Carsten Skarke

Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers.

Our objective was to quantify the extent and time course of the effects of morphine‐6‐glucuronide and morphine on pain threshold, pain tolerance, pupil diameter, and side effects.

Genetic predictors of the clinical response to opioid analgesics: Clinical utility and future perspectives

This review uses a candidate gene approach to identify possible pharmacogenetic modulators of opioid therapy, and discusses these modulators together with demonstrated genetic causes for the variability in clinical effects of opioids.Genetically caused inactivity of cytochrome P450 (CYP) 2D6 renders codeine ineffective (lack of morphine formation), slightly decreases the efficacy of tramadol (lack of formation of the active O-desmethyl-tramadol) and slightly decreases the clearance of methadone. MDR1 mutations often demonstrate pharmacogenetic consequences, and since Opioids are among the P-glycoprotein substrates, opioid pharmacology may be affected by MDR1 mutations. The single nucleotide polymorphism A118G of the μ opioid receptor gene has been associated with decreased potency of morphine and morphine-6-glucuronide, and with decreased analgesic effects and higher alfentanil dose demands in carriers of the mutated Gl 18 allele. Genetic causes may also trigger or modify drug interactions, which in turn can alter the clinical response to opioid therapy. For example, by inhibiting CYP2D6, paroxetine increases the steady-state plasma concentrations of (R)-methadone in extensive but not in poor metabolisers of debrisoquine/sparteine.So far, the clinical consequences of the pharmacogenetics of opioids are limited to codeine, which should not be administered to poor metabolisers of debrisoquine/sparteine. Genetically precipitated drug interactions might render a standard opioid dose toxic and should, therefore, be taken into consideration. Mutations affecting opioid receptors and pain perception/processing are of interest for the study of opioid actions, but with modern practice of on-demand administration of Opioids their utility may be limited to explaining why some patients need higher opioid doses; however, the adverse effects profile may be modified by these mutations. Nonetheless, at a limited level, pharmacogenetics can be expected to facilitate individualised opioid therapy.

Drug Interactions with Patient-Controlled Analgesia

Patient-controlled analgesia (PCA) has become standard procedure in the clinical treatment of pain. Its widespread use in patients with all kinds of diseases opens a variety of possible interactions between analgesics used for PCA and other drugs that might be administered concomitantly to the patient. Many of these drug interactions are of little clinical importance. However, some drug interactions have been reported to result in serious clinical problems.Drug interactions can either predominantly affect the pharmacokinetics or pharmacodynamics of the drug. Most important pharmacokinetic drug interactions occur at the level of drug metabolism or protein binding. Acceleration of methadone metabolism caused by cytochrome P450 (CYP) 3A4 induction by antiretroviral drugs or rifampicin (rifampin) has caused methadone withdrawal symptoms. Lack of morphine formation from codeine as a result of CYP2D6 inhibition by quinidine results in an almost complete loss of the analgesic effects of codeine. Alterations of methadone protein binding caused by an inhibition of α1-acid glycoprotein synthesis by alkylating substances are another possibility for predominantly pharmacokinetically based drug interactions during PCA. Furthermore, inhibition of P-glycoprotein by anticancer drugs could result in altered transmembrane transport of morphine, methadone or fentanyl, although this has not been shown to be of clinical relevance.Synergistic effects of systemically administered Opioids with spinally or topically delivered Opioids or anaesthetics have been reported frequently. The same is true for the opioid-sparing effects of coadministered non-opioid analgesics. Antidepressants, anticonvulsants or α2-adrenoreceptor agonists have also been shown to exert additive analgesic effects when administered together with an Opioid. Inconsistent findings, however, are reported regarding the treatment of patients with opioid-induced nausea and sedation, since coadministration of anti-emetics either increased or decreased the respective adverse effects or revealed additional unwanted drug effects.

Respiratory and miotic effects of morphine in healthy volunteers when P-glycoprotein is blocked by quinidine

Our objective was to evaluate whether P‐glycoprotein inhibition after quinidine pretreatment results in modified central nervous effects of morphine.

Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers

This investigation focused on the development of a predictive model of morphine, including morphine‐6‐glucuronide (M6G) for healthy young volunteers after morphine administration.

The 5-hydroxytryptamine 4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression

On the basis of experiments in rats, serotonin 4 receptor (5‐hydroxytryptamine 4 [5‐HT4]) agonists have been proposed as a novel therapeutic strategy for the selective treatment of respiratory depression caused by opioids while leaving analgesic effects unaffected. The effects in rats have been seen with the 5‐hydroxytryptamine 4a (5‐HT4a) agonist BIMU8, which is currently not available for use in humans.

On the interference of boswellic acids with 5-lipoxygenase: Mechanistic studies in vitro and pharmacological relevance

Boswellic acids are pharmacologically active ingredients of frankincense with anti-inflammatory properties. It was shown that in vitro 11-keto-boswellic acids inhibit 5-lipoxygenase (5-LO, EC 1.13.11.34), the key enzyme in leukotriene biosynthesis, which may account for their anti-inflammatory effectiveness. However, whether 11-keto-boswellic acids interfere with 5-LO under physiologically relevant conditions (i.e., in whole blood assays) and whether they inhibit 5-LO in vivo is unknown. Inhibition of human 5-LO by the major naturally occurring boswellic acids was analyzed in cell-free and cell-based activity assays. Moreover, interference of boswellic acids with 5-LO in neutrophil incubations in the presence of albumin and in human whole blood was assessed, and plasma leukotriene B(4) of frankincense-treated healthy volunteers was determined. Factors influencing 5-LO activity (i.e., Ca(2+), phospholipids, substrate concentration) significantly modulate the potency of 11-keto-boswellic acids to inhibit 5-LO. Moreover, 11-keto-boswellic acids efficiently suppressed 5-LO product formation in isolated neutrophils (IC(50)=2.8 to 8.8 muM) but failed to inhibit 5-LO product formation in human whole blood. In the presence of albumin (10 mg/ml), 5-LO inhibition by 11-keto-boswellic acids (up to 30 muM) in neutrophils was abolished, apparently due to strong albumin-binding (>95%) of 11-keto-boswellic acids. Finally, single dose (800 mg) oral administration of frankincense extracts to human healthy volunteers failed to suppress leukotriene B(4) plasma levels. Our data show that boswellic acids are direct 5-LO inhibitors that efficiently suppress 5-LO product synthesis in common in vitro test models, however, the pharmacological relevance of such interference in vivo seems questionable.

The cyclooxygenase 2 genetic variant -765G>C does not modulate the effects of celecoxib on prostaglandin E2 production.

Our objective was to assess the role of the reportedly functional PTGS2 (prostaglandin‐endoperoxide synthase 2/cyclooxygenase [COX] 2) promoter mutation −765G>C for the COX‐2–inhibiting effects of celecoxib.

Rapid genotyping for relevant CYP1A2 alleles by pyrosequencing

ObjectiveTo develop a rapid and reliable screening method for identifying the relevant cytochrome P450 (CYP) 1A2 alleles CYP1A2*1D (−2467Tdel), *1F (−163A>C), and *1K (−739T>G, −729C>T, −163A>C) that are in linkage disequilibrium with the functionally relevant CYP1A2 polymorphisms and therefore are considered to be predictive for the CYP1A2 phenotype.MethodsCYP1A2 single nucleotide polymorphisms (SNPs) −2467Tdel, −739T>G, −729C>T, and −163A>C were screened for in 495 healthy Caucasian volunteers using newly developed pyrosequencing duplex and simplex assays. Conventional sequencing of randomly selected samples served as quality control.ResultsFrequencies were 7.9% for CYP1A2*1D, 31.8% for *1F, and 0.4% for *1K. The observed distribution of homozygous and heterozygous carriers of the alleles corresponded to the predicted one according to the Hardy-Weinberg law. It also corresponded to reported allelic frequencies from Caucasians but differed significantly from the distribution seen in other ethnicities. The most frequent haplotype was −2467T/−739T/−729C/−163A (allelic frequency 61.6%), followed by −2467T/−739T/−729C/−163C (30.5%), −2467Tdel/−739T/−729C/−163A (5.1%), −2467Tdel/−739G/−729C/−163A (1.2%), and −2467Tdel/−739T/−729C/−163C (1.1%). Complete linkage disequilibrium (value of D’ nearly 1) existed between −2467Tdel, −739T>G, and −729C>T and between −729T>G and −163A>C.ConclusionsPyrosequencing facilitates rapid and reliable detection of those CYP1A2 alleles that, based on current knowledge, can be considered predictive for the CYP1A2 phenotype.

Is morphine-3-glucuronide of therapeutic relevance?

When patients present with neuroexcitatory effects or hyperalgesia/allodynia during morphine therapy, the main metabolite of morphine, morphine-3-glucuronide (M3G), has been proposed as a responsible factor. M3G is considered to exert effects that counteract those of morphine. This ranges from decreasing the analgesic effects of morphine to the initiation of side effects, such as neuroexcitation, hyperalgesia or allodynia, which are not primarily associated with those of morphine itself. In this review we propose to summarize the evidence upon which this view of M3G is based. A Medline (PubMed) search for ‘morphine-3-glucuronide or M3G’ in March 2005 produced 498 hits. By selecting original papers or case reports that focused on the pharmacodynamic effects of M3G, 88 references were found that covered the effects of M3G at the molecular level, in laboratory animals and in humans. Most of these papers were published between 1993 and 1998 with 6–11 references per year. The number has decreased in recent years, which may indicate that the contribution of M3G is considered sufficiently understood. The following review discusses whether it is justified to introduce M3G as a relevant factor to be considered in clinical morphine therapy.