epidural analgesia, but is suppressed by low-dose intravenous opioid.

Methods: The authors studied eight volunteers, each on four study days. Fever was induced each day by 150 IU/g intravenous interleukin 2. Volunteers were randomly assigned to: (1) a control day when no opioid or epidural analgesia was given; (2) epidural analgesia using ropivacaine alone; (3) epidural analgesia using ropivacaine in combination with 2 [mu]g/ml fentanyl; or (4) intravenous fentanyl at a target plasma concentration of 2.5 ng/ml.

Results: Fentanyl halved the febrile response to pyrogen, decreasing integrated core temperature from 7.0 +/- 3.2[degrees]C [middle dot] h on the control day, to 3.8 +/- 3.0[degrees]C [middle dot] h on the intravenous fentanyl day. In contrast, epidural ropivacaine and epidural ropivacaine-fentanyl did not inhibit fever. The fraction of core-temperature measurements that exceeded 38[degrees]C was halved by intravenous fentanyl, and the fraction exceeding 38.5[degrees]C was reduced more than fivefold.     

剖宫产及硬膜外吗啡术后镇痛对产妇泌乳的影响

目的：观察剖宫产及硬膜外吗啡术后镇痛产妇的泌乳状况及血清泌乳素（ＰＲＬ）变化。方法：足月初产妇１２０例均分为四组：Ⅰ组术毕行硬膜外吗啡镇痛;Ⅱ组术毕硬膜外吗啡镇痛,２４小时后追加１次;Ⅲ组未行术后镇痛;阴道自然分娩３０例为Ⅳ组。结果：产后５分钟、２４值变化各组间无显著性差异。Ⅳ组产后２４小时内开发泌乳发生率（４０％）,高于同期所有剖宫产组（２０％）;但４８小时内开始泌乳及７２小时乳汁分泌不足发生率     

酚苄明用于预防硬膜外吗啡所致尿潴留的初步观察

４３例在硬膜外阻滞下行择期腹部手术病人接受硬膜外２ｍｇ吗啡止痛，其中１８例分别于术前晚，术前１ｈ，术后５ｈ和次日晨口服酚苄明１０－２０ｍｇ。结果表明，加用酚苄明不能明显降低硬膜外吗啡止痛病人术后尿潴留的发生率。     

硬膜外咪唑安定联合吗啡用于下腹部手术后镇痛

目的 探讨硬膜外注入咪唑安定联合吗啡对下腹部手术后的镇痛效果。方法 36例择期下腹部手术患者,ASA Ⅰ-Ⅱ,随机分为实验组和对照组,各18例。实验组于手术结束时硬膜外注入咪唑安定50ug/kg复合吗啡2mg,对照组择仅使用吗啡2mg,记录术后2h,6h和12h时患者镇痛(VAS)、镇静(Ramsay)评分值。结果 实验组在术后2h时镇痛评分0.91±0.33较对照组1.45±0.38低,而镇静评分1.71±0.57较对照组0.95±0.42高。实验组恶心呕吐发生率在6h,12h时间内较对照组低。结论 硬膜外咪唑安定联合吗啡用于下腹部术后镇痛效果优于单独使用吗啡。