Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants

Background. To investigate clinical variables such as gestationalage, sex, weight, the therapeutic regimens used and mechanicalventilation that might affect morphine requirements and plasmaconcentrations of morphine and its metabolites. Methods. In a double-blind study, neonates and infants stratifiedfor age [group I 0–4 weeks (neonates), group II     

Continuous naloxone infusion in paediatric patients with pruritus associated with epidural morphine

Pruritus is a common, troublesome complication of epidural morphine analgesia in children. This report describes the successful management of pruritus with a continuous naloxone infusion in 5 patients after 6 operations.     

Intrathecal morphine overdose during combined spinal-epidural block for Caesarean delivery

We describe a 25 mg intrathecal morphine overdose duringa combined spinal–epidural block for a Caesarean delivery.Naloxone infusion (5.24 mg over 24 h) was startedprior to the patient becoming symptomatic and almost immediatelyafter the overdose. Invasive therapeutics such as mechanicalventilation were avoided. Br J Anaesth 2002; 89: 925–7     

Pharmacodynamic modelling of the analgesic effects of piritramide in postoperative patients

Background: The concentration-effect relationship of piritramide, a synthetic opioid analgesic predominantly used for postoperative analgesia and analgosedation, has not been reported so far.
Methods: Twenty-four patients of both genders aged 58.1 (11.7) yr (mean (SD)) received inhalational anaesthesia for abdominal surgery. Postoperative pain was assessed with a visual analogue scale (VAS). Analgesia was provided with piritramide, infused at a rate of 7 μg kg^-1 min^-1 until analgesia was considered sufficient (VAS<25) or up to a maximum dose of 0.2 mg/kg. The plasma concentrations of piritramide were determined by gas chromatography. An inhibitory fractional sigmoid E_max-model was used to describe the relation between effect site concentration and perceived pain.
Results: The equilibration half-life between plasma and effect site concentrations (T_1/2(k_eo) was 16.8 min (median; range: 4.4–41.6 min). The steady-state plasma concentration required to produce 50% of maximum analgesia (EC₅₀) was 12.1 ng/ml (range: 2.9–29.8 ng/ml) and correlated with initial pain intensity. The slope factor γ was 1.9 (range: 0.5–6.1) and increased with age. Clinically relevant respiratory depression did not occur. Due to the relatively large equilibration half-life of the effect compartment, the context-sensitive half-time of the effect site concentrations after short-time administration (<2 h) clearly exceeded those of alfentanil, sufentanil, and fentanyl.
Conclusions: The analgesic effect of piritramide was adequately described by an inhibitory fractional E_max-model. In order to overcome the pronounced hysteresis, piritramide should initially be administered as an intravenous bolus of at least 5 mg.     

Autonomic effects of epidural and intravenous fentanyl

BACKGROUND: We tested the hypothesis that there is greater suppression ofautonomic reflexes during general anaesthesia when fentanylis administered epidurally than when it is given intravenously. METHODS: Ten volunteers were anaesthetized with desflurane. Noxious stimuliof variable intensity were then delivered by tetanic electricalstimuli. Heart rate, arterial pressure, and pupillary dilationin response to these stimuli defined nociception. Seven of thesevolunteers participated twice using a crossover design: theyreceived i.v. fentanyl on one study day and epidurally on theother. Autonomic responses to alternative tetanic stimuli atL4 and C5 dermatomes were measured every 5 min for 3 hafter fentanyl administration. RESULTS: After a brief redistribution period, plasma fentanyl concentrationswere virtually identical on both days. After stimulation ofthe L4 dermatome only, block of pupillary reflex dilation wasgreater by 47 (22)% after epidural fentanyl compared with i.v.fentanyl. Time to maximal depression of reflex dilation afterL4 stimulation was 41 (13) min. Arterial pressure and heartrate decreased after fentanyl by either route but there wereno differences observed between L4 and C5 stimulations. CONCLUSION: We conclude that during general anaesthesia, epidural fentanylenhances antinociception by a spinal mechanism which can bedetected by pupillary dilation but not by changes in arterialpressure or heart rate.     

Activation of electrocorticographic activity with remifentanil and alfentanil during neurosurgical excision of epileptogenic focus

Background. Opioids are known to stimulate surface electroencephalographicactivity in patients with temporal lobe epilepsy. The objectiveof the current study was to compare the electrocorticographicactivation effects of the newer short-acting opioid remifentanilwith those of alfentanil during epilepsy surgery under generalanaesthesia. Methods. Thirteen patients undergoing temporal lobe epilepsysurgery under general anaesthesia received alfentanil 30 µg kg^–1and remifentanil 1 µg kg^–1 as i.v. bolusesin sequence. The design was a randomized double-blind cross-overstudy. After opening the dura, electrocorticogram (ECoG) electrodecontact strips were placed over the temporal and supratemporalneocortex and depth electrodes were inserted in the amygdalaand hippocampus. Alfentanil 30 µg kg^–1or remifentanil 1 µg kg^–1 were administeredrandomly in a blinded fashion. The ECoG was recorded continuouslybefore and after the injection of each drug. The interictalepileptiform activity (spikes and sharp waves) above baselinewas analysed. Results. Both drugs increased epileptiform activity especiallythat recorded from depth electrodes in the temporal limbic structures.No epileptiform activity was recorded from the electrodes overlyingthe supratemporal neocortex before or after drug administration.The more potent activator was alfentanil, which caused an increasein activation from baseline of 99.8% compared with 67.4% forremifentanil. In addition, alfentanil activated the epileptiformactivity in 3 patients in which remifentanil had no effect.There were no changes in heart rate after the opioid boluses.Both remifentanil and alfentanil caused significant reductionsin blood pressure at 3 and 5 min after administration. Conclusion. We conclude that at the doses used in this study,alfentanil is the better opioid for intraoperative activationof the ECoG in neurosurgical patients undergoing resection ofa temporal lobe epileptic focus. This pharmacological activationof epileptiform activity assists in localizing and confirmingthe site of surgical excision. Neither alfentanil nor remifentanilactivated epileptiform activity in non-epileptic brain tissue. Br J Anaesth 2003; 91: 651–5     

Dextromethorphan and intrathecal morphine for analgesia after Caesarean section under spinal anaesthesia

Background. Dextromethorphan is an N-methyl-D-aspartic acidantagonist which can attenuate acute pain with few side-effects.In this prospective, randomized, double-blind study of dextromethorphanand intrathecal morphine, we investigated postoperative pain,pruritus, nausea and vomiting in women undergoing Caesareansection under spinal anaesthesia. Methods. Women were allocated randomly to one of six groups,to receive intrathecal morphine 0.05, 0.1 or 0.2 mg plusoral dextromethorphan 60 mg or placebo. Results. The addition of dextromethorphan did not reduce postoperativepain scores (P=0.83). Compared with women receiving intrathecalmorphine 0.05 mg, women receiving higher doses had a significantlyhigher incidence of nausea and vomiting [odds ratio for intrathecalmorphine 0.1 mg, 4.0 (95% confidence interval 1.2–14.1);for intrathecal morphine 0.2 mg, 7.9 (2.3–27.1)].Compared with women receiving intrathecal morphine 0.05 mg,women receiving higher doses also had a significantly higherincidence of pruritus [odds ratio for intrathecal morphine 0.1 mg,3.2 (95% confidence interval 1.3–8.2); for intrathecalmorphine 0.2 mg, 3.7 (1.4–9.5)]. Women receivingdextromethorphan had a lower incidence of nausea and vomiting[odds ratio 2.6 (1.1–6.3)]. Conclusions. Postoperative pain after Caesarean section underspinal anaesthesia was not reduced by the addition of oral dextromethorphanto a multimodal approach including intrathecal morphine. Br J Anaesth 2003; 90: 653–8     

Preventive effects of perioperative parecoxib on post-discectomy pain

BACKGROUND: Cyclooxygenase inhibitor treatment is viewed increasingly critical because of safety considerations, and there are several open questions on their optimal use. METHODS: In a randomized placebo-controlled study in 320 patients undergoing discectomy, we administered parecoxib 40 mg either perioperatively (before operation and after operation), after operation (first dose given in the evening after surgery), or before operation (single parecoxib dose given 45 min before surgery). We measured the main outcome variables: average pain score, morphine consumption, and opioid-related symptom distress at 25, 49, and 73 h after surgery. RESULTS: Perioperative parecoxib significantly (i) improved the pain score compared with both placebo and postoperative parecoxib, (ii) decreased morphine consumption, and (iii) reduced the opioid-related symptom distress score. Neither a single preoperative dose nor postoperative parecoxib (first dose given in the evening after surgery) significantly improved morphine's analgesic effectiveness. CONCLUSIONS: Perioperative parecoxib compared with postoperative parecoxib improves post-discectomy pain and results in a reduction in adverse effects associated with opioid therapy. Postoperative parecoxib, or a single pre-incisional parecoxib dose, does not significantly improve post-discectomy pain or opioid side-effects up to 3 days after surgery.     

Paediatric ventilatory effects of morphine and buprenorphine revisited

The study describes long term ventilatory effects of 50 or 100 μg·kg^-1 of morphine or 1.5 or 3.0 μg·kg^-1 of buprenorphine when given in repeated intravenous (i.v.) doses, in a double blind fashion, to achieve equal levels of analgesia after thoracotomy. The patients were 56 children, six months to six years of age. Ventilatory rate (VR) was measured over the 24 h study period, and arterial carbon dioxide tension (Paco₂) was measured on arrival in the Paediatric Intensive Care Unit (PICU) and at 1, 6, 12 and 18 h. In the buprenorphine groups VRs progressively decreased during the first 2 h and remained significantly lower (P < 0.05) than in the morphine groups for 7 h. For the rest of the study period there were no differences. The Paco₂ values did not differ significantly at any point. For safety, prolonged observation of children is needed after intravenous administration of buprenorphine to ensure the ventilatory rate has stabilized.     

Effect of epidural bupivacaine vs combined epidural bupivacaine and morphine on gastrointestinal function and pain after major gynaecological surgery

In a double-blind study, we investigated the effects of postoperativeepidural local anaesthetic, with or without addition of epiduralmorphine, on postoperative pain and gastrointestinal functionin patients scheduled for radical hysterectomy and pelvic lymphadenectomy.Forty patients were randomized into two study groups: 48-h postoperativeepidural 0.2% bupivacaine 8 ml h^–1 (bupi group)or 48-h postoperative epidural 0.2% bupivacaine/morphine 50µg at 4 ml h^–1 (bupi/morph group). Patients wereobserved for at least 96 h after surgery. No differencesin pain at rest, during cough or mobilization were observed.Patients in the bupi group requested a significant greater amountof supplementary analgesics, but times to first flatus and defaecationwere reduced compared with patients in the bupi/morph group.Itching was a significant problem in patients in the bupi/morphgroup. No differences in postoperative nausea and vomiting,mobilization or time to discharge from hospital were observedbetween groups. The addition of morphine to postoperative epiduralbupivacaine has only limited effect on pain relief and increasestime to normalization of gastrointestinal function. Br J Anaesth 2001; 87: 727–32     

Cross-tolerance between spinal neostigmine and morphine in the rat

Background. Direct or indirect acting cholinergic muscarinicagonists such as neostigmine, are potent antinociceptives whenadministered intrathecally (i.t.). This study examines whetherspinal neostigmine tolerance and cross-tolerance to spinal morphineoccurs. Methods. Rats (32/group) were implanted with miniosmotic pumpsdelivering either i.t. saline 1 µl h^–1 (S), morphine10 nmol µl^–1 h^–1 (M), or neostigmine 3 nmolµl^–1 h^–1 (N). Latencies (infrared thermalwithdrawal rear paw) were measured daily for 6 days after whichfour animals from each group were given one i.t. challenge doseof morphine (m) 0.1, 1, 10, or 100 nmol, or neostigmine (n)0.3, 3, 10, or 30 nmol. Results. Neostigmine and morphine-infused animals both developedtolerance to spinal neostigmine, but neostigmine-infused animalsshowed no significant cross-tolerance to spinal morphine; meanED₅₀ nmol (CI 95%) dose–response values were Sn 2.6 (1.9–3.5),Mn 15.6 (9.9–24.6)*, Nn 18.7 (11.7–29.8)*, Sm 0.7(0.4–1.1), Nm 1.2 (0.8–2.0), Mm 152 (50–461)*(*significance vs saline infused control group). Conclusion. Thus, unidirectional cross-tolerance from morphineto neostigmine was evident. Previous studies suggest morphinehas a cholinergic mechanism of action partially accounting forits antinociceptive effect, which may explain this observedunidirectional cross-tolerance. Br J Anaesth 2003; 91: 427–9     

Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and mu-opioid receptor deficient mice

Background. Morphine-6-glucuronide (M6G) is a metabolite ofmorphine with potent analgesic properties. The influence ofM6G on respiratory and antinociceptive responses was investigatedin mice lacking the µ-opioid receptor (MOR) and comparedwith morphine. Methods. Experiments were performed in mice lacking exon 2 ofthe MOR (n=18) and their wild type (WT) littermates (n=20).The influence of M6G and morphine on respiration was measuredusing whole body plethysmography during three elevations ofinspired carbon dioxide. Antinociception was assessed usingtail flick and hotplate tests. Results. In WT but not null mutant mice, a dose-dependent depressionof the slope of the ventilatory carbon dioxide response wasobserved after M6G and morphine. Similarly, both opioids weredevoid of antinociceptive effects in null mutant mice, but showedpotent dose-dependent analgesia in WT animals. Potency differencesbetween M6G and morphine in WT mice were of the same order ofmagnitude for analgesia and respiration. Conclusions. The data indicate that the desired (antinociceptive)and undesired (respiratory depression) effects of M6G and morphineare linked to the same gene product; that is the MOR. Otheropioid- and non-opioid-receptor systems may play a minor rolein the actions of M6Gs and morphine. The clinical implicationsof our findings are that any agent acting at the MOR will invariablycause (potent) analgesia in combination with (variable) respiratorydepression. Br J Anaesth 2003; 91: 862–70     

A comparison of caudal morphine given pre- or postsurgery for postoperative analgesia in children

Twenty-eight children (mean age 4.4 years) undergoing elective major upper-abdominal or thoracic surgery were randomly selected to receive caudal morphine 0.07 mg·kg^?1 in saline either before (Group One) or immediately after surgery (Group Two). Caudal morphine injection given prior to surgery significantly prolonged postoperative analgesia when compared to caudal morphine given immediately post-surgery. Ten out of 14 children in Group One required no further analgesia over the next 24 h compared to 3 out of 14 in Group Two. There was no detectable difference in ventilatory frequency or oxygen saturation and no clinically significant respiratory depression was recorded in either group. There was no nausea, vomiting or pruritus postoperatively, which was ascribed to the use of trimeprazine and droperidol premedication, however, 30% of patients required catheterization for urinary retention.     

A comparison of intramuscular tenoxicam with intramuscular morphine for pain relief following tonsillectomy in children

A double blind trial was conducted to evaluate the analgesic efficacy of intramuscular tenoxicam for pain relief following tonsillectomy in children. Fifty children, aged 3–10 years, were randomly allocated to receive intramuscular tenoxicam 0.75 mg·kg^?1 or intramuscular morphine sulphate 0.2 mg·kg^?1 after induction of anaesthesia. Although the tenoxicam group required significantly more postoperative morphine (mean 57.8 μg·kg^?1 compared with 26.9 μg·kg^?1, P=0.025), the total morphine dose was significantly reduced after tenoxicam (57.8 μg·kg^?1 compared with 226.9 ug·kg^?1, P<0.0001). There was no difference between the quality of analgesia after discharge from recovery. The incidence of postoperative vomiting was significantly reduced after tenoxicam (20%) compared with morphine (71%).     

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

Background. This study examines the evidence from publisheddata concerning the adverse respiratory and haemodynamic effectsof 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 forpublications concerned with the management of postoperativepain. Information relating to variables indicative of respiratorydepression and of hypotension was extracted from these studies.Over 800 original papers and reviews were identified. Of thesepapers, 212 fulfilled the inclusion criteria but only 165 providedusable data on adverse effects. Pooled data obtained from thesestudies, which represent the experience of a total of nearly20 000 patients, form the basis of this study. Results. There was considerable variability between studiesin the criteria used for defining respiratory depression andhypotension. The overall mean (95% CI) incidence of respiratorydepression 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 depressionvaried 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 incidenceof respiratory depression varied between 1.2 (0.7–1.9)and 11.5 (5.6–22.0)%, using hypoventilation and oxygendesaturation, respectively, as indicators. For epidural analgesia,the mean (95% CI) reported incidence of respiratory depressionvaried 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 hypotensionfor 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 theincidence of respiratory depression decreased over the period1980–99, the incidence of hypotension did not. Conclusions. Assuming a mixture of analgesic techniques, AcutePain 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 techniqueof less than 5%.     

Pre-emptive analgesic efficacy of tramadol compared with morphine after major abdominal surgery

Background. Studies of pre-emptive analgesia in humans haveshown conflicting results. This prospective, randomized, double-blind,controlled study was designed to test the hypothesis that areduction in postoperative morphine consumption can be achievedby tramadol administered after induction of anaesthesia. Methods. Ninety patients were allocated randomly to receivei.v. tramadol (1 mg kg^–1) (Group T), morphine(0.1 mg kg^–1) (Group M) or saline 2 ml(Group S) after induction of anaesthesia. At peritoneal closure,a standardized (0.1 mg kg^–1) morphine loadingdose was given to all patients for postoperative pain management.Patients were allowed to use a patient-controlled analgesia(PCA) device giving bolus doses of morphine 0.025 mg kg^–1.Discomfort, sedation, pain scores, cumulative morphine consumption,and side-effects were recorded at 1, 2, 6, 12 and 24 hafter the start of PCA. Results. There were no significant differences between groupsin mean pain, discomfort, and sedation scores at any study period.Cumulative morphine consumption was significantly lower in GroupM at 12 and 24 h after starting the PCA than in Group S.In Group T, it was lower only after 24 h (28% less in GroupM and 17% less in Group T; P<0.017). There were no significantdifferences in morphine consumption between Groups T and M. Conclusions. Tramadol (1 mg kg^–1), administeredafter induction of anaesthesia, offered equivalent postoperativepain relief, and similar recovery times and postoperative PCAmorphine consumption compared with giving morphine 0.1 mg kg^–1.These results also suggest that presurgical exposure to systemicopioid analgesia may not result in clinically significant benefits Br J Anaesth 2003; 91: 209–13     

Adjunctive analgesia with intravenous propacetamol does not reduce morphine-related adverse effects

Background. Propacetamol is widely used in the management ofpostoperative pain. It decreases morphine requirements but itseffect on the incidence of morphine-related adverse effectsremains unknown. Methods. Patients (550) were randomly assigned to receive propacetamolor a placebo over the first 24 h after operation in a blindedstudy. Intravenous morphine titration was performed, after whichmorphine was administered s.c. every 4 h according to theirpain score. Pain was assessed using a visual analogue scale(VAS). The primary end-point was the incidence of morphine-relatedadverse effects. The main secondary end-points were morphinerequirements and VAS score. Results. After morphine titration, the VAS score and the numberof patients with pain relief did not differ between groups.Morphine requirements were decreased in the propacetamol group(21 vs 14.5 mg, P<0.001) but the incidence of morphine-relatedadverse effects did not differ between groups (42 vs 46%, notsignificant). In patients with moderate pain (n=395), morphinerequirements decreased by 37% (P<0.001) and the percentageof patients requiring no morphine was greater (21 vs 8%, P=0.002)in the propacetamol group. In patients with severe pain (n=155),morphine requirements decreased by 18% (P=0.04) in the propacetamolgroup and the number of patients who did not require morphine(3 vs 8%) did not differ significantly. Conclusions. Although propacetamol induced a small morphine-sparingeffect, it did not change the incidence of morphine-relatedadverse effects in the postoperative period. Moreover, no benefitcould be demonstrated in patients with severe postoperativepain. Br J Anaesth 2003; 90: 314–19     

Characterization of pressor and visceromotor reflex responses to bladder distention in rats: sources of variability and effect of analgesics

PURPOSE: We assessed the usefulness of cardiovascular and visceromotor responses to bladder distention as measures of acute visceral nociception in rats by determining the reliability of these responses. MATERIALS AND METHODS: Halothane anesthetized male and female Sprague-Dawley rats were acutely instrumented with tracheal, jugular venous, carotid arterial and bladder cannulas. Wires were inserted into the abdominal musculature to enable myoelectrical activity measurement. Anesthesia was decreased until flexion reflexes were present. Repeat phasic and graded bladder distention was administered, and arterial blood pressure and abdominal electromyography activity were continuously monitored. We determined the effects of gender, vaginal smear estrous cycle stage and drug treatment on the measured responses. RESULTS: Bladder distention produced reliable pressor and visceromotor (abdominal contractile) responses. There was great inter-animal variability in response vigor but good reproducibility was noted within individual animals. During slow bladder filling bladder contractions were not noted at this level of anesthesia. Sex differences included a more vigorous reflex response in females than in males, which was most vigorous in females in proestrus. Repeat bladder distention led to increasingly vigorous pressor responses and the improved reliability of visceromotor responses. Intravenous morphine and lidocaine dose dependently inhibited the reflex responses. CONCLUSIONS: Pressor and visceromotor responses to bladder distention in halothane anesthetized rats are reliable measures of acute bladder nociception that may prove useful for analgesic screening and in studies of hormonal effects on nociception.