Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability

Background. Codeine analgesia is wholly or mostly due to itsmetabolism to morphine by the cytochrome P450 enzyme CYP2D6,which shows significant genetic variation in activity. The aimsof this study were to investigate genotype, phenotype and morphineproduction from codeine in children undergoing adenotonsillectomy,and to compare analgesia from codeine or morphine combined withdiclofenac. Methods. Ninety-six children received either codeine 1.5 mg kg^–1or morphine 0.15 mg kg^–1 in a randomized, double-blinddesign. Genetic analysis was performed and plasma morphine concentrationsat 1 h were determined. Postoperative analgesia and side-effectswere recorded. Results. Forty-seven per cent of children had genotypes associatedwith reduced enzyme activity. Mean (SD) morphine concentrationswere significantly lower (P<0.001) after codeine [4.5 (0.3)ng ml^–1] than after morphine [24.7 (1.5) ng ml^–1],and morphine and its metabolites were not detected in 36% ofchildren given codeine. There was a significant relationshipbetween phenotype and plasma morphine (P=0.02). More childrenrequired rescue analgesia after codeine at both 2 (P<0.05)and 4 h after administration (P<0.01). Fifty-six per centof children vomited after morphine and 29% after codeine (P<0.01).Neither phenotype nor morphine concentration was correlatedwith either pain score or the need for rescue analgesia (r=–0.21,95% confidence interval –0.4, –0.01). Conclusions. Reduced ability for codeine metabolism may be morecommon than previously reported. Plasma morphine concentration1 h after codeine is very low, and related to phenotype.Codeine analgesia is less reliable than morphine, but was notwell correlated with either phenotype or plasma morphine inthis study. Br J Anaesth 2002; 89: 839–45     

The effect of epidural sufentanil in ropivacaine on urinary retention in patients undergoing gastrectomy

Background. Although epidural opioids have excellent analgesicproperty, their side-effects limit its use in patient-controlledepidural analgesia (PCEA). This study was designed to compareside-effects of epidural sufentanil in ropivacaine with thatof morphine in ropivacaine focusing on lower urinary tract functionafter major abdominal surgery. Methods. In total 60 patients undergoing gastrectomy were randomlyallocated to receive either sufentanil in ropivacaine (GroupS, n=30) or morphine in ropivacaine (Group M, n=30) for theirPCEA. Epidural catheter was inserted between the 7th and 8ththoracic spine. Visual analogue pain score and side-effectssuch as nausea, vomiting, pruritus, hypotension and urinaryretention were evaluated during postoperative days (PODs) 1and 2 in the postanaesthetic care unit. Results. The incidence of serious to major micturition problemin Group S was lower than that in Group M (P<0.001). Theincidence of pruritus, nausea and vomiting was also lower inGroup S than in Group M on POD 1. Conclusions. The lower incidence of major/serious micturitionproblem in patients receiving sufentanil in ropivacaine thoracicepidural analgesia suggests that continuation of urinary drainagemay not be necessary from POD 1 onwards.     

The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception.

N-methyl-D-aspartate receptor antagonism probably accounts for most of ketamine's anesthetic effects; its analgesic properties are mediated partly via N-methyl-D-aspartate and partly via opioid receptors. We assessed the involvement of the mu-opioid receptor in S(+) ketamine-induced respiratory depression and antinociception by performing dose-response curves in exon 2 mu-opioid receptor knockout mice (MOR(-/-)) and their wild-type littermates (WT). The ventilatory response to increases in inspired CO(2) was measured with whole body plethysmography. Two antinociceptive assays were used: the tail-immersion test and the hotplate test. S(+) ketamine (0, 10, 100, and 200 mg/kg intraperitoneally) caused a dose-dependent respiratory depression in both genotypes, with greater depression observed in WT relative to MOR(-/-) mice. At 200 mg/kg, S(+) ketamine reduced the slope of the hypercapnic ventilatory response by 93% +/- 15% and 49% +/- 6% in WT and MOR(-/-) mice, respectively (P < 0.001). In both genotypes, S(+) ketamine produced a dose-dependent increase in latencies in the hotplate test, with latencies in MOR(-/-) mice smaller compared with those in WT animals (P < 0.05). In contrast to WT mice, MOR(-/-) mice displayed no ketamine-induced antinociception in the tail-immersion test. These results indicate that at supraspinal sites S(+) ketamine interacts with the mu-opioid system. This interaction contributes significantly to S(+) ketamine-induced respiratory depression and supraspinal antinociception. IMPLICATIONS: The involvement of the mu-opioid receptor system in S(+) ketamine-induced respiratory depression and spinal and supraspinal analgesia was demonstrated by performing experiments in mice lacking the mu-opioid receptor and in mice with intact mu-opioid receptors.     

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     

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     

Comparison of intrathecal isobaric bupivacaine-morphine and ropivacaine-morphine for Caesarean delivery

Background. This study was designed to evaluate the effectsof intrathecal isobaric bupivacaine 0.5% plus morphine and isobaricropivacaine 0.5% plus morphine combinations in women undergoingCaesarean deliveries. Method. Twenty-five parturients received ropivacaine 15 mg andmorphine 150 µg (RM group) and twenty-five parturientsreceived bupivacaine 15 mg and morphine 150 µg (BM group)for spinal anaesthesia. Sensory and motor block, haemodynamics,postoperative analgesia, fetal outcomes, and side-effects wereevaluated. Results. Intrathecal bupivacaine–morphine and ropivacaine–morphineprovided effective sensory anaesthesia and motor block. Timeto reach complete motor block was shorter and time to completerecovery from motor block was longer in the BM group than theRM group (P<0.05). The time to regression of two dermatomesand time for the block to recede to the S2 dermatome were similarin both groups (P>0.05). Time to first complaint of painand the mean total consumption of tenoxicam were similar inboth groups (P>0.05). APGAR scores at 1 and 5 min were similarin the two groups, as were mean umbilical blood pH values (P>0.05).Hypotension and pruritus were the most common side-effects inboth groups during the operation. Conclusion. Intrathecal isobaric ropivacaine 0.5% 15 mg plusmorphine 150 µg provides sufficient anaesthesia for Caesareandelivery. The ropivacaine–morphine combination resultedin shorter motor block, similar sensory and postoperative analgesia. Br J Anaesth 2003; 90: 659–64     

Epidural versus intrathecal morphine for postoperative analgesia after Caesarean section

Background. Perispinal anaesthesia for Caesarean section allowsinjection of epidural (ED) or intrathecal (i.t.) morphine toprovide long-lasting postoperative analgesia. To compare thesetwo routes, a prospective, randomized, double-blinded studyof 53 patients undergoing elective Caesarean section was performed. Methods. Combined spinal-epidural anaesthesia with 6 mg of i.t.hyperbaric bupivacaine plus sufentanil 5 µg, and additionalED lidocaine was used. Additionally, each patient received either2 mg (2 ml) of ED morphine plus 1 ml of i.t. normal saline (EDgroup, n=28), or 0.075 mg (1 ml) of i.t. morphine plus 2 mlof ED normal saline (i.t. group, n=25). Additional postoperativeanalgesia was given in the form of propacetamol and ketoprofen,plus self-administered i.v. morphine. Results. No major respiratory depression occurred. Time to firstdemand of morphine was similar in the ED (307.5 min) and i.t.(310 min) groups, as was the incidence of side-effects suchas sedation, pruritis, nausea, and vomiting. During the first24 postoperative hours, VAS pain scores were greater in thei.t. group (P=0.032), as was additional morphine consumption(4 vs 1.5 mg) (P=0.03). Conclusions. The ED protocol was more effective than the i.t.protocol, whilst side-effects were similar. Br J Anaesth 2003; 91: 690–4     

Effect of intrathecal tramadol administration on postoperative pain after transurethral resection of prostate

Background. Tramadol administered epidurally has been demonstratedto decrease postoperative analgesic requirements. However, itseffect on postoperative analgesia after intrathecal administrationhas not yet been studied. In this double-blind, placebo-controlledstudy, the effect of intrathecal tramadol administration onpain control after transurethral resection of the prostate (TURP)was studied. Methods. Sixty-four patients undergoing TURP were randomizedto receive bupivacaine 0.5% 3 ml intrathecally premixed witheither tramadol 25 mg or saline 0.5 ml. After operation, morphine5 mg i.m. every 3 h was administered as needed for analgesia.Postoperative morphine requirements, visual analogue scale forpain at rest (VAS) and sedation scores, times to first analgesicand hospital lengths of stay were recorded by a blinded observer. Results. There were no differences between the groups with regardto postoperative morphine requirements (mean (SD): 10.6 (7.9)vs 9.1 (5.5) mg, P=0.38), VAS (1.6 (1.2) vs 1.2 (0.8), P=0.18)and sedation scores (1.2 (0.3) vs 1.2 (0.2), P=0.89). Timesto first analgesic (6.3 (6.3) vs 7.6 (6.2) h, P=0.42) and lengthof hospital stay (4.7 (2.8) vs 4.4 (2.2) days, P=0.66) weresimilar in the two groups. Conclusion. Intrathecal tramadol was not different from salinein its effect on postoperative morphine requirements after TURP. Br J Anaesth 2003; 91: 536–40     

Is morphine-induced sedation synonymous with analgesia during intravenous morphine titration?

Background. Postoperative morphine titration frequently inducessedation. The assumption is made that patients sleep when theirpain is relieved. Some patients complain of persistent painwhen they awake. We studied the time-course of sedation andanalgesia to understand the determinants of patients’sleep during morphine titration. Methods. Seventy-three patients requiring morphine titrationin a post-anaesthetic care unit after major surgery, were studied.Fifty-two patients slept (Sleep group) and 21 did not (Awakegroup). When a patient slept during titration, morphine wasdiscontinued. Visual analogue pain scale (VAS), Ramsay score(RS), and the bispectral index (BIS) were recorded at the beginningof titration (STonset), at sleep onset (STsleep), then 5, 10,20, and 30 min afterwards (ST4). Results. In the Sleep group, mean (SD) RS increased from 1.7(0.4) to 2.4 (0.6) (P<0.05 vs STonset) and BIS decreasedfrom 95 (5.0) to 89.8 (10.2) between STonset and STsleep (P<0.05),RS remained stable thereafter. Conversely, RS and BIS remainedunaltered in the Awake group. The reduction in VAS was comparablebetween groups (from 78 (17) to 39 (21), and from 64 (16) to30.4 (11), respectively). Even though mean (SD) VAS was 39 (21)at ST4 in the Sleep group, 13 patients (25%) maintained a VASabove 50 mm. Conclusion. We observed dissociated effects of morphine on thetime-course of sedation and analgesia with sedation occurringfirst, followed by analgesia. Therefore, morphine-induced sedationshould not be considered as an indicator of an appropriate correctlevel of analgesia during i.v. morphine titration. Br J Anaesth 2002; 89: 697–701     

Emetic effects of morphine and piritramide

Background. Successful management of postoperative pain requiresthat adequate analgesia is achieved without excessive adverseeffects. Opioid-induced nausea and vomiting is known to impairpatients’ satisfaction, but there are no studies providingsufficient power to test the hypothesis that the incidence ofopioid-induced nausea and vomiting differs between µ-opioidreceptor agonists. Thus, we tested the hypothesis that the incidenceof vomiting and nausea differs between morphine and piritramide. Methods. In a prospective, randomized, double-blind fashion,we administered either morphine (n=250) or piritramide (n=250)by patient-controlled analgesia (PCA) for postoperative painrelief. We used a bolus dose of 1.5 mg with a lockout time of10 min. Incidence and intensity (numerical rating scale) ofpostoperative nausea, vomiting, pain, patient satisfaction (score0–10), side-effects (score 0–3) and drug consumptionwere measured. Results. Mean drug consumption did not differ between the piritramideand morphine groups (30.8 (SD 22.4) mg day^–1 vs 28.4 (21.8)mg day^–1) during the first postoperative day and therewere no significant differences in the overall incidence ofnausea (30% vs 27%) and vomiting (19% vs 15%). Intensity ofnausea correlated inversely (P=0.01) with morphine consumptionbut not with piritramide consumption. Pain scores both at rest(2.2 (1.9) vs 2.6 (2)) and during movement (4.4 (2.2) vs 4.9(2.3)) were slightly but significantly less with morphine. Conclusions. Opioid-induced emesis was observed in about one-thirdof the patients using morphine and piritramide for PCA and theincidence of vomiting was one-half of that. Potential differencesin the incidence of vomiting during PCA therapy between theseµ-opioid receptor agonists can be excluded. Br J Anaesth 2003; 91: 218–23     

Effects of a loading dose of morphine before i.v. morphine titration for postoperative pain relief: a randomized, double-blind, placebo-control study

Background. I.V. morphine titration (MT) allows adjustment ofthe dose needed for pain relief in the post-anaesthesia careunit (PACU). However, MT has limitations such as a delay toachieve pain relief. We thus assessed the effect of a fixedintraoperative loading dose of morphine administered beforetitration. Methods. One hundred patients who were undergoing major orthopaedicsurgery were included in a double-blind, randomized study comparinga loading dose of morphine (0.15 mg kg^–1) with placeboadministered intraoperatively. MT was then administered in thePACU followed by patient-controlled analgesia (PCA) over 24h. Data are expressed as mean (SD). Results. The initial VAS [41 (36) vs 52 (35), NS] was not decreasedin the morphine group. The VAS was lower in the morphine groupin the PACU and PCA periods. The time to achieve effective painrelief was not decreased in the morphine group. The total doseof morphine administered in the PACU (including the loadingdose) was significantly increased in the morphine group (+31%in mg kg^–1, P<0.05). Morphine requirements during thePCA period were not different between groups. The incidenceof sedation was increased and a severe episode of ventilatorydepression occurred in the morphine group. Conclusions. A loading dose of morphine administered at theend of surgery slightly decreased the VAS but did not reducethe time to pain relief or morphine consumption within the first24 h. This slight improvement in analgesia was obtained at theexpense of morphine-related adverse events.     

Intrathecal morphine and clonidine for coronary artery bypass grafting

Background. After cardiac surgery adequate postoperative analgesiais necessary. We assessed analgesia using intrathecal morphineand clonidine. Methods. In a double-blind randomized study, 45 patients havingcoronary artery bypass graft surgery were allocated randomlyto receive i.v. patient-controlled analgesia (PCA) morphine(bolus, 1 mg; lock-out interval, 7 min) (control group), eitheralone or combined with intrathecal morphine 4 µg kg^–1or with both intrathecal morphine 4 µg kg^–1and clonidine 1 µg kg^–1. Intrathecal injectionswere performed before the induction of general anaesthesia.Pain was measured after surgery using a visual analogue scale(VAS). We recorded i.v. PCA morphine consumption during the24 h after operation. Results. Morphine dosage [median (25th–75th percentiles)]was less in the first 24 h in the patients who were given intrathecalmorphine + clonidine [7 (0–37) mg] than in other patients[40.5 (15–61.5) mg in the intrathecal morphine group and37 (30.5–51) mg in the i.v. morphine group]. VAS scoreswere lower after intrathecal morphine + clonidine compared withthe control group. Time to extubation was less after intrathecalmorphine + clonidine compared with the i.v. morphine group [225(195–330) vs 330 (300–360) min, P<0.05]. Conclusion. Intrathecal morphine and clonidine provide effectiveanalgesia after coronary artery bypass graft surgery and allowearlier extubation. Br J Anaesth 2003; 90: 300–3     

Randomized prospective study of the analgesic effect of nefopam after orthopaedic surgery

Background. Balanced postoperative analgesia combines non-narcoticdrugs and opioids. We organized a large study to evaluate nefopamanalgesia and tolerance in combination with morphine for patient-controlledanalgesia (PCA) after orthopaedic surgery. Methods. Two hundred and one patients scheduled to undergo hiparthroplasty were included in this multicentre (n=24), double-blind,randomized study comparing nefopam (20 mg every 4 h for 24 h)with placebo, the first dose being infused peroperatively. Theprimary outcome measure was the cumulative morphine dose receivedpostoperatively by PCA over 24 h. Secondary outcome measureswere the amount of morphine received as a loading dose in thepostanaesthesia care unit (PACU) and during the 24-h observationperiod, and pain assessments using a visual analogue scale (VAS)and a verbal pain scale (VPS), patient’s satisfactionwith analgesia and treatment tolerance. Results. The two groups were comparable with respect to theircharacteristics and preoperative pain assessment. PCA-administeredmorphine over 24 h was significantly less for the nefopam groupthan the control group (21.2 (15.3) and 27.3 (19.2) mg respectively;P=0.02). This morphine-sparing effect was greater (35.1%) forpatients with severe preoperative pain (VAS>30/100). Forthe entire study period (loading dose and PCA), morphine usewas less for the nefopam group (34.5 (19.6) vs 42.7 (23.6) mg;P=0.01). Pain VAS at PACU arrival and during the whole PACUperiod was significantly lower for the nefopam than for theplacebo group (P=0.002 and 0.04 respectively). Patient satisfactionwas similar for the nefopam and placebo groups. Conclusion. In combination with PCA morphine, nefopam givessignificant morphine-sparing with lower immediate postoperativepain scores without major side-effects. This analgesic effectseems to be particularly notable for patients with intense preoperativepain. Br J Anaesth 2003; 91: 836–41     

Epinephrine and clonidine do not improve intrathecal sufentanil analgesia after total hip replacement

Background. We compared analgesia after intrathecal sufentanilalone, sufentanil with epinephrine 200 µg and sufentanilwith clonidine 30 µg in patients after total hip replacement,the endpoints being onset and duration of action. Methods. We performed a randomized double-blind study of 45patients for elective total hip arthroplasty using continuousspinal anaesthesia. As soon as a pain score higher than 3 ona 10 cm visual analogue scale was reported, sufentanil 7.5 µgalone, sufentanil 7.5 µg + epinephrine 200 µg orsufentanil 7.5 µg + clonidine 30 µg in 2 ml normalsaline was given intrathecally. Pain scores, rescue analgesia(diclofenac and morphine) and adverse effects (respiratory depression,postoperative nausea and vomiting, itching) were observed for24 h after surgery. Results. Time to a pain score of <3 [6 (SD 1) vs 6 (1) vs5 (1) min], time to the lowest pain score [7 (2) vs 8 (2) vs8 (2) min] and time to the first dose of systemic analgesicfor a pain score >3 [281 (36) vs 288 (23) vs 305 (30) min]were similar in all three groups. Adverse effects and analgesicrequirements during the first 24 h were also similar. Conclusion. After total hip replacement, all three analgesicregimens gave good analgesia with comparable onset and durationof action, and minor adverse effects. Br J Anaesth 2002; 89: 562–6     

Heritable differences in respiratory drive and breathing pattern in mice during anaesthesia and emergence

Background. Postanaesthetic hypoxia and ischaemia can lead topostoperative morbidity and mortality. We studied the effectof isoflurane anaesthesia in two inbred mouse strains knownfor phenotypic differences in breathing pattern and respiratorydrive during carbon dioxide challenge and their first-generationoffspring (F₁). Methods. Using whole body plethysmography, we assessed respiratoryrate (RR) and pressure amplitude (Amp) in male B6 (high responderto hypercapnia), C3 (low responder), and F₁ mice at rest, duringanaesthesia with isoflurane, and during recovery from anaesthesia.At each time point, the magnitude and pattern of breathing weredetermined during hypercapnic challenge (FI_CO2 = 0.08).Data (mean (SD)) were analysed by generalized ANOVA with posthoc Bonferroni’s correction (P<0.05). Results. During isoflurane anaesthesia, strain differences betweenB6 and C3 mice in RR were obscured while differences in Amppersisted. In contrast to baseline RR responses to carbon dioxidewere significantly reduced at 0.5 MAC (increase in RR: 175 (33)bpm, 147 (44) bpm, 127 (33) bpm, for B6, C3, and F₁ strainsrespectively) and completely blocked at 1.5 MAC (change in RR:–3 (10) bpm, –2 (1) bpm, –4 (5) bpm, for B6,C3, and F₁ strains, respectively). During recovery, B6 miceshowed a significant increase in RR (77 (33) bpm; P<0.0001)as well as in Amp. This was not observed in either C3 (–22(31) bpm) or F₁ mice (23 (51) bpm). Conclusion. Isoflurane anaesthesia abolished the strain differencesin respiratory drive between B6, C3, and F₁ mice. However, duringrecovery from anaesthesia, significant strain variation in respiratorydrive reappeared and was more pronounced compared with pre-anaestheticlevels. These results suggested, that genetic differences mayhave minimal contribution to decreased respiratory drive duringanaesthesia, but may be a major risk factor for post-operativehypoventilation and the associated morbidity and mortality. Br J Anaesth 2003; 91: 541–5     

Prevention of postoperative nausea and vomiting after spinal morphine for Caesarean section: comparison of cyclizine,dexamethasone and placebo

Background. Low-dose intrathecal (spinal) morphine (0.1–0.2mg) for Caesarean section delivers excellent postoperative analgesiabut is associated with significant nausea and vomiting. We comparedthe antiemetic efficacy of cyclizine, dexamethasone, and placeboin this clinical setting. Methods. Ninety-nine women undergoing elective Caesarean sectionunder spinal anaesthesia were allocated randomly, in a double-blindstudy design, to receive either cyclizine 50 mg, dexamethasone8 mg, or placebo as a single-dose infusion in saline 0.9%, 100ml on completion of surgery. Spinal anaesthesia consisted of:hyperbaric bupivacaine 0.5%, 2.0 ml; fentanyl 10 µg; andspinal morphine 0.2 mg. The primary outcome measure was theincidence of nausea. Results. The incidence of nausea was significantly less in patientsreceiving cyclizine compared with dexamethasone and placebo(33 vs 60 and 67%, respectively, P<0.05). Severity of nauseaand number of vomiting episodes were also less at 3–6h in cyclizine patients. Overall satisfaction with postoperativecare at 24 h, expressed on a 100 mm visual analogue scale, wasgreater in cyclizine [78 (28)] than either dexamethasone [58(31), P=0.03] or placebo [51 (28), P=0.008]. Conclusion. We conclude that following spinal morphine 0.2 mgand fentanyl 10 µg analgesia for Caesarean section, cyclizine50 mg i.v. reduces the incidence of nausea compared with dexamethasone8 mg i.v. or placebo. It also lessens the severity of nauseaand vomiting, and increases maternal satisfaction in the earlypostoperative period. Br J Anaesth 2003; 90: 665–70     

Parecoxib sodium has opioid-sparing effects in patients undergoing total knee arthroplasty under spinal anaesthesia

Background. This multicentre, double-blind, placebo-controlledstudy compared the opioid-sparing effectiveness and clinicalsafety of parecoxib sodium over 48 h, in 195 postoperativepatients after routine total knee replacement surgery. Methods. Elective total primary knee arthroplasty was performedunder spinal anaesthesia, with a single dose of spinal bupivacaine10–20 mg, and intraoperative sedation with midazolam0.5–1.0 mg i.v., or propofol <6 mg kg^–1h^–1. Patients were randomized to receive either parecoxibsodium 20 mg twice daily (bd) i.v. (n=65), parecoxib sodium40 mg bd i.v. (n=67), or placebo (n=63) at the completionof surgery, and after 12, 24, and 36 h. Morphine (1–2 mg)was taken by patient-controlled analgesia or by bolus dosesafter 30 min. Results. Patients receiving parecoxib sodium 20 mg bd and40 mg bd consumed 15.6% and 27.8% less morphine at 24 hthan patients taking placebo (both P<0.05). Both doses ofparecoxib sodium administered with morphine provided significantlygreater pain relief than morphine alone from 6 h (P<0.05).A global evaluation of study medication demonstrated a greaterlevel of satisfaction among patients taking parecoxib sodiumthan those taking placebo. Parecoxib sodium administered incombination with morphine was well tolerated. However, a reductionin opioid-type side-effects was not demonstrated in the parecoxibsodium groups. Conclusion. Parecoxib sodium provides opioid-sparing analgesiceffects in postoperative patients. Br J Anaesth 2003; 90: 166–72     

Electrophysiological effects of morphine in an in vitro model of the 'border zone' between normal and ischaemic-reperfused guinea-pig myocardium

Background. Morphine is commonly used in clinical practice inpain management. Although morphine has been shown to preconditionthe myocardium, its effects on action potential parameters andischaemia–reperfusion-induced arrhythmias and conductionblocks remain unknown. Methods. In a double-chamber bath, guinea-pig right ventricularmuscle strips were subjected partly to normal conditions andpartly to 30 min of simulated ischaemia (hypoxia, hyperkalaemia,acidosis, and lack of nutritional substrate) followed by 30 minof reperfusion. Action potential parameters were recorded continuouslyin the normal zone and in the ischaemic– reperfused zone.Spontaneous arrhythmias and conduction blocks were noted. Theelectro physiological effects of morphine were studied at 0.01and 0.1 µM. Results. In control conditions, morphine did not modify actionpotential parameters of resting membrane potential, maximalupstroke velocity (V_max), action potential amplitude (APA) andaction potential duration at 50 and 90% of repolarization. Morphinereduced ischaemia-induced depolarization and lessened the ischaemia-induceddecrease in APA and V_max. Morphine significantly decreased theoccurrence of conduction block during simulated ischaemia (20%at 0.01 and 0.1 µM vs 67% in the control group, P<0.05)and reperfusion-induced arrhythmias (40% at 0.01 µMand 30% at 0.1 µM vs 92% in the control group, P<0.05). Conclusions. In ischaemic–reperfused guinea-pig myocardium,morphine at clinically relevant concentrations decreased ischaemia-inducedconduction blocks and reperfusion-induced ventricular arrhythmias. Br J Anaesth 2002; 89: 888–95     

Pharmacokinetics and efficacy of ropivacaine continuous wound instillation after joint replacement surgery

Background. As continuous wound instillation with local anaesthetichas not been evaluated after hip/knee arthroplasties, our studywas designed to determine whether this technique could enhanceanalgesia and improve patient outcome after joint replacementsurgery. Methods. Thirty-seven patients undergoing elective hip/kneearthroplasties under spinal block were randomly assigned totwo analgesia groups. Group M received continuous i.v. infusionof morphine plus ketorolac for 24 h. Then, a multi-hole 16 Gcatheter was placed subcutaneously and infusion of saline wasmaintained for 55 h. Group R received i.v. saline. Thereafterthe wound was infiltrated with a solution of ropivacaine 0.5%40 ml, then a multi-hole 16 G catheter was placed subcutaneouslyand an infusion of ropivacaine 0.2% 5 ml h^–1 wasmaintained for 55 h. Visual analogue scale scores were assessedat rest and on passive mobilization by nurses blinded to analgesictreatment. Total plasma ropivacaine concentration was measured. Results. Group R showed a significant reduction in postoperativepain at rest and on mobilization, while rescue medication requirementswere greater in Group M. Total ropivacaine plasma concentrationremained below toxic concentrations and no adverse effects occurred.Length of hospital stay was shorter in Group R. Conclusion. Infiltration and wound instillation with ropivacaine0.2% is more effective in controlling postoperative pain thansystemic analgesia after major joint replacement surgery. Br J Anaesth 2003; 91: 830–5