Date:
June 13, 2000
Promotor:
Prof. J.T.A. Knape, MD, PhD
Co-promotores:
R. Dirksen, MD, PhD
M.J.M. Gielen, MD, PhD
The optimal site to administer opioids e.g. morphine is as close as possible to the opiate receptor site (spinal cord) by the intrathecal route, as it is the place of effectiveness.
To improve the clinical effectiveness of intrathecal morphine two strategies are proposed:
1. to lower the intrathecal dose of morphine and thereby reduce the supraspinal adverse effects while maintaining the analgesic effects;
2. further research to synthesize highly selective endorphin mimetic drugs with a minimum of side effects.
We hypothesized that low doses of intrathecal morphine might probably result in similar pain relief scores but might minimize the incidence of adverse effects.
The first study was designed to determine the optimal intrathecal dose of morphine in total hip surgery. The optimal intrathecal dose was defined as the dose, which provides effective analgesia with minimal side effects during 24 h after total hip surgery. Patients (n=143) scheduled for total hip surgery were randomized to four double-blinded groups with a standardized bupivacaine dose but different doses of intrathecal morphine: group I, 0.025 mg; group II, 0.05 mg; group III, 0.1 mg; and, group IV, 0.2 mg. Pain scores, intravenous morphine intake {patient controlled analgesia (PCA)} and morphine related side effects (respiratory depression, postoperative nausea and vomiting, itching, urinary retention) were recorded for 24 h after surgery. Excellent postoperative pain relief was present in all groups. The highest pain scores were found in group I. The mean use of systemic morphine administered by PCA infusion pump was: 23.7 mg, 17.8 mg, 10.9 mg and 9.9 mg, in group I, II, III, and IV, respectively (p<0.01, group III and IV versus group I).
We conclude that 0.1 mg intrathecal morphine is the optimal dose for pain relief after hip surgery with minimal side effects.
A second study evaluated the questions: firstly, to what extent do spinal opiates contribute to PONV (post operative nausea and vomiting); and, secondly, how effectively can metoclopramide reduce the incidence of PONV after intrathecal administration of morphine. All patients were scheduled to undergo major joint surgery of the lower limb.
The patients were allocated to three groups.
Group I (n=200): intrathecal anesthesia was induced by administration of 20 mg bupivacaine and 0.2 mg morphine. Group II (n=100): intrathecal anesthesia was induced using the same dosages and drugs for intrathecal anesthesia, but in addition systemic metoclopramide was injected in two doses of 20 mg. Finally, for patients in group III (n=100) intrathecal anesthesia was induced by the administration of 20 mg bupivacaine only.
The maximum PONV percentages were 41.1%, 32.7% and 37% in group I, II and III respectively. The consumption of antiemetics was similar in all groups. The number of patients who needed one or more additional antiemetics during the first 24 hours after surgery was 112 (56.6%), 57 (58%) and 60 (60%) in group I, II and III, respectively. Administration of metoclopramide did not reduce the overall incidence of PONV.
Our study shows no relationship between the use of 0.2 mg intrathecal morphine and the incidence of PONV during 24 hours postoperatively. The third study was designed to determine whether low doses of intrathecal morphine still result in itching and it evaluates the outcome of using standardized treatment with promethazine and - for intractable itch - naloxon. Patients (n=143) scheduled for total hip surgery were randomized to four double-blinded groups with a standardized bupivacaine dose but different doses of intrathecal morphine: group I, 0.025 mg; group II, 0.05 mg; group III, 0.1 mg; and, group IV, 0.2 mg (same patients as Chapter 3). The presence or absence of itching was noted every three hours for a twenty-four hour period. When requested by the patient, the standard procedure for treatment was initiated.
The incidence of itching was: Group I: 14.3%; Group II: 21.6%; Group III: 48.6%; and, Group IV: 61.7%. Itch was treated by administering promethazine intramuscularly in 2,9% (Group I); 8,1% (Group II); 10.8% (Group III); and, 8.9% (Group IV) respectively. Only in group IV there was 1 patient who needed naloxon to treat itching.
The incidence and severity of itching is a dose related side effect in the dose range of 0.025 – 0.2 mg of intrathecal morphine. Itching even occurs after the low doses of intrathecal morphine, but symptoms vanish after promethazine 25 mg intramuscularly.