Massimo Allegri

Morphine metabolism, transport and brain disposition

The chemical structures of morphine and its metabolites are closely related to the clinical effects of drugs (analgesia and side-effects) and to their capability to cross the Blood Brain Barrier (BBB). Morphine-6-glucuronide (M6G) and Morphine-3-glucuronide (M3G) are both highly hydrophilic, but only M6G can penetrate the BBB; accordingly, M6G is considered a more attractive analgesic than the parent drug and the M3G. Several hypotheses have been made to explain these differences. In this review we will discuss recent advances in the field, considering brain disposition of M6G, UDP-glucoronosyltransferases (UGT) involved in morphine metabolism, UGT interindividual variability and transport proteins.

Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside?

The 118A>G single nucleotide polymorphism (SNP) in the μ-opioid receptor (OPRM1) gene has been the most described variant in pharmacogenetic studies regarding opioid drugs. Despite evidence for an altered biological function encoded by this variant, this knowledge is not yet utilized clinically. The aim of the present review was to collect and discuss the available information on the 118A>G SNP in the OPRM1 gene, at the molecular level and in its clinical manifestations. In vitro biochemical and molecular assays have shown that the variant receptor has higher binding affinity for β-endorphins, that it has altered signal transduction cascade, and that it has a lower expression compared with wild-type OPRM1. Studies using animal models for 118A>G have revealed a double effect of the variant receptor, with an apparent gain of function with respect to the response to endogenous opioids but a loss of function with exogenous administered opioid drugs. Although patients with this variant have shown a lower pain threshold and a higher drug consumption in order to achieve the analgesic effect, clinical experiences have demonstrated that patients carrying the variant allele are not affected by the increased opioid consumption in terms of side effects.

Genetic variability at COMT but not at OPRM1 and UGT2B7 loci modulates morphine analgesic response in acute postoperative pain

PurposeTo investigate interindividual variability in response to pain treatment, we characterized postoperative patients for morphine metabolism and for COMT, OPRM1 and UGT2B7 polymorphisms.MethodsA total of 109 patients treated with morphine were genotyped by DNA sequencing for 12 DNA polymorphisms of the COMT, OPRM1 and UGT2B7 genes. The plasma concentration of morphine and of M3G/M6G metabolites were evaluated by means of reversed phase high-performance liquid chromatography coupled with mass spectrometry.ResultsAn association between average morphine consumption during the first 24 postoperative hours by patient-controlled analgesia (PCA) and COMT haplotypes was found. Specifically, patients with the diplotype for average pain intensity (APS/APS) required the lowest morphine doses compared to the other subjects (p = 0.011). The APS haplotype contains an adenine corresponding to methionine, instead of valine, at position 158 of the COMT protein. Met/Met homozygous patients consumed significantly lower morphine doses than other subjects (p = 0.014); accordingly, Val158Met genotyping alone might be used in the clinical setting to predict PCA morphine need. Considering both COMT Val158Met and OPRM1 A118G polymorphisms, carriers of both the Met/Met and AA genotypes required less morphine than other subjects, although the difference was not significant. The analysis of UGT2B7 revealed the occurrence of two common haplotypes (G_C_C_A_C and A_T_T_G_T) that did not prove to be related with plasma morphine and M3G/M6G concentration.ConclusionsBy considering COMT, OPRM1, and UGT2B7 genotypes, as well as pharmacokinetic results, only COMT polymorphisms appear to be predictive of morphine need in postoperative pain therapy.

How and why to screen for CYP2D6 interindividual variability in patients under pharmacological treatments

Cytochromes P450 are members of a superfamily of hemoproteins that catalyze a variety of oxidative reactions in the metabolism of endogenous and exogenous hydrophobic substrates. Fifty-eight cytochrome P450 (CYP) isoenzymes belonging to 18 families have been identified in human cells; the corresponding genes are highly polymorphic, and genetic variability underlies interindividual differences in drug response. The polymorphisms of CYP2D6 significantly affect the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. The number of functional CYP2D6 alleles per genome determines the existence of four different phenotypes, i.e. poor, intermediate, extensive, and ultrarapid metabolizers. CYP2D6 genetic variants include copy number variations, single nucleotide substitutions, frameshift and insertion/deletion mutations. This review reports some of the different methodological approaches used to screen for CYP2D6 variants and focuses on methods that have improved variation detection, from conventional techniques to more recent microarray technology and high throughput DNA sequencing. In addition, this review reports some results on clinical relevance of CYP2D6 polymorphisms and provides examples of variability in drug response associated with interindividual phenotypic differences.

Inflammation-based scores: a new method for patient-targeted strategies and improved perioperative outcome in cancer patients.

Systemic inflammatory response (SIR) has actually been shown as an important prognostic factor associated with lower postoperative survival in several types of cancer. Thus, the challenge for physicians is to find specific, low-cost, and highlyreliable inflammatory markers, clearly correlated with prognosis and able to preoperatively stratify patients risk. Inflammation is a promising target to improve perioperative outcome, and data show that anti-inflammation techniques have a great potential in the perioperative period of cancer surgery. Inflammation scores could be useful to stratify patients with a potential better response to anti-inflammation strategies. Furthermore, inflammation scores could prevent failure of clinical trials by a better definition of patients to be included in such trials; inflammation scoring could clarify the real role of different drugs and techniques on outcome after cancer surgery, defining if different therapies are required for different patients. The role of this review is to focus on the currently available scores, in order to clarify their rationale and to analyze the actual evidence and limits, providing physicians with an updated overview of the possible inflammation-based prognostic scores for cancer patients undergoing surgery.

Continuous peripheral nerve blocks: state of the art.

Purpose of review This review was performed through a Medline research to evaluate articles published between January 2004 and April 2005. Technical procedures, indications, drugs, infusion regimens, and complications of continuous peripheral nerve blocks were considered. Recent findings A total of 27 articles were reviewed. With respect to technical procedures, the authors focused on advantages of stimulating catheters or ultrasound guidance. With the help of these techniques, a correct catheter placement as close to the targeted nerve as possible was obtained. The total amount of local anesthetic administered was thereby reduced. Using ultrasound needle guidance, the spread of local anesthetic around the nerve could be visualized. Articles dealing with the choice of local anesthetic showed equianalgesia and equipotency of continuous perineural infusion of levobupivacaine 0.125% and ropivacaine 0.2%. The best infusion regimen for postoperative analgesia appears to be a combination of a preset basal rate administered together with small bolus doses in almost all continuous peripheral nerve blocks. Overall, complications such as infections, local anesthetic toxic plasma levels, hematoma formation, or nerve injury seem to be rare in continuous peripheral nerve blockade. Summary Continuous peripheral nerve blockade is an effective and safe technique for postoperative analgesia, even when administered at home. To optimize this technique, further studies are needed to help minimize the risk of side effects, improve techniques to locate the targeted nerve (stimulating catheters or ultrasound imaging) and choose less toxic drugs (levobupivacaine and ropivacaine) with more effective infusion regimens.

Changes in total plasma and serum N-glycome composition and patient-controlled analgesia after major abdominal surgery

Systemic inflammation participates to the complex healing process occurring after major surgery, thus directly affecting the surgical outcome and patient recovery. Total plasma N-glycome might be an indicator of inflammation after major surgery, as well as an anti-inflammatory therapy response marker, since protein glycosylation plays an essential role in the inflammatory cascade. Therefore, we assessed the effects of surgery on the total plasma N-glycome and the association with self-administration of postoperative morphine in two cohorts of patients that underwent major abdominal surgery. We found that plasma N-glycome undergoes significant changes one day after surgery and intensifies one day later, thus indicating a systemic physiological response. In particular, we observed the increase of bisialylated biantennary glycan, A2G2S[3,6]2, 12 hours after surgery, which progressively increased until 48 postoperative hours. Most changes occurred 24 hours after surgery with the decrease of most core-fucosylated biantennary structures, as well as the increase in sialylated tetraantennary and FA3G3S[3,3,3]3 structures. Moreover, we observed a progressive increase of sialylated triantennary and tetraantennary structures two days after surgery, with a concomitant decrease of the structures containing bisecting N-acetylglucosamine along with bi- and trisialylated triantennary glycans. We did not find any statistically significant association between morphine consumption and plasma N-glycome.

Clinical pharmacokinetics of morphine and its metabolites during morphine dose titration for chronic cancer pain.

Background: Pain is one of the most prevalent and distressing symptoms in patients with cancer. There is evidence from observational studies that many patients do not get adequate relief. Although data in the literature confirm the effectiveness of most opioid drugs for the treatment of chronic pain, there is limited information about opioid titration. Methods: The aim of this study was to evaluate the clinical pharmacokinetics of morphine (M) and their correlation with pharmacodynamic results (effective daily dose of M and side effects) during the M titration phase, in the management of chronic cancer pain. Fifty-two consecutive patients were administered Oramorph (Molteni Farmaceutici, Scandicci, Florence, Italy; beginning with 5 mg every 6 hours), to maintain pain intensity at low levels (visual analog scale <4). M, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) plasma concentrations were determined by a mass spectrometric assay. Results: Expected pharmacokinetic parameters were based on a pharmacokinetic profile extrapolated from 39 patients: M total clearance varied between 1.5 and 6.42 L·h−1·kg−1; the median apparent volume of M distribution was 25.0 L/kg, and the elimination half-life was 4.4 hours. Over the entire period of treatment, a weak correlation between M and M3G or M6G concentrations was found, but the metabolite ratio (M3G/M6G) remained quite stable for each patient and at different sampling times. At the end of titration, the M6G/M ratio was significantly higher in the patients whose effective M concentration was below the median (5.2 ng/mL), than in patients in whom the concentration was above the median (M6G/M: 13.0 and 9.0, respectively). Conclusions: This article presents the pharmacokinetic profiles of M and its metabolites: their concentration ratio could help clinicians to optimize individual therapies and tailor the dose to individual needs. Our results indicate that the relationship between M6G and M could represent a potentially useful parameter to personalize M dosing.

Postoperative Analgesia after Laparoscopic Ovarian Cyst Resection: Double-blind Multicenter Randomized Control Trial Comparing Intraperitoneal Nebulization and Peritoneal Instillation of Ropivacaine

STUDY OBJECTIVE To compare the effects of local anesthetic intraperitoneal nebulization with intraperitoneal instillation during laparoscopic ovarian cystectomy on postoperative morphine consumption and pain. DESIGN Multicenter, randomized, case-control trial. DESIGN CLASSIFICATION Canadian Task Force Classification I. SETTING University hospitals in Italy. PATIENTS One hundred forty patients scheduled for laparoscopic ovarian cystectomy. INTERVENTIONS Patients were randomized to receive either nebulization of ropivacaine 150 mg before surgery or instillation of ropivacaine 150 mg before surgery. Nebulization was performed using the Aeroneb Pro device (Aerogen, Galway, Ireland). MEASUREMENTS AND MAIN RESULTS One hundred forty patients were enrolled, and 123 completed the study. There was no difference between the 2 groups in average morphine consumption (7.3 ± 7.5 mg in the nebulization group vs 9.2 ± 7.2 mg in the instillation group; p = .17). Eighty-two percent of patients in the nebulization group required morphine compared with 96% in the instillation group (p < .05). Patients receiving nebulization had a lower dynamic Numeric Ranking Scale compared with those in the instillation group in the postanesthesia care unit postanesthesia care unit and 4 hours after surgery (p < .05). Ten patients (15%) in the nebulization group experienced shivering in the postanesthesia care unit compared with 2 patients (4%) in the instillation group (p = .035). CONCLUSION Nebulization of ropivacaine prevents the use of morphine in a significant proportion of patients, reduced postoperative pain during the first hours after surgery, and was associated with a higher incidence of postoperative shivering when compared with instillation.

Reduction of painful area as new possible therapeutic target in post-herpetic neuropathic pain treated with 5% lidocaine medicated plaster: a case series

Post-herpetic neuralgia (PHN) is neuropathic pain persisting after an acute episode of herpes zoster, and is associated with severe pain and sensory abnormalities that adversely affect the patient’s quality of life and increase health care costs. Up to 83% of patients with PHN describe localized neuropathic pain, defined as “a type of neuropathic pain characterized by consistent and circumscribed area(s) of maximum pain”. Topical treatments have been suggested as a first-line treatment for localized neuropathic pain. Use of 5% lidocaine medicated plaster could reduce abnormal nervous peripheral discharge and via the plaster could have a “protective” function in the affected area. It has been suggested that use of this plaster could reduce pain as well as the size of the painful area. To evaluate this possible outcome, we retrospectively reviewed eight patients with PHN, treated using 5% lidocaine medicated plaster. During a follow-up period of 3 months, we observed good pain relief, which was associated with a 46% reduction in size of the painful area after one month (from 236.38±140.34 cm2 to 128.80±95.7 cm2) and a 66% reduction after 3 months (81.38±59.19 cm2). Our study cohort was composed mainly of elderly patients taking multiple drugs to treat comorbidities, who have a high risk of drug–drug interactions. Such patients benefit greatly from topical treatment of PHN. Our observations confirm the effectiveness of lidocaine plasters in the treatment of PHN, indicating that 5% lidocaine medicated plaster could reduce the size of the painful area. This last observation has to be confirmed and the mechanisms clarified in appropriate larger randomized controlled trials.