Detection and identification of 2‐nitro‐morphine and 2‐nitro‐morphine‐6‐glucuronide in nitrite adulterated urine specimens containing morphine and its glucuronides

In vitro urine adulteration is a well‐documented practice adopted by individuals aiming to evade detection of drug use, when required to undergo mandatory sports and workplace drug testing. Potassium nitrite is an effective urine adulterant due to its oxidizing potential, and has been shown to mask the presence of many drugs of abuse. However, limited research has been conducted to understand its mechanism of action, and to explore the possibility of the drugs undergoing direct oxidation to form stable reaction products. In this study, opiates including morphine, codeine, morphine‐3‐glucuronide and morphine‐6‐glucuronide were exposed to potassium nitrite in water and urine to mimic the process of nitrite adulteration. It was found that two stable reaction products were detected by liquid chromatography‐mass spectrometry (LC‐MS) when morphine and morphine‐6‐glucuronide were exposed to nitrite. Isolation and elucidation using spectrometric and spectroscopic techniques revealed that they were 2‐nitro‐morphine and 2‐nitro‐morphine‐6‐glucuronide, respectively. These reaction products were also formed when an authentic morphine‐positive urine specimen was fortified with nitrite. 2‐Nitro‐morphine was found to be stable enough to undergo the enzymatic hydrolysis procedure and also detectable by gas chromatography‐mass spectrometry (GC‐MS) after forming a trimethylsilyl derivative. On the contrary, morphine‐3‐glucuronide did not appear to be chemically manipulated when exposed to potassium nitrite in urine. These reaction products are not endogenously produced, are relatively stable and can be monitored with both LC‐MS and GC‐MS confirmatory techniques. As a result, these findings have revealed the possibility for the use of 2‐nitro‐morphine and 2‐nitro‐morphine‐6‐glucuronide as markers for the indirect monitoring of morphine and morphine‐6‐glucuronide in urine specimens adulterated with nitrite. Copyright © 2013 John Wiley & Sons, Ltd.     

The Effect of Oral Morphine on Pain‐Related Brain Activation – An Experimental Functional Magnetic Resonance Imaging Study

Knowledge about cerebral mechanisms underlying pain perception and effect of analgesic drugs is important for developing methods for diagnosis and treatment of pain. The aim was to explore altered brain activation before and after morphine treatment using functional magnetic resonance imaging recorded during experimental painful heat stimulation. Functional magnetic resonance imaging data were recorded and analysed in 20 healthy volunteers (13 men and 7 women, 24.9 ± 2.6 years) in a randomized, double‐blind, placebo‐controlled, cross‐over study. Painful stimulations were applied to the right forearm using a contact heat evoked potential stimulator (CHEPS) before and after treatment with 30 mg oral morphine and placebo. CHEPS stimulations before treatment induced activation in the anterior cingulate cortex, secondary somatosensory cortex/insula, thalamus and cerebellum (n = 16, p < 0.05). In response to morphine treatment, the spatial extent of these pain‐specific areas decreased (n = 20). Reduced pain‐induced activation was seen in the right insula, anterior cingulate cortex and inferior parietal cortex after morphine treatment compared to before treatment (n = 16, p < 0.05), and sensory ratings of pain perception were significantly reduced after morphine treatment (p = 0.02). No effect on pain‐induced brain activation was seen after placebo treatment compared to before treatment (n = 12, p > 0.05). In conclusion, heat stimulation activated areas in the ‘pain matrix’ and a clinically relevant dose of orally administered morphine revealed significant changes in brain areas where opioidergic pathways are predominant. The method may be useful to investigate the mechanisms of analgesics.     

The ED95 of Nalbuphine in Outpatient‐Induced Abortion Compared to Equivalent Sufentanil

This prospective study evaluated the 95% effective dose (ED₉₅) of nalbuphine in inhibiting body movement during outpatient‐induced abortion and its clinical efficacy versus the equivalent of sufentanil. The study was divided into two parts. For the first part, voluntary first‐trimester patients who needed induced abortions were recruited to measure the ED₉₅ of nalbuphine in inhibiting body movement during induced abortion using the sequential method (the Dixon up‐and‐down method). In the second part, this was a double‐blind, randomized study. Sixty cases of first‐trimester patients were recruited and were randomly divided into two groups (n = 30), including group N (nalbuphine at the ED₉₅ dose) and group S (sufentanil at an equivalent dose). Propofol was given to both groups as the sedative. The circulation, respiration and body movement of the two groups in surgery were observed. The amount of propofol, the awakening time, the time to leave the hospital and the analgesic effect were recorded. The ED₉₅ of nalbuphine in inhibiting body movement during painless surgical abortion was 0.128 mg/kg (95% confidence intervals 0.098–0.483 mg/kg). Both nalbuphine and the equivalent dose of sufentanil provided a good intraoperative and post‐operative analgesic effect in outpatient‐induced abortion. However, the post‐operative morbidity of dizziness for nalbuphine was less than for sufentanil (p < 0.05), and the awakening time and the time to leave the hospital were significantly shorter than those of sufentanil (p < 0.05). Nalbuphine at 0.128 mg/kg was used in outpatient‐induced abortion as an intraoperative and post‐operative analgesic and showed a better effect compared with sufentanil.     

Synthesis of morphine‐[N‐methyl‐14C]‐6‐β‐D‐glucuronide

Protected morphine‐6‐glucuronide was converted into morphine‐[N‐methyl‐¹⁴C]‐6‐glucuronide by a three‐step procedure. Methyl (3‐pivaloylmorphin‐6‐yl 2,3,4‐tri‐O‐isobutyryl‐β‐D‐glucopyranosid)uronate was N‐demethylated by treatment with 1‐chloroethyl chloroformate to afford protected normorphine‐6‐glucuronide as its hydrochloride salt. The normorphine‐6‐glucuronide derivative was alkylated with iodomethane‐[¹⁴C] in the presence of potassium carbonate to produce C‐14 labelled protected morphine‐6‐glucuronide. Finally, hydrolysis of the protecting groups using 5% sodium hydroxide solution gave morphine‐[N‐methyl‐¹⁴C]‐6‐β‐D‐glucuronide with a specific activity of 41.8 mCi mmol^?1 and radiochemical purity of 99.2% (HPLC). Copyright © 2002 John Wiley & Sons, Ltd.     

Meta‐analysis: pre‐operative infliximab treatment and short‐term post‐operative complications in patients with ulcerative colitis

Aliment Pharmacol Ther 31 , 486–492

Summary

Background Infliximab was approved for use in ulcerative colitis in recent years. It has been debated if infliximab increases the risk of post‐operative complications in patients with ulcerative colitis. Aim To perform a meta‐analysis that examines the relationship between preoperative infliximab treatment and short‐term post‐operative complications in patients with ulcerative colitis. Methods We searched the PubMed and MEDLINE databases to identify observational studies on the impact of pre‐operative infliximab use on short‐term post‐operative complications in ulcerative colitis. Infectious complications mainly included wound infection, sepsis and abscess, whereas non‐infectious complications included intestinal obstruction, thromboembolism and gastrointestinal haemorrhage. Pooled odds ratios (ORs) were calculated for each relationship. Results A total of 5 studies and 706 patients were included in our meta‐analysis. Overall, we did not find a strong association between pre‐operative treatment of infliximab and short‐term infectious [OR 2.24, 95% confidence interval (CI) 0.63–7.95] or non‐infectious (OR 0.85, 95% CI 0.50–1.45) post‐operative complications in ulcerative colitis patients. On the contrary, we discovered that pre‐operative infliximab use increased short‐term total post‐operative complications (OR 1.80, 95% CI 1.12–2.87). Conclusions Pre‐operative infliximab use increased the risk of short‐term post‐operative complications. Subgroup analysis is underpowered to assess the nature of these complications but shows a trend towards increased post‐operative infection.     

氟比洛芬酯复合吗啡硬膜外腔镇痛对妇科术后镇痛效果的观察

目的：探讨氟比洛芬酯复合吗啡硬膜外腔多模式镇痛对妇科术后镇痛效果的观察。方法：选择ASAⅠ～Ⅱ级、择期全子宫切除患者90例,随机等分为A、B、C组（各30例）。A组：采用硬膜外腔自控镇痛（吗啡5mg＋罗哌卡因125mg＋氟哌利多2.5mg）,术毕时连接PCEA泵;B组：采用吗啡硬膜外腔镇痛,术毕时硬膜外注射吗啡2mg＋氟哌利多1.5mg,18h后硬膜外再追加吗啡2mg,拔出硬膜外导管;C组：采用吗啡单次硬膜外腔镇痛术复合氟比洛芬酯静脉镇痛,术毕硬膜外注射吗啡2mg＋氟哌利多1.5mg后拔出硬膜外导管,18h后静脉注射氟比洛芬酯100mg,8h后重复注射氟比洛芬酯100mg。观察记录3组的镇痛效果（VAS评分）和不良反应。结果：3组均能取得良好的镇痛效果,VAS评分无显著性差异（P〉0.05）。C组恶心、呕吐、皮肤瘙痒和尿潴留等不良反应的发生率组明显少于A、B组（P〈0.05）。结论：3组均取得了良好的镇痛效果,但是氟比洛芬酯复合吗啡硬膜外镇痛方式可明显减少不良反应的发生。     

Synthesis of [2H3]‐dextromethorphan and its major urinary metabolites [2H3]‐dextrorphan and [2H3]‐dextrorphan‐β‐glucuronide

Starting from dextromethorphan, [²H₃]‐dextrorphan‐β‐glucuronide was synthesized in four steps with [²H₃]‐dextromethorphan and [²H₃]‐dextrorphan as intermediates with an overall yield of 11%. Copyright © 2002 John Wiley & Sons, Ltd.     

Pre‐operative management is associated with low rate of post‐operative morbidity in penetrating Crohn’s disease

Aliment Pharmacol Ther 2010; 32: 459–465

Summary

Background Ileocaecal resection for penetrating Crohn’s disease is still challenging with a high rate of post‐operative morbidity and faecal diversion. Aim To report retrospectively the results of pre‐operative management for penetrating Crohn’s disease focusing on the rate of post‐operative major morbidities and need for faecal diversion. Methods Between 1997 and 2007, 78 patients with penetrating Crohn’s disease underwent a first ileocaecal resection after a pre‐operative management consisting in bowel rest, nutritional therapy, intravenous antibiotics, weaning off steroids and immunosuppressors, and drainage of abscesses when appropriate. Results Resection was performed for terminal ileitis associated with (n = 41), abscesses (n = 37) or both (n = 5). A pre‐operative nutritional therapy was performed in 50 patients (68%) for 23 days (range, 7–69 days) along with a weaning off steroids and immunosuppressors. A diverting stoma was performed for six patients (7.7%). There was no post‐operative death. Post‐operative complications were classified as minor in 10 patients (12.8%), and major in four patients (5%). Overall, the post‐operative course was uneventful in 58 patients (74%). Conclusion Pre‐operative management for penetrating Crohn’s disease allowed ileocaecal resection with low rates of post‐operative morbidity and faecal diversion.     

Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and Transdermal Administration to the Ewe

Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non‐pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5–2 ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118–127 gestational days were used. In the first protocol, 1 week before surgery, 10 animals received 2 μg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 μg/kg/hr were applied to antebrachium, and ewes were then given a 2 μg/kg intravenous bolus followed by an intra‐operative 2.5 μg/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra‐ and post‐operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep.     

Pharmacokinetics of codeine after single- and multiple-oral-dose administration to normal volunteers

The pharmacokinetics of codeine, codeine glucuronide, morphine, and morphine glucuronide were assessed after single- (60 mg) and multiple-dose (60 mg every six hours for nine doses) oral administration of codeine sulfate to six normal volunteers. Multiple blood and urine samples were collected after administration of the single- and last multiple-oral doses. Drug concentrations were analyzed using radioimmunoassay techniques. No significant alterations in codeine pharmacokinetics were noted after multiple-dose oral administration. However, accumulation of morphine during multiple dosing was significant (AUC24 = 102 +/- 33 ng/mL/hr after single dose versus 212 +/- 118 ng/mL/hr after the last multiple dose). Peak concentration and AUC24 data for morphine glucuronide indicated that significant accumulation of this compound occurs upon multiple-dose administration. These data indicate that morphine and morphine glucuronide serum concentrations are significantly increased during chronic oral codeine therapy and suggest that morphine, and perhaps morphine glucuronide, contribute significantly to the analgesic activity of chronic oral codeine therapy.     

Interactions of (2S,6S;2R,6R)‐Hydroxynorketamine,a Secondary Metabolite of (R,S)‐Ketamine,with Morphine

Ketamine and its primary metabolite norketamine attenuate morphine tolerance by antagonising N‐methyl‐d ‐aspartate (NMDA) receptors. Ketamine is extensively metabolized to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)‐hydroxynorketamine (6‐hydroxynorketamine) is not an NMDA antagonist. However, it may modulate nociception through negative allosteric modulation of α7 nicotinic acetylcholine receptors. We studied whether 6‐hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings. Male Sprague Dawley rats received subcutaneous 6‐hydroxynorketamine or ketamine alone or in combination with morphine, as a cotreatment during induction of morphine tolerance, and after the development of tolerance induced by subcutaneous minipumps administering 9.6 mg morphine daily. Tail flick, hot plate, paw pressure and rotarod tests were used. Brain and serum drug concentrations were quantified with high‐performance liquid chromatography–tandem mass spectrometry. Ketamine (10 mg/kg), but not 6‐hydroxynorketamine (10 and 30 mg/kg), enhanced antinociception and decreased rotarod performance following acute administration either alone or combined with morphine. Ketamine efficiently attenuated morphine tolerance. Acutely administered 6‐hydroxynorketamine increased the brain concentration of morphine (by 60%), and brain and serum concentrations of 6‐hydroxynorketamine were doubled by morphine pre‐treatment. This pharmacokinetic interaction did not, however, lead to altered morphine tolerance. Co‐administration of 6‐hydroxynorketamine 20 mg/kg twice daily did not influence development of morphine tolerance. Even though morphine and 6‐hydroxynorketamine brain concentrations were increased after co‐administration, the pharmacokinetic interaction had no effect on acute morphine nociception or tolerance. These results indicate that 6‐hydroxynorketamine does not have antinociceptive properties or attenuate opioid tolerance in a similar way as ketamine.     

Meta‐analysis: targeting the intestinal microbiota in prophylaxis for post‐operative Crohn’s disease

Aliment Pharmacol Ther 31 , 802–809

Summary

Background Enteric bacteria play an important early role in the pathogenesis of Crohn’s disease. Aim To perform a meta‐analysis of trials testing antibiotics or probiotics for prevention of post‐operative recurrence of Crohn’s disease. Methods Review of all randomized controlled trials comparing antibiotics or probiotics with placebo in prevention of endoscopic or clinical recurrence of Crohn’s disease after surgical resection. Fixed‐effect meta‐analysis was performed with dichotomous data summarized using relative risk with 95% confidence intervals, where appropriate. Results Seven studies were identified as suitable for inclusion (two comparing antibiotics with placebo, five comparing probiotics with placebo). The use of nitroimidazole antibiotics (metronidazole, ornidazole) reduced the risk of clinical (RR 0.23; 95% CI 0.09–0.57, NNT = 4) and endoscopic (RR 0.44; 95% CI 0.26–0.74, NNT = 4) recurrence relative to placebo. However, these agents were associated with higher risk of adverse events (RR 2.39, 95% CI 1.5–3.7) and patient withdrawal. Probiotic administration was not associated with any significant difference in risk of recurrence compared with placebo. Conclusions Nitroimidazole antibiotics are effective in the prevention of post‐operative Crohn’s disease recurrence, but their side‐effects limit acceptability. Probiotics have failed to show efficacy for post‐operative prophylaxis, but may merit further study.     

Morphine hyposensitivity in streptozotocin‐diabetic rats: Reversal by dietary l‐arginine treatment

Painful diabetic neuropathy (PDN) is a long‐term complication of diabetes. Defining symptoms include mechanical allodynia (pain due to light pressure or touch) and morphine hyposensitivity. In our previous work using the streptozotocin (STZ)‐diabetic rat model of PDN, morphine hyposensitivity developed in a temporal manner with efficacy abolished at 3 months post‐STZ and maintained for 6 months post‐STZ. As this time course mimicked that for the temporal development of hyposensitivity to the pain‐relieving effects of the furoxan nitric oxide (NO) donor, PRG150 (3‐methylfuroxan‐4‐carbaldehyde) in STZ‐diabetic rats, we hypothesized that progressive depletion of endogenous NO bioactivity may underpin the temporal loss of morphine sensitivity in STZ‐diabetic rats. Furthermore, we hypothesized that replenishment of NO bioactivity may restore morphine sensitivity in these animals. Diabetes was induced in male Dark Agouti rats by intravenous injection of STZ (85 mg/kg). Diabetes was confirmed on day 7 if blood glucose concentrations were ≥15 mmol/L. Mechanical allodynia was fully developed in the bilateral hindpaws by 3 weeks of STZ‐diabetes in rats and this was maintained for the study duration. Morphine hyposensitivity developed in a temporal manner with efficacy abolished by 3 months post‐STZ. Administration of dietary l ‐arginine (NO precursor) at 1 g/d to STZ‐diabetic rats according to a 15‐week prevention protocol initiated at 9 weeks post‐STZ prevented abolition of morphine efficacy. When given as an 8‐week intervention protocol in rats where morphine efficacy was abolished, dietary l ‐arginine at 1 g/d progressively rescued morphine efficacy and potency. Our findings implicate NO depletion in the development of morphine hyposensitivity in STZ‐diabetic rats.     

Effects of Prenatally-administered Morphine on Brain Development and Resultant Tolerance to the Analgesic Effect of Morphine in Offspring of Morphine Treated Rats

Abstract: Timed-pregnant Sprague-Dawley rats were injected subcutaneously with morphine 20 mg/kg on gestational days 17–20 or infused intravenously with morphine 5 mg/kg for 4 hrs on gestational day 21 or 22. They were then allowed to litter normally except when studied at 1 hr after birth. The body weight, brain weight, total brain DNA, RNA and protein and the incorporation of labelled thymidine, uridine and amino acids into corresponding brain macro-molecules of young of morphine treated and control rats were measured at the age of 1 hr and 1, 2, 12, 13, 20, 26 and 32 days after birth. Separate groups of young were tested for analgesic response to morphine using a nocioceptive (55$dG surface) stimulus. Offspring of morphine injected mothers exhibited significant reduction in body weight at every age level, except at 26 days. The reduced body weight was paralleled by reduced brain weights up to the age of 12 days. The values for brain weight expressed as a percentage of body weight were significantly higher for the morphine than the control young in every age group even though the brain weights of the morphine young in the three oldest groups were the same or higher than those of controls. It was concluded that the brain is less affected than the body as a whole. The lower brain weights of the 1, 2 and 12 day old morphine offspring were paralleled by consistently lower total amounts of brain DNA, RNA and protein. RNA/DNA and protein/DNA ratios in brain thus remained unchanged. The decreased macromolecular contents in the morphine young were in general paralleled by decreased incorporation of radioactive precursors into brain macromolecules up to the age of 12 days. It was concluded that suppression of macromolecular synthesis and growth retardation in brain resulted from suppressed cell division. Offspring of morphine infused mothers exhibited no significant difference in weight at birth, brain weight, and total amounts of DNA, RNA and protein in the brain. It was, however, found that incorporation of labelled precursors tended to be lower in the brain of the morphine young at birth and at one day and that body weights were significantly less at the age of 12–13 days whereas incorporation into brain macromolecules was significantly higher than that in the control young at 13 days. The results were interpreted in terms of a rebound phenomenon which followed an inhibitory effect of morphine on cell division in the brain. Offspring of morphine injected mothers exhibited a pronounced rebound elevation of brain weight and macromolecular contents but not incorporation at the age of 20 days. After 20 days these differences levelled out, except for total RNA which was found to be significantly greater in 26 day old morphine offspring. Analgesic experiments with young of morphine injected mothers showed that tolerance to morphine analgesia, except for decreased duration of analgesia, disappeared between 12 to 20 days of age, whereas experiments with 12 to 13 day old young of morphine infused mothers showed that the analgesic action of morphine was significantly greater in the morphine than in the control young. The above results of morphine analgesia can best be explained by the hypothesis that tolerance to morphine analgesia is characterized by suppressed cell division and reduced macromolecular synthesis in brain, and different stages of recovery from these effects of morphine in the brain are associated with differences in sensitivity to morphine analgesia, i. e. ongoing recovery with high sensitivity and complete recovery with normal sensitivity.     

Comparison of the analgesic effect of patient‐controlled oxycodone and fentanyl for pain management in patients undergoing colorectal surgery

Oxycodone is a μ‐opioid receptor agonist and is generally indicated for the relief of moderate to severe pain. The aim of this study was to compare the analgesic efficacy of patient‐controlled oxycodone and fentanyl for postoperative pain in patients undergoing colorectal surgery. Patients scheduled to undergo elective colorectal surgery (n=82) were allocated to receive oxycodone (n=41, concentration of 1 mg/mL) or fentanyl (n=41, concentration of 15 μg/mL) for postoperative pain management. After the operation, pain using a numerical rating scale (NRS), delivery to demand ratio, infused dose of patient‐controlled analgesia (PCA), side effects, and sedation levels were evaluated. Median (25%–75%) cumulative PCA dose of oxycodone group at 48 hours (66.9, 58.4–83.7 mL) was significantly less than that of fentanyl group (80.0, 63.4–103.3 mL, P=.037). Six hours after surgery, the mean (SD) NRS scores of the oxycodone and fentanyl groups were 6.2 (2.4) and 6.8 (1.9), respectively (P=.216). The mean equianalgesic potency ratio of oxycodone to fentanyl was 55:1. The groups did not differ in postoperative nausea, vomiting, and level of sedation. Patient‐controlled oxycodone provides similar effects for pain relief compared to patient‐controlled fentanyl in spite of less cumulative PCA dose. Based on these results, oxycodone can be a useful alternative to fentanyl for PCA in patients after colorectal surgery.     

低剂量吗啡复合曲马多用于胸科手术后镇痛的观察

目的观察低剂量吗啡复合曲马多硬膜外PCA(PCEA)用于胸科手术后镇痛的安全性和有效性。方法行开胸肺叶切除患者48例,年龄45～68岁,术前肺功能检查为基本正常,麻醉分级ASAⅠ～Ⅱ级,随机分两组:A1吗啡复合曲马多组24例,用MT配方(0.004%吗啡、0.5%曲马多、0.004%氟哌利多、0.15%罗呢卡因);A2吗啡组24例,用M配方(0.01%吗啡、0.004%氟哌利多、0.15%罗哌卡因)。麻醉诱导前于T6～7间隙行硬膜外穿刺置管,术中两组都采用静-吸复合麻,术前30min在硬外分别对应给上述药液5mL作负荷量,术毕待患者清醒拔除双腔导管后接持续微量镇痛泵,观察血压、心率、血氧、呼吸频率、疼痛评分、镇静评分、恶心呕吐等情况。结果两组患者术后疼痛评分差别无显著性(P>0.05),镇痛效果均达到优良,术毕12hA2组有2例血氧在89%、90%,经吸氧维持95%以上。结论两组配方用于行胸科术后镇痛效果均确切,与A2组相比,A1组吗啡用量小,更为安全。     

The Analgesic Concentration of Oxycodone with Co‐administration of Paracetamol – A Dose‐Finding Study in Adult Patients Undergoing Laparoscopic Cholecystectomy

We have previously shown that paracetamol has an opioid‐sparing effect in tonsillectomy, and now, we evaluated the analgesic efficacy of paracetamol i.v. in early post‐operative pain after laparoscopic cholecystectomy (LCC). Twenty‐four patients with LCC were randomized to receive paracetamol i.v. 1 g (group 1) or 2 g (group 2) at the end of surgery. All patients were provided 0.1 mg/kg of oxycodone i.v. 15 min. before the end of surgery. At the recovery room when the wound pain at rest was ≥3/10 and/or ≥5/10 during the wound compression, plasma sample was taken for the determination of oxycodone (minimum effective concentration, MEC), its metabolites and paracetamol. After that the patients were titrated with further doses of oxycodone i.v. to wound pain < 3/10 at rest and < 5/10 during wound compression, plasma sample was taken for the determination of minimum effective analgesic concentration (MEAC) of oxycodone. The total oxycodone dose needed for pain relief was similar, about 0.3 mg/kg (range 0.2–0.5), in both groups (p = 0.80). At the onset of pain, P‐oxycodone (MEC) was similar in both groups, 25 ng/ml (19–32) in group 1 and 24 ng/ml (16–34) in group 2. The pain relief (MEAC) was achieved in group 1 with P‐oxycodone 70 ng/ml (30–131) and in group 2 with 62 ng/ml (36–100) (p = 0.48). In conclusion, in the early‐phase after LCC, there was no significant difference between the effect of paracetamol doses of 1 g and 2 g i.v. on the need of i.v. oxycodone.     

卡马西平联合吗啡对慢性坐骨神经缩窄损伤模型大鼠的镇痛作用研究

目的:研究卡马西平联合吗啡对慢性坐骨神经缩窄损伤(CCI)模型大鼠的镇痛作用。方法:取大鼠行手术建立CCI模型,建模成功后随机分为模型组、卡马西平组(5mg·kg-1)、吗啡组(3mg·kg-1)和联用组(卡马西平5mg·kg-1+吗啡3mg·kg-1),每组16只,术后第8天分别注射相应药物,连续5d,同时设立假手术组进行比较,观察各组大鼠术后和给药过程中有无感染、自残等现象,检测给药前和给药第1、3、5天以及停药2d后机械缩足反射阈值(PWMT)和热辐射缩足反射潜伏期(PWL)变化。结果:所有大鼠术后和给药期间均无感染和自残等现象;与假手术组比较,模型组大鼠给药前和给药后各时间点的PWMT、PWL均明显减弱或缩短(P<0.01);与吗啡组比较,联用组大鼠给药后各时间点的PWMT、PWL均明显增强或延长(P<0.05或P<0.01);与给药前比较,联用组大鼠给药后各时间点的PWMT、PWL均明显增强或延长(P<0.01),卡马西平组和吗啡组大鼠停药2d后的PWMT、PWL均无明显变化。结论:卡马西平联合吗啡能明显减弱CCI模型大鼠的机械痛和热痛反应,延长吗啡作用时间,改善吗啡耐受。     

Studies on the possible role of pharmacokinetics in the development of tolerance to morphine in the rat.

1. The possible role of pharmacokinetics of morphine in the development of tolerance to the analgesic and hyperthermic effects of morphine was studied in the rat. 2. Male Sprague-Dawley rats were made tolerant to morphine by implanting 6 morphine pellets each containing 75 mg of morphine base for 7 days. The assessment of the degree of tolerance to morphine and pharmacokinetic parameters were done 72 hr after pellet removal. 3. Tolerance developed to both the analgesic and hyperthermic effects of morphine as evidenced by decreased responses to morphine in morphine pellet implanted rats compared with placebo pellet implanted rats. 4. The pharmacokinetic parameters, AUC0-->infinity, Cmax, t1/2, k, MRT, Vss and Clt were determined after injecting 5 and 10 mg/kg doses of morphine intravenously to placebo and morphine pellet implanted rats and using a highly sensitive and specific RIA method to quantitate serum levels of morphine. For a 5 mg/kg dose of morphine, the AUC0-->infinity and t1/2 in morphine pellet implanted rats were significantly higher than in placebo pellet implanted rats, but the k value was lower. The other pharmacokinetic parameters for morphine in the two treatment groups did not differ. For 10 mg/kg dose, the only change was an increase in the MRT in morphine tolerant rats when compared to nontolerant rats. 5. The results establish that the development of tolerance to the analgesic and hyperthermic effects of morphine is not related to pharmacokinetics of morphine in serum but may be related to modification of receptor systems in the central nervous system.