Joy R. Ross

Genetic variation in the Catechol-O-Methyltransferase (COMT) gene and morphine requirements in cancer patients with pain

BackgroundGenetic variation contributes to differences in pain sensitivity and response to different analgesics. Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Genetic variability in the COMT gene may therefore contribute to differences in pain sensitivity and response to analgesics. It is shown that a polymorphism in the COMT gene, Rs4680 (Val158Met), influence pain sensitivity in human experimental pain and the efficacy for morphine in cancer pain treatment. In this study we wanted to investigate if variability in other regions in the COMT gene also contributes to interindividual variability in morphine efficacy.ResultsWe genotyped 11 single nucleotide polymorphisms (SNPs) throughout the COMT gene, and constructed haplotypes from these 11 SNPs, which were in Hardy-Weinberg equilibrium. We compared both genotypes and haplotypes against pharmacological, demographical and patient symptoms measurements in a Caucasian cancer patient cohort (n = 197) receiving oral morphine treatment for cancer pain. There were two frequent haplotypes (34.5% and 17.8%) in our cohort. Multivariate analyses showed that patients carrying the most frequent haplotype (34.5%) needed lower morphine doses than patients not carrying the haplotype, with a reduction factor of 0.71 (p = 0.005). On the allele level, carriers of alleles for six of the SNPs show weak associations in respect to morphine dose and the alleles associated with the lowest morphine doses constitute part of the most frequent haplotype.ConclusionThis study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.

Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects.

Pain is a common symptom for patients with cancer, and opioids are the treatment of choice for moderate or severe cancer‐related pain. Central side effects, such as drowsiness, confusion, and hallucinations, can limit the use of opioids in clinical practice.

No pain relief from morphine? Individual variation in sensitivity to morphine and the need to switch to an alternative opioid in cancer patients.

Goals of workThe aims of this study were (1) to prospectively evaluate the clinical benefits of switching from morphine to an alternative opioid, using oxycodone as first-line alternative opioid, in patients with cancer, (2) to evaluate the consistency of the clinical decision for the need to switch by comparing two hospital sites, and (3) to evaluate whether there were objective predictors that would help identify morphine non-responders who require switching to an alternative opioid and from this to construct a clinical model to predict the need to switch.Patients and methodsOne hundred eighty-six palliative care patients were prospectively recruited from two hospital sites. Responders were patients treated with morphine for more than 4 weeks with good analgesia and minimal side effects. Non-responders (switchers) were patients who had either uncontrolled pain or unacceptable side effects on morphine and therefore required an alternative opioid. The differentiation between responders and switchers was made clinically and later confirmed by objective parameters.ResultsIn this prospective study 74% (138/186) had a good response to morphine (responders). One patient was lost to follow up. Twenty-five percent (47/186) did not respond to morphine. These non-responders were switched to alternative opioids (switchers). Furthermore, of 186 patients, 37 achieved a successful outcome when switched to oxycodone and an additional 4 were well controlled when switched to more than one alternative opioid. Overall successful pain control with minimal side effects was achieved in 96% (179/186) of patients. There were no significant differences in the need to switch between the two hospital sites.ConclusionsThis study has shown that proactive clinical identification and management of patients that require opioid switching is reproducible in different clinical settings and significantly improves pain control. Further studies are required to develop and test the predictive model.

The palliative care needs for fibrotic interstitial lung disease: A qualitative study of patients, informal caregivers and health professionals

Background: While there have been some studies looking at the impact on quality of life of patients with idiopathic pulmonary fibrosis, to date no qualitative research looking at the specialist palliative needs of these patients has been conducted. Aim: This study aims to explore the specialist palliative care needs of people living with end-stage progressive idiopathic fibrotic interstitial lung disease. Design and settings/participants: In total, 18 qualitative semi-structured in-depth interviews were conducted with patients, their informal caregivers and health professionals across two specialist interstitial lung disease centres in London and in the community. Results: Many participants reported uncontrolled symptoms of shortness of breath, cough and insomnia, which profoundly impacted every part of patients’ and informal caregivers’ lives. Psychologically, patients were frustrated and angry at the way in which their illness severely limited their ability to engage in activities of daily living and compromised their independence. Furthermore, both patients and informal caregivers also reported that the disease seriously affected family relationships where strain was pronounced. There was varied knowledge and confidence among health professionals in managing symptoms, and psychosocial needs were often underestimated. Conclusion: This study is the first of its kind to examine in depth the impact of symptoms and psychosocial needs revealing the profound effect on every aspect of progressive idiopathic fibrotic interstitial lung disease patients’ and informal caregivers’ lives. Education and guidance of appropriate palliative care interventions to improve symptom control are needed. A case conference intervention with individualised care plans may help in addressing the substantial symptom control and psychosocial needs of these patients and informal caregivers.

Constipation in cancer patients on morphine

Goals of workConstipation is a significant problem in patients taking morphine for cancer pain. The aims of this study were (1) to assess the magnitude of constipation in this study cohort, (2) to analyse the constipation treatment strategies and (3) to look for evidence of inter-individual variation in both susceptibility to constipation and response to treatment with laxatives in this patient group.Materials and methodsThis was an observational study carried out in a tertiary referral cancer hospital. Two hundred seventy four patients were recruited to the study. All had a diagnosis of cancer and were on oral morphine for cancer pain. The main outcomes measured were subjective patient assessment of constipation severity in the preceding week and laxative use. Patients were asked to grade constipation in the preceding week on a four-point categorical scale: “not at all” (grade 0), “a little” (grade 1), “quite a bit” (grade 2) and “very much” (grade 3). Laxative dose groups (LDGs) were developed to assess laxative dosing.ResultsConstipation affects 72% of this cohort of patients. Constipation in this population is poorly managed. Eighty nine percent of constipated patients were on inadequate laxative therapy. Inter-individual variation in constipation on morphine exists: some patients do not experience constipation and do not need to take any laxatives, some patients do not experience constipation because they are taking laxatives and some patients experience constipation despite being on high dose laxatives. These three groups were compared in terms of cancer diagnosis, time on morphine, dose of morphine and other concomitant factors. No factor was identified to account for this inter-individual variation. Improvement in the clinical management of constipation is needed, with titration of laxatives according to individual patient need.ConclusionConstipation affects a large proportion of cancer patients taking oral morphine. Constipation in these patients is generally inadequately treated.

Palliative care for people with non-malignant lung disease: summary of current evidence and future direction

Background: The physical and psychosocial needs of patients with chronic non-malignant lung disease are comparable to those with lung cancer. This article will focus on chronic obstructive pulmonary disease, interstitial lung disease and cystic fibrosis as examples of life-limiting, non-curable and non-malignant lung diseases. The need for supportive and palliative care: Recent national guidance has demanded that palliative care is inclusive of all patients with life-limiting disease, irrespective of diagnosis, and that specialist palliative care teams are involved in the management of patients on a basis of need rather than prognosis. What is known: Despite medical therapy, most patients with moderate to severe chronic obstructive pulmonary disease, interstitial lung disease and cystic fibrosis experience pain, fatigue and dyspnoea, with the majority not getting relief from dyspnoea towards the end of life. Furthermore, dyspnoea causes social isolation and difficulty performing activities of daily living and impairs quality of life. There is an increasing evidence base for the assessment of supportive and palliative care needs, symptom interventions, prognostication, models of service delivery and implications of these for clinical practice and research in non-malignant lung diseases. What is unknown: Despite advances, much still remains unknown regarding assessment, management and prognostication in individual chronic non-malignant lung diseases. Although different service models are being used in clinical practice, the optimal model(s) of service delivery remain unknown. Implication for future research, policy and practice: We describe key areas for further research, which include the need for large, high-quality trials of pharmacological and non-pharmacological interventions and their combinations as well as evaluation of the efficacy and cost-effectiveness of models of care. As access to palliative care is poor for these patients, the barriers to referral need to be understood and reduced, which along with effective working between palliative care teams, with respiratory services backup, should optimise delivery of care in patients with life-limiting non-malignant lung disease.

Interventions to improve symptoms and quality of life of patients with fibrotic interstitial lung disease: a systematic review of the literature

Background Patients with fibrotic interstitial lung disease have symptom control and quality of life (QoL) needs. This review aims to evaluate the evidence for the use of interventions in improving dyspnoea, other symptoms and QoL. Methods Eleven databases, relevant websites and key journals were hand-searched. Studies were assessed and data extracted independently by two researchers using standardised proformas. Meta-analyses were performed where possible with 95% CI. Results 34 papers with 19 interventions in 3635 patients were included. Meta-analyses showed no significant effect of interferon γ-1b or sildenafil on 6-minute walking distance (6MWD) or dyspnoea. Pulmonary rehabilitation and pirfenidone had a positive effect on 6MWD (mean difference (95% CI) 27.4 (4.1 to 50.7)) and 24.0 (4.3 to 43.7), respectively), and pulmonary rehabilitation had a mixed effect on dyspnoea. Both pulmonary rehabilitation and sildenafil showed a trend towards significance in improving QoL. There was weak evidence for the improvement of 6MWD using oxygen; dyspnoea using prednisolone, diamorphine, D-pencillamine and colchicine; cough using interferon α and thalidomide; anxiety using diamorphine; fatigue using pulmonary rehabilitation; and QoL using thalidomide and doxycycline. A wide range of outcome scales was used and there were no studies with economic evaluation. Conclusions There is strong evidence for the use of pulmonary rehabilitation and pirfenidone to improve 6MWD and moderate evidence for the use of sildenafil and pulmonary rehabilitation to improve QoL. Future recommendations for research would include careful consideration of the dichotomy of radical and palliative treatments when deciding on how symptom and QoL outcome measures are used and data presented.

Palliative care for patients with advanced fibrotic lung disease: a randomised controlled phase II and feasibility trial of a community case conference intervention

Background Those affected by advanced fibrotic interstitial lung diseases (ILDs) have considerable unmet symptom and psychological needs. Case conferencing has been proposed to address these issues, but requires evaluation. Aim To obtain preliminary information on the impact of a case conference intervention delivered in the home (Hospital2Home) on palliative care concerns of patients and their carers, and to evaluate feasibility and acceptability. Methods Hospital2Home was trialled at a specialist centre using a Phase II fast-track randomised controlled trial with qualitative interviews. The primary outcome for effect was mean change from baseline of Palliative Care Outcome Scale (POS) (a measure of symptoms and concerns) at 4 weeks. Secondary outcomes included symptom control, quality of life, consent and recruitment rates and percentage of patients in the fast-track group receiving case conferences within 14 days. Results 53 patients were recruited (26 fast-track, 27 controls). Mean (SD) POS scores at 4 weeks were −5.7 (7.5) fast-track vs −0.4 (8.0) control, (mean change difference between the two arms was −5.3 (95% CI −9.8 to −0.7) independent t test p=0.02); effect size (95% CI) −0.7 (−1.2 to −0.1). The secondary outcomes of quality of life, anxiety and depression were superior in the fast-track arm, and none were worse. Qualitative findings corroborate these data. Recruitment was successful and 53/67 (79%) of eligible patients consented. 6/25 (24%) had case conferences within 14 days. Conclusions Community case conferences improve palliative symptoms and quality of life after 4 weeks. Hospital2Home for the most part is both feasible and acceptable. It now requires further testing in multicentre trials. Trial registration number NCT01450644

‘I wish I knew more ...’ the end-of-life planning and information needs for end-stage fibrotic interstitial lung disease: views of patients, carers and health professionals

The importance at the end of life of developing effective communication and meeting information needs is recognised as being central to enhance patient and family centred experience. This qualitative study aimed to explore understanding of the disease, preferences regarding end-of-life planning, and views on communication and coordination of care in patients with Progressive Idiopathic Fibrotic Interstitial Lung Disease (PIF-ILD). Twelve semistructured in-depth qualitative interviews were conducted among PIF-ILD patients and carers attending two London hospitals. Six Interviews were also conducted among health professionals from one London Hospital, a palliative care service and primary care. There was good understanding of the terminal nature of the disease among both patients and carers, but a poor understanding of prognosis, and how the disease would manifest at the end stages. Both patients and carers expressed a wish to receive more information from clinicians. Health professionals recognised the difficulty of balancing information needs with maintaining hope. No participants were aware of any palliative care input, and no participants had considered important end-of-life issues, such as preferred place of care and preferred place of death. Our work shows that palliative interventions need to be developed for this group of patients which should aim to improve communication and coordination of care, while facilitating discussions surrounding information needs and important end-of-life preferences.

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.