Ruth Branford

Opioid genetics: the key to personalized pain control?

There are now several strong opioids available to choose from for the relief of moderate to severe pain. On a population level, there is no difference in terms of analgesic efficacy or adverse reactions between these drugs; however, on an individual level there is marked variation in response to a given opioid. The genetic influences to this variation are complex, and although current research has shown some promising results, these have not been replicated across larger studies and as such the ultimate aim of personalized prescribing remains elusive. If personalized prescribing could be achieved this would have a major impact at an individual level to facilitate safe, effective and rapid symptom control. This review presents some of the recent positive advances in opioid pharmacogenetic studies, focusing on associations between candidate genes and the three main elements of opioid response: analgesic, upper gastrointestinal and central adverse reactions.

Morphine or Oxycodone for Cancer-Related Pain? A Randomized, Open-Label, Controlled Trial

CONTEXTnThere is wide interindividual variation in response to morphine for cancer-related pain; 30% of patients do not have a good therapeutic outcome. Alternative opioids such as oxycodone are increasingly being used, and opioid switching has become common clinical practice.nnnOBJECTIVESnTo compare clinical response to oral morphine vs. oral oxycodone when used as first-line or second-line (after switching) treatment in patients with cancer-related pain.nnnMETHODSnIn this prospective, open-label, randomized, controlled trial (ISRCTN65155201) with a selected crossover phase, patients with cancer-related pain were randomized to receive either oral morphine or oxycodone as first-line treatment. Dose was individually titrated until the patient reported adequate pain control. Patients who did not respond to the first-line opioid (either because of inadequate analgesia or unacceptable adverse effects) were switched to the alternative opioid.nnnRESULTSnTwo hundred patients were recruited. On intention-to-treat analysis (nxa0=xa0198, morphine 98, oxycodone 100), there was no significant difference between the numbers of patients responding to morphine (61/98xa0=xa062%) or oxycodone (67/100xa0=xa067%) when used as a first-line opioid. Similarly, there was no significant difference in subsequent response when patients were switched to either morphine (8/12xa0=xa067%) or oxycodone (11/21xa0=xa052%). Per-protocol analysis demonstrated a 95% response rate when both opioids were available. There was no difference in adverse reaction scores between morphine and oxycodone either in first-line responders or nonresponders.nnnCONCLUSIONnIn this population, there was no difference between analgesic response or adverse reactions to oral morphine and oxycodone when used as a first- or second-line opioid. These data provide evidence to support opioid switching to improve outcomes.

Analgesia and central side-effects: two separate dimensions of morphine response

AIMSnTo present a statistical model for defining interindividual variation in response to morphine and to use this model in a preliminary hypothesis-generating multivariate genetic association study.nnnMETHODSnTwo hundred and sixty-four cancer patients taking oral morphine were included in a prospective observational study. Pain and morphine side-effect scores were examined using principal components analysis. The resulting principal components were used in an exploratory genetic association study of single nucleotide polymorphisms across the genes coding for the three opioid receptors, OPRM1, OPRK1 and OPRD1. Associations in multivariate models, including potential clinical confounders, were explored.nnnRESULTSnTwo principal components corresponding to residual pain and central side-effects were identified. These components accounted for 42 and 18% of the variability in morphine response, respectively, were independent of each other and only mildly correlated. The genetic and clinical factors associated with these components were markedly different. Multivariate regression modelling, including clinical and genetic factors, accounted for only 12% of variability in residual pain on morphine and 3% of variability in central side-effects.nnnCONCLUSIONSnAlthough replication is required, this data-driven analysis suggests that pain and central side-effects on morphine may be two separate dimensions of morphine response. Larger study samples are necessary to investigate potential genetic and clinical associations comprehensively.

Association Between Human Pain-Related Genotypes and Variability in Opioid Analgesia: An Updated Review

On an individual level, there is a difference in the analgesic response to a given opioid. Various factors such as gender, age, and genetic variation can affect the analgesic response. The genetic variation can influence pharmacokinetics (eg drug transporters and drug‐metabolizing enzymes) and/or pharmacodynamics (eg opioid receptor and catechol‐O‐methyltransferase enzymes). We present recent experimentally induced pain, postoperative pain, and cancer pain and chronic non‐malignant pain conditions studies in humans, focusing on the association between genetic variation and analgesic response assessed as opioid consumption or changes in pain scores. Studies have shown promising results regarding pharmacogenetics as a diagnostic tool for predicting the individual response to a given opioid in the experimental settings; however, in the clinic, it is a more complicated task to accomplish.

Gender, variation in opioid receptor genes and sensitivity to experimental pain

BackgroundPain tolerance is subject to considerable inter-individual variation, which may be influenced by a number of genetic and non-genetic factors. The mu, delta and kappa opioid receptors play a role in pain perception and are thought to mediate different pain modalities. The aim of this study was to explore associations between pain thresholds and gender and genetic variants in the three opioid receptor genes (OPRM, OPRD and OPRK). Experimental multi-modal pain data from previously published studies carried out in healthy Caucasian volunteers were used in order to limit the number of confounders to the study outcome. Data on thermal skin pain (n=36), muscle pressure pain (n=31) and mechanical visceral pain (n=50)) tolerance thresholds were included.ResultsNineteen genetic polymorphisms were included in linear regression modeling. Males were found to tolerate higher thermal and muscle pressure pain than females (p=0.003 and 0.02). Thirty four percent of variability in thermal skin pain was accounted for by a model consisting of OPRK rs6473799 and gender. This finding was just outside significance when correction for multiple testing was applied. Variability in muscle pressure pain tolerance was associated with OPRK rs7016778 and rs7824175. These SNPs accounted for 43% of variability in muscle pressure pain sensitivity and these findings remained significant after adjustment for multiple testing. No association was found with mechanical visceral pain.ConclusionThis is a preliminary and hypothesis generating study due to the relatively small study size. However, significant association between the opioid receptor genes and experimental pain sensitivity supports the influence of genetic variability in pain perception. These findings may be used to generate hypotheses for testing in larger clinical trials of patients with painful conditions.

Adverse event reporting in randomised controlled trials of neuropathic pain: considerations for future practice.

Summary Improving adverse event reporting and developing standardize methods for collection of data will facilitate comparisons of information across trials of neuropathic pain. ABSTRACT High‐quality information on the potential benefit and harm of a drug is required for patients and clinicians to make informed treatment decisions and to enable cost‐effectiveness modeling to be undertaken. This systematic review describes the collection and reporting of adverse event data as presented in published clinical trials of neuropathic pain for the evaluation of antidepressant or antiepileptic drugs. A total of 74 studies in 16,323 patients published between 1965 and 2012 were identified, of which 43 were published from 2004 onwards. The review found that methods used to collect adverse event data, the frequency of collection, and the selection criteria used by authors for reporting adverse events vary substantially, and these events are often inadequately reported. Consequently, a potential synthesis of valuable harm information across trials is hampered. We make recommendations regarding the reporting of methods used to collect, assess, select, and present adverse event data in publications. Through the Core Outcome Measures in Effectiveness Trials (COMET) initiative, core outcome sets (which include effectiveness and harm) are developed by disease condition. To facilitate data synthesis for adverse events of drug therapies, we suggest that core outcome sets for harms could be developed by therapeutic class (ie, individualized for each class of drug). To improve comparability of information across trials collection methods need to be standardized for patient reports (spontaneous or prompted) and active surveillance (clinical examinations and laboratory tests). Uniform methods for presenting summary information regarding recurrent events, duration and timing of events requires further research.

Pharmacogenetics of analgesic drugs

Summary points •u2003Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined. •u2003Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications. •u2003While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype–phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor). •u2003Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future. •u2003This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors’ views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain.

Adverse event reporting in randomised trials of neuropathic pain: challenges for clinical usefulness of safety data

Background Monitoring the safety of therapies is of paramount importance in protecting patients from harm and enabling risk-benefit assessment. The recording and reporting of measures of efficacy has received considerable attention and while by no means perfect, has advanced further than the parallel assessment of harm. The stimulus for this study came from a commissioned effectiveness and cost-effectiveness review of treatments for neuropathic pain in patients (the CEAN study) [1]. CEAN noted that the completeness of adverse event (AE) reporting varied between trials and some expert opinion was required where primary data were insufficient for modeling cost-effectiveness. Further, clinicians indicated that trials sometimes failed to provide adequate information for clinical decision-making and informing patients.

The genetic influences on oxycodone response characteristics in human experimental pain

Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu‐, kappa‐ and delta‐opioid receptor genes (OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold (PTT) (n = 37), muscle pressure PTT (n = 31), mechanical visceral PTT (n = 43) and thermal visceral PTT (n = 41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single‐nucleotide polymorphisms (SNPs) rs589046 (P < 0.0001) and rs563649 (P < 0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 (P = 0.015), rs1799971 (P = 0.045), rs9479757 (P = 0.009) and rs533586 (P = 0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance (P = 0.015). Another OPRD1 SNP rs2234918 (P = 0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone.

The Characteristics and Quality of Randomized Controlled Trials in Neuropathic Pain A Descriptive Study Based on a Systematic Review

Background:Evidence from randomized controlled trials is regarded as the gold standard in clinical research and yet the quality of the conduct and reporting of trials is variable, even post-Consolidated Standards of Reporting Trials. This study arose from a systematic review and cost-effectiveness analysis of treatment for neuropathic pain. The aim was to provide a description of the included trials and investigate trends in study characteristics and measures of quality over time. Methods:The review provided data regarding study characteristics (patients, place, time, drugs, outcomes), methodological factors (sample size calculations, randomization, reporting baseline patient data, withdrawals, intention-to-treat (ITT), and statistical analysis (completeness and correctness of reporting of results, methods of analysis). Results:A total of 131 trials from 1969 to 2007 were included. Of these, 63% were parallel-group designs, the remainder were cross-over; 73% were placebo-controlled. Several trial features increased or improved over time: trial size, quality (using Jadad score), presentation of baseline data by group, reporting of power calculations, use of visual analogue score or numerical rating scale scales to assess pain, completeness of reporting of statistical results, use of modeling to allow for baseline pain scores. The proportion of withdrawals was constant over time with a mean of 14.3%. The proportion of studies stating the analysis as ITT, increased over time, but inspection of papers indicated that the proportion confirmed as ITT was unchanged. Conclusions:There have been a number of improvements regarding the quality and reporting of randomized controlled trials in neuropathic pain, but some failings remain that at best make some results difficult to interpret and at worst lead to bias.