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.

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

PURPOSE: To investigate interindividual variability in response to pain treatment, we characterized postoperative patients for morphine metabolism and for COMT, OPRM1 and UGT2B7 polymorphisms. METHODS: A 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. RESULTS: An 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. CONCLUSIONS: By 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.

'Omics' biomarkers associated with chronic low back pain: protocol of a retrospective longitudinal study.

INTRODUCTION: Chronic low back pain (CLBP) produces considerable direct costs as well as indirect burdens for society, industry and health systems. CLBP is characterised by heterogeneity, inclusion of several pain syndromes, different underlying molecular pathologies and interaction with psychosocial factors that leads to a range of clinical manifestations. There is still much to understand in the underlying pathological processes and the non-psychosocial factors which account for differences in outcomes. Biomarkers that may be objectively used for diagnosis and personalised, targeted and cost-effective treatment are still lacking. Therefore, any data that may be obtained at the '-omics' level (glycomics, Activomics and genome-wide association studies-GWAS) may be helpful to use as dynamic biomarkers for elucidating CLBP pathogenesis and may ultimately provide prognostic information too. By means of a retrospective, observational, case-cohort, multicentre study, we aim to investigate new promising biomarkers potentially able to solve some of the issues related to CLBP. METHODS AND ANALYSIS: The study follows a two-phase, 1:2 case-control model. A total of 12 000 individuals (4000 cases and 8000 controls) will be enrolled; clinical data will be registered, with particular attention to pain characteristics and outcomes of pain treatments. Blood samples will be collected to perform -omics studies. The primary objective is to recognise genetic variants associated with CLBP; secondary objectives are to study glycomics and Activomics profiles associated with CLBP. ETHICS AND DISSEMINATION: The study is part of the PainOMICS project funded by European Community in the Seventh Framework Programme. The study has been approved from competent ethical bodies and copies of approvals were provided to the European Commission before starting the study. Results of the study will be reviewed by the Scientific Board and Ethical Committee of the PainOMICS Consortium. The scientific results will be disseminated through peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02037789; Pre-results.

Ultrasound-Guided Approach for L5 Dorsal Ramus Block and Fluoroscopic Evaluation in Unpreselected Cadavers.

BACKGROUND AND OBJECTIVES: Medial branch blocks are frequently performed to diagnose lumbar facet-joint-mediated pain. Ultrasound guidance can increase practicability and eliminate exposure to ionizing radiation when compared with fluoroscopy. However, ultrasound-guided L5 dorsal ramus block, which, together with L4 medial branch block is necessary to anesthetize the most commonly affected facet joint L5/S1, has not been described so far. The objective of this study was to develop a technique and to evaluate its accuracy with standard fluoroscopy in unpreselected cadavers. METHODS: Twenty ultrasound-guided L5 dorsal ramus block approaches were performed with a new oblique out-of-plane technique in a rotated cross-axis view bilaterally in 10 cadavers. After checking the needle position in a second perpendicular sonographic plane, the final needle position was confirmed with conventional fluoroscopy by an independent observer. RESULTS: All cadavers had significant degenerations of the lumbar spine, and 5 of them had moderate to severe spondylolisthesis. Skin-to-target distances were 42 ±7 mm. Sixteen L5 dorsal ramus block attempts were located at the exact radiological target, 1 was slightly too lateral, and 3 were slightly too caudal (3-10 mm away). The overall success rate in unpreselected cadavers reached 80% (95% confidence interval, 56%-94%) and in the subgroup of corpses without spondylolisthesis 100% (95% confidence interval, 69%-100%). CONCLUSIONS: This is the first study to show that ultrasound-guided L5 dorsal ramus block is accurate and feasible in the absence of significant spondylolisthesis when performed with an oblique out-of-plane technique.

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 cm(2) to 128.80±95.7 cm(2)) and a 66% reduction after 3 months (81.38±59.19 cm(2)). 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.

Population-based study of central post-stroke pain in Rimini district, Italy.

Central post-stroke pain (CPSP) is still an underestimated complication of stroke, resulting in impaired quality of life and, in addition to the functional and cognitive consequences of stroke, the presence of CPSP may be associated with mood disorders, such as depression, anxiety, and sleep disturbances. This type of pain may also impair activities of daily living and further worsen quality of life, negatively influencing the rehabilitation process. The prevalence of CSPS in the literature is highly variable (1%-12%) according to different studies, and this variability could be influenced by selection criteria and the different ethnic populations being investigated. With this scenario in mind, we performed a population-based study to assess the prevalence of CPSP and its main features in a homogeneous health district (Rimini, Italy), including five hospitals for a total population of 329,970 inhabitants. From 2008 to 2010, we selected 1,494 post-stroke patients and were able to interview 660 patients, 66 (11%) of whom reported pain with related tactile and thermal hyperesthesia, accompanied by needle puncture, tingling, swelling, and pressure sensations. Patients reported motor impairment and disability, which influenced their working ability, rehabilitation, and social life. Despite this severe pain state, there was a high percentage of patients who did not receive adequate treatment for pain.