Cristina E. Minella

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.

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.

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.

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.

Spontaneous cervical (C1-C2) cerebrospinal fluid leakage repaired with computed tomography-guided cervical epidural blood patch.

To the Editor: Intracranial hypotension syndrome (IHS) is often caused by persistent cerebrospinal fluid (CSF) leakage. IHS usually presents with orthostatic headache, exacerbated by an increase in intracranial pressure, but other symptoms can be present such as nausea, vomiting, dizziness, neck pain, and paresis of the VIth cranial nerve. It can be spontaneous or related to a trauma, such as dural puncture or surgery, or medical causes such as dehydration. Thanks to improvements in neuroradiological imaging quality, magnetic resonance imaging (MRI) diagnosis of IHS is now more common and easier. IHS is a benign condition, often treated conservatively. If it does not resolve by itself, it usually can be treated with epidural blood patch (EBP), even if a Cochranemeta-analysis showed a lack of randomized controlled trials that confirm the efficacy of this approach. Rarely, IHS is caused by a high cervical problem and, to our knowledge, in the literature there are only three cases of C2 leakage treated with EBP with a large volume of blood (the authors repeated the procedure twice, with 10 mL each time). Case

Effect of postoperative analgesia on acute and persistent postherniotomy pain: a randomized study

STUDY OBJECTIVE The study objective is to identify differences in postoperative pain management according to different analgesic treatments, targeting 2 main pathways involved in pain perception. DESIGN The design is a randomized, parallel groups, open-label study. SETTING The setting is in an operating room, postoperative recovery area, and surgical ward. PATIENTS There are 200 patients undergoing open inguinal hernia repair (IHR) with tension-free technique (mesh repair). INTERVENTIONS The intervention is a randomization to receive ketorolac (group K) or tramadol (group T) for 3 days after surgery. MEASUREMENTS The measurements are differences in analgesic efficacy (numeric rating scale [NRS]) in the postoperative (up to 5 days) period, chronic pain incidence (1 and 3 months), side effects, and complications. MAIN RESULTS We found no differences in analgesic efficacy (NRS value ≥4 in the first 96 hours: 26% in group K vs 32% in group T, P = .43); the proportion of patients with NRS ≥4 was similar in both groups, and the time trajectories were not significantly different (P for interaction = .24). Side effects were higher (12% vs 6%) in the tramadol group, although not significantly (P = .14), with a case of bleeding in the ketorolac group and higher incidence of constipation in tramadol group. One patient in each group developed chronic pain. CONCLUSIONS Ketorolac or weak opioids are equally effective on acute pain and on persistent postsurgical pain development after IHR, and drug choice should be based on their potential side effects and patients comorbidities. Further studies are needed to standardize the most rational approach to prevent persistent postsurgical pain after IHR.

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.

‘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.

Pharmacokinetic considerations for therapies used to treat interstitial cystitis.

Introduction: Interstitial cystitis (IC) or bladder pain syndrome (BPS) is defined as supra-pubic pain related to bladder filling. IC is characterized by a particular symptom complex with no identifiable causes; as with bladder hypersensitivity it is usually associated with urinary frequency and urgency with bladder pain. No current treatments have a significant impact on symptoms over time. Areas covered: This systematic review examines the pharmacokinetic aspects and adverse event of present IC therapy to highlight appropriate treatment to improve the symptoms of IC. This article reviews material obtained via Medline, PubMed, and EMBASE literature searches up to October 2013. Expert opinion: The correct approach to IC should consider a multidisciplinary team of specialists and a multimodal treatment package that include psychotherapy, behavior change, physical activation, and analgesic treatment. Unfortunately, a single therapeutic target for IC is not yet known. With regard to pathophysiology and therapy, there is more to discover. The first insult damages the bladder urothelium, hence vehicles that lead the drug to penetrate the wall of the bladder might be a novel strategic approach.

Validation of standard operating procedures in a multicenter retrospective study to identify-omics biomarkers for chronic low back pain

Chronic low back pain (CLBP) is one of the most common medical conditions, ranking as the greatest contributor to global disability and accounting for huge societal costs based on the Global Burden of Disease 2010 study. Large genetic and -omics studies provide a promising avenue for the screening, development and validation of biomarkers useful for personalized diagnosis and treatment (precision medicine). Multicentre studies are needed for such an effort, and a standardized and homogeneous approach is vital for recruitment of large numbers of participants among different centres (clinical and laboratories) to obtain robust and reproducible results. To date, no validated standard operating procedures (SOPs) for genetic/-omics studies in chronic pain have been developed. In this study, we validated an SOP model that will be used in the multicentre (5 centres) retrospective “PainOmics” study, funded by the European Community in the 7th Framework Programme, which aims to develop new biomarkers for CLBP through three different -omics approaches: genomics, glycomics and activomics. The SOPs describe the specific procedures for (1) blood collection, (2) sample processing and storage, (3) shipping details and (4) cross-check testing and validation before assays that all the centres involved in the study have to follow. Multivariate analysis revealed the absolute specificity and homogeneity of the samples collected by the five centres for all genetics, glycomics and activomics analyses. The SOPs used in our multicenter study have been validated. Hence, they could represent an innovative tool for the correct management and collection of reliable samples in other large-omics-based multicenter studies.