Tolerability of acute postoperative pain management: nausea, vomiting, sedation, pruritus, and urinary retention. Evidence from published data.

This review examines the evidence from published data concerning the tolerability (indicated by the incidence of nausea, vomiting, sedation, pruritus, and urinary retention), of three analgesic techniques after major surgery; intramuscular analgesia (i.m.), patient-controlled analgesia (PCA), and epidural analgesia. A MEDLINE search of publications concerned with the management of postoperative pain and these indicators identified over 800 original papers and reviews. Of these, data were extracted from 183 studies relating to postoperative nausea and vomiting, 89 relating to sedation, 166 relating to pruritus, and 94 relating to urinary retention, giving pooled data which represent a total of more than 100,000 patients. The overall mean (95% CI) incidence of nausea was 25.2 (19.3-32.1)% and of emesis was 20.2 (17.5-23.2)% for all three analgesic techniques. PCA was associated with the highest incidence of nausea but the emesis was unaffected by analgesic technique. There was considerable variability in the criteria used for defining sedation. The overall mean for mild sedation was 23.9 (23-24.8)% and for excessive sedation was 2.6 (2.3-2.8)% for all three analgesic techniques (significantly lower with epidural analgesia). The overall mean incidence of pruritus was 14.7 (11.9-18.1)% for all three analgesic techniques (lowest with i.m. analgesia). Urinary retention occurred in 23.0 (17.3-29.9)% of patients (highest with epidural analgesia). The incidence of nausea and excessive sedation decreased over the period 1980-99, but the incidence of vomiting, pruritus, and urinary retention did not. From these published data it is possible to set standards of care after major surgery for nausea 25%, vomiting 20%, minor sedation 24%, excessive sedation 2.6%, pruritus 14.7%, and urinary retention requiring catheterization 23%. Acute Pain Services should aim for incidences less than this standard of care.

Respiratory and haemodynamic effects of acute postoperative pain management: evidence from published data.

BACKGROUND: This study examines the evidence from published data concerning the adverse respiratory and haemodynamic effects of three analgesic techniques after major surgery; i.m. analgesia, patient-controlled analgesia (PCA), and epidural analgesia. METHODS: A MEDLINE search of the literature was conducted for publications concerned with the management of postoperative pain. Information relating to variables indicative of respiratory depression and of hypotension was extracted from these studies. Over 800 original papers and reviews were identified. Of these papers, 212 fulfilled the inclusion criteria but only 165 provided usable data on adverse effects. Pooled data obtained from these studies, which represent the experience of a total of nearly 20,000 patients, form the basis of this study. RESULTS: There was considerable variability between studies in the criteria used for defining respiratory depression and hypotension. The overall mean (95% CI) incidence of respiratory depression of the three analgesic techniques was: 0.3 (0.1-1.3)% using requirement for naloxone as an indicator; 1.1 (0.7-1.7)% using hypoventilation as an indicator; 3.3 (1.4-7.6)% using hypercarbia as an indicator; and 17.0 (10.2-26.9)% using oxygen desaturation as an indicator. For i.m. analgesia, the mean (95% CI) reported incidence of respiratory depression varied between 0.8 (0.2-2.5) and 37.0 (22.6-45.9)% using hypoventilation and oxygen desaturation, respectively, as indicators. For PCA, the mean (95% CI) reported incidence of respiratory depression varied between 1.2 (0.7-1.9) and 11.5 (5.6-22.0)%, using hypoventilation and oxygen desaturation, respectively, as indicators. For epidural analgesia, the mean (95% CI) reported incidence of respiratory depression varied between 1.1 (0.6-1.9) and 15.1 (5.6-34.8)%, using hypoventilation and oxygen desaturation, respectively, as indicators. The mean (95% CI) reported incidence of hypotension for i.m. analgesia was 3.8 (1.9-7.5)%, for PCA 0.4 (0.1-1.9)%, and for epidural analgesia 5.6 (3.0-10.2)%. Whereas the incidence of respiratory depression decreased over the period 1980-99, the incidence of hypotension did not. CONCLUSIONS: Assuming a mixture of analgesic techniques, Acute Pain Services should expect an incidence of respiratory depression, as defined by a low ventilatory frequency, of less than 1%, and an incidence of hypotension related to analgesic technique of less than 5%.

A pilot study of the effect of the Queen's Square external bladder stimulator on urinary retention after knee replacement surgery.

Postoperative urinary retention remains an important problem after major orthopaedic surgery and can increase morbidity. External vibration applied to the suprapubic region has improved bladder emptying and urinary symptoms in patients with neurogenic bladders. Forty-three patients undergoing elective major knee surgery were randomly assigned to receive either a Queen's Square bladder stimulator or placebo device for 24 h postoperatively. No statistically significant differences in rates of urinary retention could be demonstrated in the bladder stimulator group compared to the placebo group (41% and 33%, respectively). There were no differences between the two groups when analysed for prostatic symptoms, type and effectiveness of analgesia and fluid balance. We conclude that, while the Queen's Square external bladder stimulator may be effective in treating chronic urinary retention associated with a neurogenic bladder, it does not appear to be effective in preventing postoperative urinary retention.

Presacral neurolytic block for relief of pain from pelvic cancer: description and use of a CT-guided lateral approach.

A CT guided lateral approach for neurolysis of the presacral plexus is described for treatment of pelvic pain due to advanced cancer. The technique was evaluated in two patients with unrelieved pelvic and perineal pain. Other neurolytic techniques used to treat pelvic pain due to advanced cancer are reviewed with a discussion of benefits and potential side effects of this technique.

Effectiveness of acute postoperative pain management: I. Evidence from published data.

BACKGROUND: This review examines the evidence from published data concerning the incidence of moderate-severe and of severe pain after major surgery, with three analgesic techniques; intramuscular (i.m.) analgesia, patient controlled analgesia (PCA), and epidural analgesia. METHODS: A MEDLINE search of the literature was conducted for publications concerned with the management of postoperative pain. Over 800 original papers and reviews were identified. Of these 212 papers fulfilled the inclusion criteria but only 165 provided usable data on pain intensity and pain relief. Pooled data on pain scores obtained from these studies, which represent the experience of a total of nearly 20,000 patients, form the basis of this review. RESULTS: Different pain measurement tools provided comparable data. When considering a mixture of three analgesic techniques, the overall mean (95% CI) incidence of moderate-severe pain and of severe pain was 29.7 (26.4-33.0)% and 10.9 (8.4-13.4)%, respectively. The overall mean (95% CI) incidence of poor pain relief and of fair-to-poor pain relief was 3.5 (2.4-4.6)% and 19.4 (16.4-22.3)%, respectively. For i.m. analgesia the incidence of moderate-severe pain was 67.2 (58.1-76.2)% and that of severe pain was 29.1 (18.8-39.4)%. For PCA, the incidence of moderate-severe pain was 35.8 (31.4-40.2)% and that of severe pain was 10.4 (8.0-12.8)%. For epidural analgesia the incidence of moderate-severe pain was 20.9 (17.8-24.0)% and that of severe pain was 7.8 (6.1-9.5)%. The incidence of premature catheter dislodgement was 5.7 (4.0-7.4)%. Over the period 1973-1999 there has been a highly significant (P < 0.0001) reduction in the incidence of moderate-severe pain of 1.9 (1.1-2.7)% per year. CONCLUSIONS: These results suggest that the UK Audit Commission (1997) proposed standards of care might be unachievable using current analgesic techniques. The data may be useful in setting standards of care for Acute Pain Services.

Coeliac plexus block using computed tomography guidance.

Coeliac plexus blocks have been used successfully in the treatment of abdominal pain in advanced cancer and in benign chronic abdominal pain. However, concern remains about occasional potentially serious complications. One possible way to reduce the risks of this procedure may be to improve imaging during the procedure. We report a series of 38 coeliac plexus blocks carried out under computer tomographic (CT) guidance, mostly using the anterior approach. The technique is described. Effectiveness and side-effect rates were similar to other reported series. There were no major complications. Analysis of contrast spread would indicate that anterior preaortic or bilateral contrast spread is necessary to obtain pain relief. Our experience would indicate that routine CT guidance can be a simple aid to coeliac plexus block, and can be achieved easily in a district general hospital. Improved imaging allows accurate needle placement, while avoiding vital structures such as the aorta and pleura. Accurate placement may also allow the use of reduced volumes of neurolytic drugs.

Rehabilitation of chronic low back pain using continuous epidural analgesia.

PURPOSE: Physical rehabilitation is one of the major forms of treatment of chronic low back pain. The ability of some patients to cooperate is limited by pain. Since 1992 continuous epidural analgesia has been combined with a physical rehabilitation programme for patients with chronic low back pain who have been unable to make progress with conventional physical rehabilitation due to severity of pain. METHOD: This study reports a series of 46 consecutive patients with chronic back pain admitted over a 6 month period to a 5-day inpatient rehabilitation programme. A lumbar epidural catheter was inserted and bupivacaine 0.125% was infused at a rate that produced analgesia without sensory or motor deficit over a period of 5 days. An intensive mobilizing physiotherapy programme was instituted. Physical and psychological parameters were measured on day 1, after 1 week, after 1 month and after 1 year. RESULTS: Time to complete a 50 m walk, time from sitting to standing, and spinal flexion were improved at 1 week and 1 month, but only time to complete the walk remained improved at 1 year. In Goldberg's General Health Questionnaire 28 scores were improved for social dysfunction, somatic symptoms, anxiety and insomnia, and depression, at 1 week and 1 month but only social dysfunction remained improved at 1 year. Using a Visual Analogue Scale pain ratings were unaltered after 1 year. CONCLUSION: Continuous 5 day epidural analgesia combined with intensive physiotherapy may offer a means of initial rehabilitation of chronic low back pain. The initial benefit was most marked at 1 week, with benefit still evident after 1 month. However, the benefit decreased with time. This technique may be of value as part of a more comprehensive programme of physical and psychological rehabilitation.

Calcium channel antagonists prevent adaptive responses to ethanol.

Prolonged ethanol administration causes upregulation of dihydropyridine-sensitive binding sites, thought to represent neuronal calcium channels, and these channels appear to play an important role in ethanol physical dependence. Dihydropyridine calcium channel antagonists, when given chronically with ethanol, prevent the development of tolerance to ethanol and the ethanol withdrawal syndrome. The upregulation of binding sites for these compounds was also prevented. Epileptiform activity has been described in isolated hippocampal slices after chronic ethanol treatment in vivo. This was prevented, stereoselectively, by the dihydropyridine calcium channel antagonist, isradipine, that did not affect the hyperexcitability produced in control slices by the GABAA antagonist, bicuculline.

Does glycine antagonism underlie the excitatory effects of methohexitone and propofol?

We have investigated the pharmacological basis of CNS excitation that occurs in association with general anaesthesia in mice. Propofol produced sustained clonic movements during anaesthesia. Methohexitone produced intermittent non-rhythmic jerking during anaesthesia. Ethanol and pentobarbitone produced anaesthesia without associated clonic movements. Doses of all anaesthetic drugs were equipotent. Surface EEG recordings showed paroxysmal discharges consistent with interictal manifestations of cortical seizures with methohexitone or propofol, but not with ethanol or pentobarbitone. Strychnine, a glycine antagonist without effects on the cerebral cortex, and bicuculline, a GABAA antagonist with effects on the cerebral cortex, were used in doses that were equipotent-0.5 log units less than the ED10 for clonic convulsions. Strychnine potentiated both excitatory behaviour and EEG paroxysmal discharges when given with methohexitone or propofol, but not with ethanol or pentobarbitone. Bicuculline did not affect either behaviour or EEG with any of the anaesthetic drugs. Our data show that methohexitone and propofol produced CNS excitation, while pentobarbitone and ethanol did not. We propose that the pharmacological basis of this excitation may be glycine antagonism occurring in subcortical structures.

The effects of chronic treatment with the dihydropyridine, Bay K 8644, on hyperexcitability due to ethanol withdrawal, in vivo and in vitro.

1. The effects of chronic treatment with the dihydropyridine, Bay K 8644, were studied on the ethanol withdrawal syndrome, in vivo and in vitro. 2. Addition of racemic Bay K 8644 to the drinking mixture, throughout the chronic ethanol treatment, decreased the behavioural excitability seen during ethanol withdrawal in vivo. 3. All the signs of hyperexcitability in field potentials in the isolated hippocampal slice, caused by ethanol withdrawal, were decreased by the chronic administration of Bay K 8644. 4. These effects resembled those previously reported for chronic administration of calcium channel antagonists; racemic Bay K 8644 has both calcium channel activating and antagonist properties. 5. Measurement of brain levels of Bay K 8644 at the end of the chronic treatment showed that the compound reached micromolar concentrations during the treatment, but none could be detected in the tissues at the time of the above measurements. 6. It is possible that the results might be explained by predominance of the calcium channel antagonist properties of this compound, owing to the high central concentrations achieved during the treatment. Tolerance to the calcium channel activating properties of Bay K 8644 may also have occurred during the chronic treatment.

Chronic dihydropyridine treatment can reverse the behavioural consequences of and prevent adaptations to, chronic ethanol treatment.

1. Chronic treatment with the dihydropyridine calcium channel antagonist, nitrendipine, given concurrently with ethanol, prevented the ethanol withdrawal syndrome in mice, even though the chronic nitrendipine treatment was stopped 24 h or 48 h before the withdrawal testing. 2. This effect was seen in two strains of mice with different methods of ethanol administration. Nitrendipine was effective when given for two weeks but not after only two days' treatment. 3. Two other dihydropyridine calcium antagonists, nimodipine and PN 200-110, given chronically with ethanol, also prevented the withdrawal syndrome. The tests were again made 24 h after the last administration of dihydropyridine. 4. The chronic nitrendipine treatment also prevented the rise in the number of central dihydropyridine binding sites that occurs on chronic ethanol administration. 5. Chronic administration of nitrendipine alone did not cause any withdrawal behaviour. 6. Chronic nitrendipine treatment did not affect the seizure threshold to bicuculline in mice that were not given ethanol. 7. Whole brain concentration measurements showed that the effects were not due to residual nitrendipine in the CNS at the time of withdrawal testing or to differences in central ethanol concentrations during the treatment. 8. It is suggested that the results provide evidence for a functional role for dihydropyridine-sensitive calcium channels in ethanol dependence.

Differential interactions between benzodiazepines and the dihydropyridines, nitrendipine and Bay K 8644.

The effects of the dihydropyridine calcium antagonist, nitrendipine and the calcium channel activator, Bay K 8644, have been compared on the anaesthetic, ataxic and anticonvulsant effects of benzodiazepines. Possible interactions between the peripheral benzodiazepine receptor antagonist, PK11195, and the classical benzodiazepines were also examined. Nitrendipine considerably potentiated the anaesthetic effects of benzodiazepines and increased their ataxic effects but had no effect on the anticonvulsant actions. Clonazepam did not produce anaesthesia, at doses up to 1 g kg-1 or when given with nitrendipine. When given alone, nitrendipine did not cause general anaesthesia. Nitrendipine did not appear to alter the metabolism of midazolam. The calcium channel activator, Bay K 8644, reduced the anaesthetic potency of midazolam and, when given alone, produced ataxia. It did not significantly alter central concentrations of midazolam. The "peripheral" benzodiazepine antagonist, PK11195, did not affect the ataxic or anaesthetic actions of benzodiazepines. These results suggest that dihydropyridine-sensitive calcium channels may be more important to the general anaesthetic than to the anticonvulsant actions of benzodiazepines. The "peripheral" benzodiazepine site did not appear to play a role in either of these properties.

Nitrendipine decreases benzodiazepine withdrawal seizures but not the development of benzodiazepine tolerance or withdrawal signs.

1. The effects of the calcium channel blocking agent, nitrendipine, were studied on seizures in mice produced during withdrawal from chronic benzodiazepine treatment and on the development of tolerance to benzodiazepines. 2. Nitrendipine produced a dose-dependent decrease in seizure incidence, when seizures were produced by the partial inverse agonist FG7142 during withdrawal from seven days treatment with flurazepam. 3. Nitrendipine did not raise the seizure thresholds in naïve mice to the full inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), or to the gamma-aminobutyric acid (GABA) antagonist, bicuculline. 4. When given concurrently with flurazepam for seven days, nitrendipine did not affect the incidence of seizures during flurazepam withdrawal. 5. When given concurrently with the benzodiazepines, nitrendipine did not prevent the development of tolerance to midazolam general anaesthesia or tolerance to the ataxic actions of flurazepam or midazolam. 6. Chronic treatment with flurazepam for seven days did not affect the Kd or Bmax of [3H]-nimodipine binding in mouse whole brain or cerebral cortex. 7. These results with benzodiazepines are partially in contrast with those for ethanol, where nitrendipine not only decreased ethanol withdrawal seizures when given acutely, but also prevented the development of tolerance and withdrawal signs when given concurrently with ethanol. However, they do confirm the selectivity of nitrendipine for withdrawal-induced seizures.

Effects of N-methyl-D-aspartate on [Ca2+]i and the energy state in the brain by 19F- and 31P-nuclear magnetic resonance spectroscopy.

The effects of N-methyl-D-aspartate (NMDA) on the free intracellular Ca2+ concentration [( Ca2+]i) and the energy state in superfused cerebral cortical slices have been studied using 19F- and 31P-nuclear magnetic resonance spectroscopy. [Ca2+]i was measured using the calcium indicator 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid (5FBAPTA). NMDA (10 microM) in the absence of extracellular Mg2+ caused the expected rise in [Ca2+]i but produced an impairment of the energy state: the phosphocreatine (PCr) content was decreased by 42%, and the Pi/PCr ratio was increased by 55%. There was no detectable change in ATP or free intracellular Mg2+ concentration. Increasing the NMDA concentration in the superfusing medium to 100 or 400 microM caused no further increase in [Ca2+]i or further decrease in PCr content, but the Pi/PCr ratio continued to rise. The impairment of the energy state preceded the effect on [Ca2+]i, and these changes were irreversible on return to control conditions. Repeating the experiments in the presence of 1.2 mM extracellular Mg2+ resulted in similar changes in the energy state, with no change in [Ca2+]i. The possibilities that the effects were due to membrane depolarisation or to the presence of 5FBAPTA within the tissues were eliminated. The results suggest that low concentrations (10 microM) of NMDA produce an impaired energy state independent of the presence of extracellular Mg2+ and that the decreased energy state is not due to the changes in [Ca2+]i, which are seen only in the absence of extracellular Mg2+.

Use of 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid (5FBAPTA) in the measurement of free intracellular calcium in the brain by 19F-nuclear magnetic resonance spectroscopy.

We have applied the 19F-nuclear magnetic resonance (NMR) calcium indicator 1,2-bis(2-amino-5-fluoro-phenoxy)ethane-N,N,N',N'-tetraacetic acid (5FBAPTA) to the measurement of the free intracellular calcium concentration [( Ca2+]i) in superfused brain slices. A mean +/- SD control value of 380 +/- 71 nM (n = 18) was obtained at 37 degrees C using 2.4 mM extracellular Ca2+. Subcellular fractionation studies using [3H]5FBAPTA showed that after loading of its tetraacetoxymethyl ester, approximately 55% was de-esterified, with the other 45% remaining as the tetraester bound to membranes. Of the de-esterified 5FBAPTA, greater than 90% was in the cytosolic fractions, with less than 1% in the mitochondria or microsomes. The NMR-visible de-esterified 5FBAPTA slowly disappeared from the tissue with a t1/2 of 4 h. A time course after loading confirmed that the calculated [Ca2+]i was constant over a 5-h period, although the scatter of individual results was +/- 20%. The [Ca2+]i was increased by a high extracellular K+ concentration ([K+]e), by a low extracellular concentration of Na+, and by the calcium ionophore A23187. On recovery from high [K+]e, the [Ca2+]i "overshot" to values lower than the original control value. The [Ca2+]i was surpisingly resistant to changes in extracellular Ca2+ concentration.

Are changes in neuronal calcium channels involved in ethanol tolerance?

Effects on the development of tolerance to ethanol of concurrent administration of the dihydropyridine calcium channel antagonist, nitrendipine, were investigated. Ethanol tolerance was induced in rats by repeated i.p. injections and measured by performance on the rotarod apparatus. Concurrent injections of nitrendipine prevented the development of tolerance to the ataxic action of ethanol. A similar effect was seen with the calcium channel antagonist PN 200-110 on tolerance to the general anesthetic effects of ethanol in mice. As previously reported, chronic ethanol administration increased the number of dihydropyridine binding sites in rat cerebral cortex. This was also prevented by the nitrendipine treatment; repeated administration of both ethanol and nitrendipine caused a decrease in the number of binding sites. The effect of nitrendipine on the tolerance was not due to alterations in body temperature, changes in blood pressure, differences in brain ethanol concentrations or residual nitrendipine in the brain at the time of testing. The results suggest that alterations in dihydropyridine-sensitive calcium channels may be involved in the adaptations that occur on chronic treatment with ethanol.

Effects of "nitrendipine" on nitrous oxide anesthesia, tolerance, and physical dependence.

Studies with ethanol have indicated that dihydropyridine-sensitive calcium (Ca++) channels may be involved in the adaptation to prolonged exposure to ethanol. This study investigated the effects, in mice, of the dihydropyridine Ca++ antagonist, nitrendipine, on acute tolerance to nitrous oxide after 60 min exposure to anesthetizing concentrations, and also the withdrawal syndrome which occurred following removal from nitrous oxide. Control mice were anesthetized by nitrous oxide concentrations in the range 1.28-1.51 atmospheres. Nitrendipine 10, 50, and 100 mg.kg-1, i.p., produced a dose-dependent potentiation of nitrous oxide anesthesia (P less than 0.05 for nitrendipine 50 and 100 mg.kg-1). Tolerance to nitrous oxide anesthesia developed over 60 min (13% increase in ED50, P less than 0.05). Concurrent administration of nitrendipine at all doses prevented the development of nitrous oxide tolerance. After 60 min exposure to nitrous oxide 1-1.5 atmospheres, all control mice showed handling seizures. Nitrendipine diminished or prevented nitrous oxide withdrawal seizures, in a dose-dependent manner (P less than 0.05 for nitrendipine 50 and 100 mg.kg-1). These results support the importance of the role of dihydropyridine-sensitive Ca++ channels in the mechanism of tolerance and dependence to central depressant drugs. They also suggest that acute and chronic tolerance to sedative drug action may share some common pathways, and that tolerance and physical dependence may share a common mechanism through voltage-operated Ca++ channels.

Measurement of free intracellular calcium in the brain by 19F-nuclear magnetic resonance spectroscopy.

We report the first measurement of the free intracellular calcium level in an actively metabolising intact cerebral tissue preparation. To this end, we applied the recently developed 19F-nuclear magnetic resonance calcium chelator, 5,5'-F2-1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (5FBAPTA), in superfused cerebral cortical slices to give values for the intracellular Ca2+ concentration of 350 and 480 nM, at external calcium concentrations of 1.2 and 2.4 mM, respectively. Under both conditions, the intracellular Ca2+ concentration was increased by depolarisation using a high external K+ concentration. Interleaved 31P spectra showed that the presence of the 5FBAPTA had a deleterious effect on the metabolic state of the tissue with an external Ca2+ concentration of 1.2 mM, but normal viability was maintained using 2.4 mM.