[Show abstract][Hide abstract] ABSTRACT: Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment. Innate immune activation has been implicated generally in pain, opioid analgesia, cognitive dysfunction, and sickness type symptoms reported by cancer patients. We aimed to determine if genetic polymorphisms in neuroimmune activation pathways alter the serum fentanyl concentration-response relationships for pain control, cognitive dysfunction, and other adverse symptoms, in cancer pain patients. Cancer pain patients (468) receiving transdermal fentanyl were genotyped for 31 single nucleotide polymorphisms in 19 genes: CASP1, BDNF, CRP, LY96, IL6, IL1B, TGFB1, TNF, IL10, IL2, TLR2, TLR4, MYD88, IL6R, OPRM1, ARRB2, COMT, STAT6 and ABCB1. Lasso and backward stepwise generalised linear regression were used to identify non-genetic and genetic predictors, respectively, of pain control (average Brief Pain Inventory < 4), cognitive dysfunction (Mini-Mental State Examination ≤ 23), sickness response and opioid adverse event complaint. Serum fentanyl concentrations did not predict between-patient variability in these outcomes, nor did genetic factors predict pain control, sickness response or opioid adverse event complaint. Carriers of the MYD88 rs6853 variant were half as likely to have cognitive dysfunction (11/111) than wild-type patients (69/325), with a relative risk of 0.45 (95% CI: 0.27 to 0.76) when accounting for major non-genetic predictors (age, Karnofsky functional score). This supports the involvement of innate immune signalling in cognitive dysfunction, and identifies MyD88 signalling pathways as a potential focus for predicting and reducing the burden of cognitive dysfunction in cancer pain patients.
PLoS ONE 09/2015; 10(9):e0137179. DOI:10.1371/journal.pone.0137179 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patient-reported outcomes should ideally be adapted to the individual patient while maintaining comparability of scores across patients. This is achievable using computerized adaptive testing (CAT). The aim here was to develop an item bank for CAT measurement of the pain domain as measured by the EORTC QLQ-C30 questionnaire.
The development process consisted of four steps: (1) literature search, (2) formulation of new items and expert evaluations, (3) pretesting and (4) field-testing and psychometric analyses for the final selection of items.
In step 1, we identified 337 pain items from the literature. Twenty-nine new items fitting the QLQ-C30 item style were formulated in step 2 that were reduced to 26 items by expert evaluations. Based on interviews with 31 patients from Denmark, France and the UK, the list was further reduced to 21 items in step 3. In phase 4, responses were obtained from 1103 cancer patients from five countries. Psychometric evaluations showed that 16 items could be retained in a unidimensional item bank. Evaluations indicated that use of the CAT measure may reduce sample size requirements with 15-25 % compared to using the QLQ-C30 pain scale.
We have established an item bank of 16 items suitable for CAT measurement of pain. While being backward compatible with the QLQ-C30, the new item bank will significantly improve measurement precision of pain. We recommend initiating CAT measurement by screening for pain using the two original QLQ-C30 pain items. The EORTC pain CAT is currently available for "experimental" purposes.
Quality of Life Research 08/2015; DOI:10.1007/s11136-015-1069-5 · 2.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors.
Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1).
The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini-Hochberg criterion for a 10% false discovery rate.
Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment.
Clinical and Translational Gastroenterology 06/2015; 6(6):e90. DOI:10.1038/ctg.2015.19
[Show abstract][Hide abstract] ABSTRACT: Opioids modulate the perception of breathlessness with a considerable variation in response, with poor correlation between the required opioid dose and symptom severity. The objective of this hypothesis-generating, secondary analysis was to identify candidate single nucleotide polymorphisms (SNP) from those associated with opioid receptors, signalling or pain modulation to identify any related to intensity of breathlessness while on opioids. This can help to inform prospective studies and potentially lead to better tailoring of opioid therapy for refractory breathlessness.
17 hospice/palliative care services (tertiary services) in 11 European countries.
2294 people over 18 years of age on regular opioids for pain related to cancer or its treatment.
The relationship between morphine dose, breathlessness intensity (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EORTCQLQC30 question 8) and 112 candidate SNPs from 25 genes (n=588).
The same measures for people on oxycodone (n=402) or fentanyl (n=429).
SNPs not in Hardy-Weinberg equilibrium or with allele frequencies (<5%) were removed. Univariate associations between each SNP and breathlessness intensity were determined with Benjamini-Hochberg false discovery rate set at 20%. Multivariable ordinal logistic regression, clustering over country and adjusting for available confounders, was conducted with remaining SNPs. For univariate morphine associations, 1 variant on the 5-hydroxytryptamine type 3B (HTR3B) gene, and 4 on the β-2-arrestin gene (ARRB2) were associated with more intense breathlessness. 1 SNP remained significant in the multivariable model: people with rs7103572 SNP (HTR3B gene; present in 8.4% of the population) were three times more likely to have more intense breathlessness (OR 2.86; 95% CIs 1.46 to 5.62; p=0.002). No associations were seen with fentanyl nor with oxycodone.
This large, exploratory study identified 1 biologically plausible SNP that warrants further study in the response of breathlessness to morphine therapy.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BMJ Open 05/2015; 5(5):e006818. DOI:10.1136/bmjopen-2014-006818 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Renal impairment and the risk of toxicity caused by accumulation of opioids and/or active metabolites is an under-investigated issue. This study aimed at analysing if symptoms/adverse effects in opioid-treated patients with cancer were associated with renal function.Methods
Cross-sectional multicentre study (European Pharmacogenetic Opioid Study, 2005–2008), in which 1147 adult patients treated exclusively with only one of the most frequently reported opioids (morphine/oxycodone/fentanyl) for at least 3 days were analysed. Fatigue, nausea/vomiting, pain, loss of appetite, constipation and cognitive dysfunction were assessed (EORTC QLQ-C30). Glomerular filtration rate (GFR) was estimated using Cockcroft–Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations.ResultsMild to severe low GFR was observed among 40–54% of patients. CG equation showed that patients with mild and moderate/severe low GFR on morphine treatment had higher odds of having severe constipation (P < 0.01) than patients with normal GFR. In addition, patients with moderate/severe low GFR on morphine treatment were more likely to have loss of appetite (P = 0.04). No other significant associations were found.Conclusion
Only severe constipation and loss of appetite were associated with low GFR in patients treated with morphine. Oxycodone and fentanyl, in relation to the symptoms studied, seem to be safe as used and titrated in routine cancer pain care.
[Show abstract][Hide abstract] ABSTRACT: Purpose of review: This review considers the role of physical therapies in osteoarthritis management, highlighting key findings from systematic reviews and randomized controlled trials published in the last 2 years. Recent findings: Three new trials question the role of manual therapy for hip and knee osteoarthritis. No between-group differences in outcome were detected between a multimodal programme including manual therapy and home exercise, and placebo in one trial; a second trial found no benefit of adding manual therapy to an exercise programme, while a third trial reported marginal benefits over usual care that were of doubtful importance. Recent trials have also found no or uncertain clinical benefits of transcutaneous electrical nerve stimulation (TENS) or acupuncture, or of valgus braces or lateral wedge insoles for pain and function in knee osteoarthritis. Available evidence suggests a small to moderate effect of exercise in comparison with not exercising for hip or knee osteoarthritis, although optimum exercise prescription and dosage are unclear. One trial also observed a delay in joint replacement in people with hip osteoarthritis. Two trials have reported conflicting findings about the effects of exercise for hand osteoarthritis. Summary: Other than exercise, recent data suggest that the role of physical therapies in the treatment of osteoarthritis appears limited.
[Show abstract][Hide abstract] ABSTRACT: Depressive symptoms are common in patients with cancer and tend to increase as death approaches. The study aims were to examine the prevalence of depressive symptoms in patients with cancer in their final 24 h, and their association with other symptoms, sociodemographic and care characteristics.
A stratified sample of deaths was drawn by Statistics Netherlands. Questionnaires on patient and care characteristics were sent to the physicians (N=6860) who signed the death certificates (response rate 77.8%). Adult patients with cancer with non-sudden death were included (n=1363). Symptoms during the final 24 h of life were assessed on a 1-5 scale and categorised as 1=no, 2-3=mild/moderate and 4-5=severe/very severe.
Depressive symptoms were registered in 37.6% of the patients. Patients aged 80 years or more had a reduced risk of having mild/moderate depressive symptoms compared with those aged 17-65 years (OR 0.70; 95% CI 0.50 to 0.99). Elderly care physicians were more likely to assess patients with severe/very severe depressive symptoms than patients with no depressive symptoms (OR 4.18; 95% CI 1.48 to 11.76). Involvement of pain specialists/palliative care consultants and psychiatrists/psychologists was associated with more ratings of severe/very severe depressive symptoms. Fatigue and confusion were significantly associated with mild/moderate depressive symptoms and anxiety with severe/very severe symptoms.
More than one-third of the patients were categorised with depressive symptoms during the last 24 h of life. We recommend greater awareness of depression earlier in the disease trajectory to improve care.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Supportive and Palliative Care 02/2015; DOI:10.1136/bmjspcare-2014-000722
[Show abstract][Hide abstract] ABSTRACT: Purpose:
The aims of this study were to explore the efficacy of intranasal fentanyl spray* (INFS) 400 μg to evaluate 12-week tolerability of the nasal mucosa and to explore safety data for all dose strengths of INFS in patients with cancer-related breakthrough pain (BTP).
Patients received a test dose of INFS 50 μg, followed by a titration phase. Those patients with doses titrated to 200 or 400 μg entered a randomized, double-blind, cross-over efficacy phase, in which 8 episodes of BTP were randomly treated with INFS 400 μg (6 episodes) and placebo (2 episodes), followed by a tolerability phase. Patients with doses titrated to 50 or 100 μg entered the tolerability phase directly. Primary outcome was measured by pain intensity difference at 10 minutes, analyzed using ANCOVA, and presented as least square mean difference. Examination of the nasal cavity was conducted at inclusion and after 12 weeks of treatment by an otorhinolaryngologist.
Forty-six patients were included. Thirty-eight patients' doses were titrated to an effective dose of INFS; 50 μg (n = 8), 100 μg (n = 9), 200 μg (n = 9), and 400 μg (n = 12); 15 patients entered the efficacy phase and 31 entered the tolerability phase. In the efficacy phase, 88 and 29 episodes of BTP were treated with INFS 400 μg and placebo, respectively. Pain intensity difference at 10 minutes least square mean for INFS 400 μg was 2.5 (95% CI, 1.42-3.49) (P < 0.001) and least square mean difference between INFS 400 μg and placebo was 1.1 (95% CI, 0.41-1.79) (P = 0.002). Runny nose (10%) and change in color of the mucosa (9%) were the most frequent findings of nasal examination, and nausea and dizziness were the most frequent treatment-related adverse events. One serious adverse event (ie, respiratory depression) was considered related to INFS.
INFS 400 μg is effective and nasal tolerability and overall safety profile is acceptable during 12 weeks of use. ClinicalTrials.gov identifier: NCT01429051.
[Show abstract][Hide abstract] ABSTRACT: Evidence-based treatment guidelines embedded in computer-based clinical decision support systems (CCDSS) may improve patient-reported outcomes (PRO). We systematically reviewed the literature for content and application of CCDSS, and their effects on PRO.
A systematic review in MEDLINE and EMBASE was conducted according to PRISMA standards. Searches were limited to the publication period 1996-May 2014 and the English language. The search terms covered "computerized clinical decision systems" and "patient-reported outcomes". Screening and extraction was done independently by two reviewers according to predefined inclusion (computer and guideline) and exclusion criteria (no trial, no PRO). Study and CCDSS quality was rated according to predefined criteria.
The database searches identified 1,331 references. Eighty-seven full-text articles were analyzed. The main reason for exclusion was no PRO as a study outcome measure. Fifteen studies met the inclusion criteria, representing 13,480 patients. Nine studies used a computerized device to fill in data; in four studies, this was used by the patients themselves. Most of the studies presented the data to the clinician at point of care and incorporated international guidelines. Three studies showed a positive effect on PRO, but only on symptoms. Overall, no negative effects were reported. There was no association with study quality or year of study publication.
There are marginal positive effects of CCDSS on specific PRO. Factors that facilitate the use and effect are identified. Easy to use systems with difficult to ignore evidence-based advice need to be developed and tested.
The patient 11/2014; DOI:10.1007/s40271-014-0100-1 · 1.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
The study objective was to evaluate whether there are clinical or genetic differences between patients with cancer-induced bone pain (CIBP) and patients with non-CIBP, and, in the CIBP group, in those with good versus poor opioid response.
Materials and methods:
A total of 2,294 adult patients with cancer who were receiving opioids for moderate or severe pain were included in the European Pharmacogenetic Opioid Study. Pain intensity and pain relief were measured using the Brief Pain Inventory. Linkage disequilibrium of 112 single nucleotide polymorphisms was evaluated in 25 candidate genes, and 43 haplotypes were assessed. Correlations among demographical factors, disease-related factors, genetic factors, CIBP, and pain relief were analyzed by logistic regression models corrected for multiple testing. Patients with bone metastases and bone/soft tissue pain were defined as having prevalent bone pain (CIBP population). This population was compared with patients who had other types of cancer pain (non-CIBP).
A total of 577 patients (26.2%) had CIBP, and 1,624 patients (73.8%) had non-CIBP. Patients with CIBP had more breakthrough cancer pain episodes (64.2% vs. 56.4%, p = .001), had significantly higher pain interference in "walking ability in the past 24 hours" (p < .0001), used more adjuvant drugs (84.1% vs. 78.3%, p = .003), and had a higher, albeit nonsignificant, median overall survival (3.8 vs. 2.9 months, p = .716) than patients with non-CIBP. None of the examined haplotypes exceeded p values corrected for multiple testing for the investigated outcomes.
Patients with CIBP who were taking opioids had a clinical profile slightly different from that of the non-CIBP group. However, no specific genetic pattern emerged for CIBP versus non-CIBP or for responsive versus nonresponsive patients with CIBP.
The Oncologist 10/2014; 19(12). DOI:10.1634/theoncologist.2014-0174 · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neuropathic pain (NP) in cancer patients lacks standards for diagnosis. This study is aimed at reaching consensus on the application of the NeuPSIG criteria to the diagnosis of NP in cancer patients and on the relevance of patient reported outcome (PRO) descriptors for the screening of NP in this population. An international group of 42 experts was invited to participate in a consensus process through a modified two-round internet-based Delphi survey. Relevant topics investigated were: peculiarities of NP in patients with cancer, IASP NeuPSIG diagnostic criteria adaptation and assessment, standardized PRO assessment for NP screening. Median consensus scores (MED) and inter-quartile ranges (IQR), were calculated to measure expert consensus after both rounds. 29 experts answered and good agreement was found on the statement "the pathophysiology of NP due to cancer can be different from non-cancer NP" (MED=9, IQR=2). Satisfactory consensus was reached for the first three NeuPSIG criteria (pain distribution, history and sensory findings) (MEDs>=8, IQRs<=3), but not for the fourth one (diagnostic test/imaging) (MED=6, IQR=3). Agreement was also reached on clinical examination by soft brush or pin stimulation (MEDs>=7 and IQRs<=3) and on the use of PRO descriptors for NP screening (MED=8, IQR=3). Based on the study results a clinical algorithm for NP diagnostic criteria in cancer patients with pain was proposed. Clinical research on PRO in the screening phase and on the application of the algorithm will be needed to examine their effectiveness in classifying NP in cancer patients.