Julia Riley

Clinical response to morphine in cancer patients and genetic variation in candidate genes

Morphine is the analgesic of choice for moderate to severe cancer pain; however, 10–30% of patients do not tolerate morphine. This study evaluated genetic variation in the μ-opioid receptor, βarrestin2, stat6 and uridine diphosphate-glucuronysltransferase 2B7 (UGT2B7) genes, in patients who responded to morphine vs those who were switched to alternative opioids. We prospectively recruited and genotyped 162 Caucasian patients (117 controls, 39 switchers). Switchers, were more likely to carry the common allele at 1182 G/A, 5864 G/A, 8622T/C and 11143 G/A in the βarrestin2 gene (P=0.021, 0.043, 0.013, 0.043, respectively). Switchers had increased carriage of the T allele (−1714 C/T) and a significant difference in the allelic frequency at 9065 C/T (χ2=3.86, P=0.049) in the stat6 gene. No differences were seen in genotype or allele frequencies of SNPs in the μ-opioid receptor gene or UGT2B7 gene. This study presents novel data suggesting that variation in genes involved in μ-opioid receptor signalling influence clinical response to morphine.

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.

Oxycodone: a review of its use in the management of pain

ABSTRACT Background: Oxycodone is a strong opioid that acts at mu- and kappa-opioid receptors. It has pharmacological actions similar to strong opioids, but with a specific pharmacologic profile and greater analgesic potency to morphine. The efficacy of oxycodone in managing neuropathic and somatic pain, both of malignant and non-malignant origin, has been established in a wide range of settings. Scope: This review aims to provide a comprehensive evaluation of oxycodone and its role within clinical settings in order to provide an evidence-based perspective on its use in the clinic. Literature searches using Medline, EMBASE and Cochrane Databases were used to compile data for review. The review provides information on the pharmacokinetics and pharmacodynamics of oxycodone and also profiles established clinical data in neuropathic and somatic pain as well as emerging data to support the use of oxycodone in visceral pain, which may be due to its interaction with kappa-opioid receptors. Oxycodone is available in a range of formulations for oral, intraspinal and parenteral administration. Findings: The prolonged-release form of oxycodone offers a fast onset of analgesia, controlling pain for 12 hours and providing clinically meaningful relief of moderate to severe pain and improving quality of life across a broad spectrum of pain types. Conclusions: Oxycodone provides significant pain relief. It has relevant points of difference from other opioids and as such may be a suitable alternative to morphine.

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.

Differences between opioids: pharmacological, experimental, clinical and economical perspectives

Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs. Hence, recommendations of the regulatory authorities have been driven by costs with a general tendency in many countries to restrict physicians use of opioids to morphine. Although this approach is recognized as cost‐effective in most cases there is solid evidence that, on an individual patient basis, opioids are not all equal. Therefore it is important to have an armamentarium of strong analgesics in clinical practice to ensure a personalized approach in patients who do not respond to standard treatment. In this review we highlight differences between opioids in human studies from a pharmacological, experimental, clinical and health economics point of view. We provide evidence that individuals respond differently to opioids, and that general differences between classes of opioids exist. We recommend that this recognition is used to individualize treatment in difficult cases allowing physicians to have a wide range of treatment options. In the end this will reduce pain and side effects, leading to improved quality of life for the patient and reduce the exploding pain related costs.

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

Differences between opioids

Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs. Hence, recommendations of the regulatory authorities have been driven by costs with a general tendency in many countries to restrict physicians use of opioids to morphine. Although this approach is recognized as cost‐effective in most cases there is solid evidence that, on an individual patient basis, opioids are not all equal. Therefore it is important to have an armamentarium of strong analgesics in clinical practice to ensure a personalized approach in patients who do not respond to standard treatment. In this review we highlight differences between opioids in human studies from a pharmacological, experimental, clinical and health economics point of view. We provide evidence that individuals respond differently to opioids, and that general differences between classes of opioids exist. We recommend that this recognition is used to individualize treatment in difficult cases allowing physicians to have a wide range of treatment options. In the end this will reduce pain and side effects, leading to improved quality of life for the patient and reduce the exploding pain related costs.