Opioid analgesic prescribing and use – an audit of analgesic prescribing by general practitioners and The Multidisciplinary Pain Centre at Royal Brisbane Hospital

AIMS: This study evaluated the use of and need for opioids in patients attending the Multidisciplinary Pain Centre at the Royal Brisbane Hospital (RBH). METHODS: All consecutive in-patient admissions in 1998 were reviewed. A 10-point scoring system based on the World Health Organization (WHO) analgesic ladder was devised to facilitate comparison of analgesic prescribing on admission and at the time of discharge. A conversion table was used to standardize opioid analgesic doses to an oral morphine equivalent. RESULTS: Of the 370 patients reviewed, 233 (81%) were by their general practitioners. Records of 288 (78%) were available for full review and 270 (94%) of these had noncancer pain. On admission, 239 (83%) were taking an opioid analgesic, with 135 (47%) taking strong opioids (e.g. morphine, oxycodone, methadone). There was a significant decrease in the mean total daily oral morphine equivalent prescribed on discharge 36.9 mg (95% CI: 33.4, 40.4) compared with that on admission 88.7 mg (95% CI: 77.6, 99.8) (P < 0.001). There was a significant decrease (P < 0.05) in the proportion of patients taking a primary opioid on discharge 153 (58%) compared with admission 239 (83%), although the proportion of patients taking a strong opioid on discharge 150 (52%) compared with admission 135 (47%) was not significantly different (P > 0.05). The proportion of patients taking a laxative showed a significant increase on discharge 110 (73%) compared with admission 38 (28%) (P < 0.05). CONCLUSIONS: Our analgesic prescribing scoring system and opioid conversion table have the potential to be developed further as tools for assessing opioid analgesic prescribing. The significant decrease in total daily oral morphine equivalents signifies the value of prescribing in accordance with the WHO analgesic ladder, and the necessity of general practitioner education. The management of chronic pain is complex, and it requires interventions additional to pharmacological therapy. Evaluation by a multidisciplinary team, coupled with experience in and an understanding of analgesic prescribing and rehabilitation provides an effective basis for improving the management of patients with chronic pain.     

Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics

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Enkephalin Antisense Peptides: Design,Synthesis, and Biological Activity

The antisense mRNA complementary to the sense strand of Met-enkephalin encodes the antisense peptides, His-Glu-Ala-Pro-Ile (compound 88/62). The antisense peptide and its (Gln¹)-analogue (compound 88/63) have synergestic effects on the opioid activity of Met-enkephalin in the GPI test system.     

Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective,randomized, double-blind,placebo- and active-controlled Phase III study

Objective: To evaluate the efficacy and safety of tapentadol extended release (ER) for the management of moderate to severe chronic low back pain.

Research design: Patients (N = 981) were randomized 1:1:1 to receive tapentadol ER 100 – 250 mg b.i.d., oxycodone HCl controlled release (CR) 20 – 50 mg b.i.d., or placebo over 15 weeks (3-week titration period, 12-week maintenance period).

Main outcome measures: Efficacy was assessed as change from baseline in average pain intensity (11-point NRS) at week 12 of the maintenance period and throughout the maintenance period; last observation carried forward was used to impute missing pain scores. Adverse events (AEs) were monitored throughout the study.

Results: Tapentadol ER significantly reduced average pain intensity versus placebo at week 12 (least squares mean difference vs placebo [95% confidence interval], ?0.8 [?1.22, ?0.47]; p < 0.001) and throughout the maintenance period (?0.7 [?1.06,?0.35]; p < 0.001). Oxycodone CR significantly reduced average pain intensity versus placebo at week 12 (?0.9 [?1.24,?0.49]; p < 0.001) and throughout the maintenance period (?0.8 [?1.16,?0.46]; p < 0.001). Tapentadol ER was associated with a lower incidence of treatment-emergent AEs (TEAEs) than oxycodone CR. Gastrointestinal TEAEs, including constipation, nausea, and vomiting, were among the most commonly reported TEAEs (placebo, 26.3%; tapentadol ER, 43.7%; oxycodone CR, 61.9%). The odds of experiencing constipation or the composite of nausea and/or vomiting were significantly lower with tapentadol ER than with oxycodone CR (both p < 0.001).

Conclusions: Tapentadol ER (100 – 250 mg b.i.d.) effectively relieved moderate to severe chronic low back pain over 15 weeks and had better gastrointestinal tolerability than oxycodone HCl CR (20 – 50 mg b.i.d.).     

Synthesis and SAR Study of Opioid Receptor Ligands: Mono‐ and Bis‐Indolomorphinans

Mono‐ and bis‐indolomorphinans were synthesized through a multi‐step synthetic approach from the alkaloid, thebaine, to further explore the C‐ring SAR (structure‐activity relationship) of morphinan scaffold. Both mono‐indoles displayed good binding affinity and selectivity for the δ receptor, with compound 6b possessed the highest K_i value of 1.45 nm at this receptor. Bisindolomorphinans 7a,b did not have appreciable affinity for both δ and κ receptors, but moderate binding at the μ receptor was observed. Functional assays indicated that the newly synthesized mono‐indole 6b was δ‐agonist, opposite to the δ‐antagonist profile of naltrindole. Bisindoles 7a,b were μ‐agonists. This work further confirms that the phenol component in opioids is essential for higher binding to the opioid receptors. The different binding ability, receptor selectivity, and the functional activity profiles of naltrindole 2, monoindole 6b, and bisindole 7b clearly indicated that they interact with the opioid receptors in different modes.     

Synthesis and Biological Evaluation of the First Example of NO-Donor Histone Deacetylase Inhibitor

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Synthesis of New Lipoic Acid Conjugates and Evaluation of Their Free Radical Scavenging and Neuroprotective Activities

A series of new lipoic acid derivatives were designed and synthesized as multitarget ligands against Alzheimer's disease. In particular, analogues combining both lipoic acid and cysteine core structures were synthesized. The antioxidant properties of these compounds were evaluated by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH), 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid (ABTS^?+) radical cation scavenging assays and ferrous ion chelation. The antioxidant potential of the synthesized compounds was also evaluated in a cellular context and compared to α‐lipoic acid and its reduced form, dihydrolipoic acid. The antioxidant effects observed for these compounds in vitro confirmed the importance of free thiol functions for effective antioxidant capacities. However, these promising in vitro results were not mirrored by the antioxidant activity in T67 cell line. This suggests that multiple factors are at stake and warrant further investigations.     

Design,Synthesis, and Biological Evaluation of Pyrazole Derivatives

In this in vitro study, a series of novel pyrazole derivatives were designed, synthesized, and evaluated against five human cancer cell lines (PC3, A549, HL60, HCT116, and SW620) for their antiproliferative and p53‐MDM2 binding inhibitory activities. Although biological evaluations showed that this series of compounds possessed weak p53‐MDM2 inhibitory activities, most of them displayed moderate to potent antiproliferative activities against the tested cells lines. Compound 11c exhibited the best potency for MDM2 (FP‐IC₅₀ = 29.22 μm ) and demonstrated antiproliferative activities in response to the five tested cell lines (IC₅₀ = 4.09–16.82 μm ). Compared with the positive control Nutlin‐1, there was enhanced antiproliferative activity to p53‐mutated or p53‐deficient cell lines (SW620, HL60, and PC3).     

阿片类药物对行机械通气新生儿疼痛程度、生命体征及远期神经功能发育的影响

目的:探讨阿片类药物对行机械通气新生儿疼痛程度、生命体征及远期神经功能发育的影响。方法:选取我院2010年1月至2014年11月收治的行机械通气新生儿135例,按照随机区组法分为对照组68例和试验组67例,排除死亡和失访病例,实际纳入研究128例,对照组和试验组各64例。两组患儿气管插管后分别给予安慰剂和芬太尼静脉给药,比较两组患儿用药前后新生儿疼痛(PIPP)评分、生命体征指标水平,随访智力发育指数(MDI) 和精神运动发育指数(PDI)。结果:试验组患儿用药后30 min、1 h及2 h PIPP评分均显著低于对照组,差异有统计学意义(P<0.05);两组患儿用药前后平均动脉压和经皮血氧饱和度水平比较差异无统计学意义(P>0.05);试验组患儿用药后30 min、1 h及2 h呼吸频率和心率水平均显著低于对照组,差异有统计学意义(P<0.05);两组患儿随访不同月龄MDI和PDI水平比较差异无统计学意义(P>0.05)。结论:阿片类药物可有效缓解行机械通气新生儿气管插管疼痛,降低心率和呼吸频率,且对远期神经功能发育无不良影响。     

PEG Mediated Synthesis and Biological Evaluation of Asymmetrical Pyrazole Curcumin Analogues as Potential Analgesic,Anti-Inflammatory and Antioxidant Agents

The new series of asymmetrical pyrazole curcumin analogues 4a – g were synthesized by using polyethylene glycol (PEG-400) as a green reaction medium and evaluated for their in vivo analgesic and in vitro antioxidant (H₂O₂, DPPH, Ferrous reducing power and Nitric oxide scavenging activity) and anti-inflammatory activities. All the compounds synthesized 4a – g showed the potential to demonstrate analgesic activity as compared to the standard ibuprofen. Among the tested series, compounds 4e and 4b exhibited good hydrogen peroxide scavenging activity as compared to the standard butylated hydroxy toluene (BHT). Compounds 4b , 4d , 4f , and 4g showed good DPPH free radical scavenging activity. Compounds 4b , 4c , 4d , 4e and 4g showed excellent ferrous-reducing power activity, whereas all the compounds showed better nitric oxide scavenging activity than standard ascorbic acid. Additionally, all the synthesized compounds were also screened for their in vitro anti-inflammatory activity. Compounds 4b , 4d , 4f and 4g showed good anti-inflammatory activity as compared to standard diclofenac sodium.     

Design,Synthesis and Biological Evaluation of Cinnamic Acyl Shikonin Derivatives

Inducing apoptosis is an important and promising therapeutic approach to overcome cancer. Here, we described a series of novel synthesized compounds, cinnamic acyl shikonin derivatives ( 1b – 19b ), which were synthesized starting from shikonin and cinnamic acids, which exhibit anticancer activity via inducing apoptosis in vitro. Our flow cytometry results showed that compound 8b ((E)‐1‐(5,8‐dihydroxy‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)‐4‐methylpent ‐3‐enyl‐3‐(3‐(trifluoromethyl) phenyl)acrylate) (IC₅₀ = 0.69, 0.65, 1.62 μm for human SW872‐s, A875 and A549 cell lines, respectively) exhibited conspicuous anticancer activities and has low cell toxicity in vitro. Therefore, we considered that compound 8b is potentially to be a candidate of anticancer agent. The proliferation inhibitory effect of compound 8b was associated with its apoptosis‐inducing effect by activating caspase‐3, caspase‐7, caspase‐9, and PARP. When the level of cleaved caspase‐3, cleaved caspase‐7, cleaved caspase‐9, and cleaved PARP are rise, apoptosis of cancer cells will be induced.     

Design,Synthesis, and Biological Evaluation of Prenylated Chalcones as Vasorelaxant Agents

Five prenylated chalcones and one allylated chalcone were prepared according to the analysis based on support vector machine (SVM) classification model. Most of the synthesized chalcones showed potent vasorelaxant activities through evaluation in aortic rings with the endothelium pre‐contracted by phenylephrine (PE), indicating that the experimental activities were in good agreement with the theoretical ones. Structure‐activity relationship of these compounds showed that the substituent pattern and number of hydroxyl groups were crucial for their vasorelaxant activities and that the replacement of prenyl group with allyl group retained the potent activity.     

Synthesis and Biological Activity of Isodithiobiurets,Dithiobiurets, and Dithiazoles

A series of isodithiobiurets, dithiobiurets, and dithiazoles was synthesized and tested for biological activity. Generally, the compounds potentiated the hypnosis induced by pentobarbitone (50 mg/kg ip) in albino mice and exhibited antifungal and insecticidal activity against Fusarium oxysporum and Periplanata americana, respectively. Some compounds showed anticonvulsant and analgesic activity in albino rats.     

Design,Synthesis and Biological Evaluation of Pazopanib Derivatives as Antitumor Agents

A novel series of pazopanib derivatives were designed, synthesized, and evaluated for their inhibitory activity against a series of kinases including VEGFR‐2, EGFR, AKT1, ALK1, and ABL1. The anti‐angiogenic activities ex vivo of some compounds were also investigated. Compounds P2d and P2e demonstrated outstanding inhibitory activity against VEGFR‐2 and ABL1 and higher anti‐angiogenic activity compared with Pazopanib, the reference standard. These two compounds ( P2d and P2e ) could be used as novel lead compounds for further development of anticancer agents.     

Design,Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs

Interleukin-1 receptor associated kinase 4 (IRAK4) is a promising therapeutic target for diffuse large B-cell lymphoma driven by MYD88 L265P mutant, acting both as a kinase and a scaffolding protein for downstream signaling molecules. While previous efforts to modulate IRAK4 activity with kinase inhibitors alone displayed moderate efficacy, protein degradation may offer a solution to blocking both IRAK4 kinase activity and scaffolding capabilities. To this end, the potent IRAK4 degrader 9 was discovered, and it effectively inhibited the activation of downstream NF-κB signaling and outperformed the parent compound 1. In addition, compound 9 displayed a substantial advantage in reduction of the viability of OCI-LY10 and TMD8 cells over the parent compound 1. These results underline the potential that eliminating both the kinase and scaffolding functions of IRAK4 may result in superior and broader efficacy than inhibiting the kinase activity alone.     

Design,Synthesis, and Biological Evaluation of Andrographolide Derivatives as Potent Hepatoprotective Agents

Poor water solubility limits the clinical use of andrographolide and its derivatives. In an attempt to develop potent hepatoprotective drugs, a strategy was proposed to improve the aqueous solubility of andrographolide. Ten andrographolide derivatives were designed, synthesized, evaluated for aqueous solubility and in vivo hepatoprotective activity against CCl₄‐induced liver injury in mice. As expected, the aqueous solubility of synthetic derivatives was effectively improved. All compounds demonstrated the effect of different degrees in improving the liver enzyme (ALT and AST) activity, especially the most promising compound 9d significantly improved liver enzyme activity, with high potency to be a new lead.     

Design,Synthesis, and Biological Evaluation of Catecholamine Vehicle for Studying Dopaminergic System

Catecholamine mimetic EDTA‐bis(tyramide) was synthesized and characterized by various spectroscopic techniques (NMR, mass spectroscopy) and λ_em 310 nm for the excitation at 270 nm. Molecular docking studies were performed with human serum albumin (PDB 1E78), showing binding pattern with amino acid residues Arg218, Arg222, and Lys444, identifies the ligand‐human serum albumin interaction for the transportation affinity of the ligand at the specific site of the target. Subsequently, binding study with human serum albumin at λ_ex = 350 nm found to be 5.847 × 10⁴ m ^?1 shows effective quenching effect. Additionally, to go more insight, acetylcholinesterase binding affinity was investigated, which shows 90% binding affinity for the 10 mm concentration. IC50 value was found 18.60 μm for MAO‐B inhibition. Finally, EDTA‐bis(tyramide) labeled with ^99mTc to investigate its in vivo radiopharmaceutical efficiency having 97% binding affinity with 98% radiochemical purity. In vivo studies were carried out for ^99mTc‐EDTA‐bis(tyramide) included blood kinetics showed a quick wash out from the circulation via renal route, and biodistribution revealed that maximum %ID/g was found in kidney at 1 h, and its scintigraphy image shows 3.96% brain uptake with respect to whole body.     

Anti-inflammatory Properties of New Adamantane Derivatives. Design,Synthesis, and Biological Evaluation

A series of adamantane-containing molecules consisting of two lipophilic centers which are linked by different bridges (oxime esters, oxime ethers, amides, and symmetric alcohols), were designed and synthesized as anti-inflammatory agents. Their anti-inflammatory activity was evaluated as their ability to inhibit phlogistic-induced mouse paw edema. Some of the tested compounds exhibited activity comparable to that of diclofenac, others had a weaker activity, while some oxime esters proved to enhance the inflammatory response. In all cases, activity was dose-dependent. The deacylated compound 10 was found to be the most active of the series, inhibiting inflammation due to Baker’s yeast, the mechanism of which involves mainly the activation of lipoxy-genase and/or complement systems, a property which is absent from most selective cyclooxygenase only inhibiting non-steroidal anti-inflammatory drugs (NSAIDs).