Opioids for breathlessness in heart failure

Breathlessness is a common and problematic symptom in heart failure. Opioids have traditionally been considered as analgesics, but a potential role for their use in breathlessness is beginning to emerge. This thesis commences with a review of the existing literature in support of a possible role for opioids in the management of breathless in heart failure. A systematic review of existing human symptom control studies in this thesis suggests that opioid administration may have a small but significant benefit in chronic heart failure. However, only six studies were included in the review and most were either small or of poor methodological quality. This presents a relative gap in the knowledge on this topic. A randomised controlled trial was therefore performed to assess the effect of opioids on breathlessness in chronic heart failure. This crossover trial involved the comparison of two oral opioids with placebo. Thirty-five participants completed the trial, making it the largest trial of its type in this area. Opioid administration was shown to be safe in this patient cohort. No statistically significant differences were demonstrated for breathlessness severity between treatments. Participants were subsequently invited to participate in a three month open label extension. Thirty three participants in total were followed up with thirteen remaining on active therapy. This is the first trial of its type in breathlessness in heart failure and represents the longest participant follow-up in this area. Whilst not as robust as the initial trial, this extension period revealed that opioid continuers rated a statistically significant improvement in breathlessness severity from baseline compared to non-continuers. Finally, a semi-structured interview study in ten participants with heart failure revealed for the first time that opioids are acceptable in this population and they describe troublesome symptoms that might respond to opioid treatment

Transcutaneous electrical nerve stimulation for cancer pain in adults.

Background Cancer-related pain is complex and multi-dimensional but the mainstay of cancer pain management has predominately used a biomedical approach. There is a need for non-pharmacological and innovative approaches. Transcutaneous Electric Nerve Stimulation (TENS) may have a role for a significant number of patients but the effectiveness of TENS is currently unknown. Objectives The aim of this systematic review was to determine the effectiveness of TENS for cancer-related pain in adults. Search strategy We searched The Cochrane Library, MEDLINE, EMBASE, CINAHL, PsychINFO, AMED and PEDRO databases (11/04/08). Selection criteria Only randomised controlled trials (RCTS) investigating the use of TENS for the management of cancer-related pain in adults were included. Data collection and analysis The search strategy identified 37 possible published studies which were divided between two pairs of review authors that decided on study selection. A study eligibility form was used to screen each abstract and where study eligibility could not be determined from the abstract, the full paper was obtained and assessed by one pair of review authors. A standardised data extraction sheet was used to collect information on the studies and the quality of the studies was assessed independently by two review authors using the validated five-point Oxford Quality Scale. Final scores were discussed and agreed between all four review authors. The small sample sizes and differences in patient study populations of the two included studies prevented meta-analysis. Main results Only two RCTs met the eligibility criteria (64 participants). These studies were heterogenous with respect to study population, sample size, study design, methodological quality, mode of TENS, treatment duration, method of administration and outcome measures used. In one RCT, there were no significant differences between TENS and placebo in women with chronic pain secondary to breast cancer treatment. In the other RCT, there were no significant differences between acupuncture-type TENS and sham in palliative care patients; this study was underpowered. Authors' conclusions The results of this systematic review are inconclusive due to a lack of suitable RCTs. Large multi-centre RCTs are required to assess the value of TENS in the management of cancer-related pain in adults

Clinically important differences in the intensity of chronic refractory breathlessness

Context: Clinically important differences in chronic refractory breathlessness are ill defined but important in clinical practice and trial design. Objectives: To estimate the clinical relevance of differences in breathlessness intensity using distribution and patient anchor methods. Methods: This was a retrospective data analysis from 213 datasets from four clinical trials for refractory breathlessness. Linear regression was used to explore the relationship between study effect size and change in breathlessness score (0-100 mm visual analogue scale) and to estimate the change in score equivalent to small, moderate, and large effect sizes. Pooled individual blinded patient preference data from three randomized controlled trials were analyzed. The difference between the mean change in Day 4 minus baseline scores between preferred and non-preferred arms was calculated. Results: There was a strong relationship between change in score and effect size (P = 0.001; R 2 = 0.98). Values for small, moderate, and large effects were -5.5, -11.3, and -18.2 mm. The participant preference change in score was -9 mm (95% CI, -15.8, -2.1) (P = 0.008). Conclusion: This larger dataset supports a clinically important difference of 10 mm. Studies should be powered to detect this difference

Blinded patient preference for morphine compared to placebo in the setting of chronic refractory breathlessness – an exploratory study

Context Patients’ preference for morphine therapy has received little attention in the setting of chronic refractory breathlessness. However, this is one important factor in considering longer term therapy. Objectives The aim of this secondary analysis is to explore blinded patient preference of morphine compared to placebo for this indication and to define any predictors of preference. Methods Data were pooled from three randomized, double-blind, crossover, placebo-controlled studies of morphine (four days each) in chronic refractory breathlessness. Blinded patient preferences were chosen at the end of each study. A multivariable regression model was used to establish patient predictors of preference. Results Sixty-five participants provided sufficient data (60 males; median age 74 years; heart failure 55%, chronic obstructive pulmonary disease 45%; median Eastern Cooperative Oncology Group performance status 2). Forty-three percent of participants preferred morphine (32% placebo and 25% no preference). Morphine preference and younger age were strongly associated: odds ratio = 0.85, 95% confidence interval 0.78, 0.93;

Minimally clinically important difference in chronic breathlessness: every little helps

ObjectivesThe aim of the study was to determine the minimally clinically important difference (MCID) for breathlessness due to chronic heart failure (CHF). BackgroundThe measurement of breathlessness is difficult because it is subjective and multifactorial. Statistically significant changes in assessment may not be clinically meaningful. This is the first determination of MCID in chronic breathlessness in CHF using patient-rated data. MethodsMeasurements were made as part of a randomized, controlled, crossover trial of morphine, oxycodone, or placebo for breathlessness in CHF. Breathlessness intensity was assessed at baseline and at the end of each intervention (day 4) using 11-point numerical rating scales (NRS), modified Borg (mBorg) scales, and global impression of change (GC) in breathlessness at day 4. From these data, the change in NRS or mBorg associated with a 1-point change in GC was calculated. ResultsThirty-five patients completed all study interventions, resulting in 105 data sets. We defined MCID as a 1-point change in GC. Regression analysis found that the MCID, including 95% CIs, equaled change in average NRS breathlessness per 24 hours of 0.5 to 2.0 U (P < .001), change in worst NRS breathlessness per 24 hours of 0.4 to 2.9 (P < .001), change in average mBorg score of 0.2 to 2.0 (P < .001), and change in worst mBorg score as between 0.3 and 1.9 (P < .001). Corresponding effect size calculations lay within the 95% CIs for the regression analysis for each measure

A Cochrane systematic review of transcutaneous electrical nerve stimulation for cancer pain.

Cancer-related pain is complex and multi-dimensional; yet, the mainstay of cancer pain management has been the biomedical approach. There is a need for nonpharmacological and innovative pain management strategies. Transcutaneous electrical nerve stimulation (TENS) may have a role. The aim of this systematic review was to determine the effectiveness of TENS for cancer-related pain in adults. The Cochrane Library, MEDLINE, EMBASE, CINAHL, PsychINFO, AMED, and PEDro databases were searched for randomized controlled trials (RCTs) investigating the use of TENS for the management of cancer-related pain in adults. Once relevant studies were identified, two pairs of reviewers assessed eligibility for inclusion in the review based on a study eligibility form and using the 5-point Oxford Quality Scale. Two RCTs met the study eligibility criteria (these involved 64 patients). These studies were heterogeneous with respect to study population, methodology, and outcome measures. This prevented meta-analysis. In one RCT, there were no significant differences between TENS and placebo in women with chronic pain secondary to breast cancer treatment. In the other RCT, there were no significant differences between acupuncture-like TENS (AL-TENS) and sham in palliative care patients; this study was significantly underpowered. There is insufficient available evidence to determine the effectiveness of TENS in treating cancer-related pain. Further research is needed to help guide clinical practice, and large multi-center RCTs are required to assess the value of TENS in the management of cancer-related pain in adults

The relationship between two performance scales : New York Heart Association Classification and Karnofsky Performance Status Scale

Context: Performance status is used to quantify the well-being and functional status of people with illness. Clinicians and researchers from differing fields may not instinctively understand the scales, typically disease specific, used in other disciplines. Objectives: To provide a preliminary description of the relationship between the Karnofsky Performance Status Scale (KPS) and the New York Heart Association Classification (NYHA) and to stimulate discussion in research and clinical practice. Methods: Simultaneous KPS and NYHA data (172 observations) from three studies of people with chronic heart failure were pooled. Linear regression was used to predict the mean KPS from NYHA. The strength of association between the scales was investigated using a Kendall's Tau-b correlation coefficient. The agreement between the predicted and observed KPS scores was investigated using weighted kappa with quadratic weights. Results: Linear regression demonstrated a relationship between KPS and NYHA (P < 0.0001; R2 = 0.3). Predicted KPS from NYHA class rounded to the nearest 10 gave the following values: Class I, predicted KPS 90%; Class II, predicted KPS 80%; Class III, predicted KPS 70%; and Class IV, predicted KPS 60%. A moderate strength of association between KPS and NYHA (Kendall's Tau-b correlation coefficient of -0.49; P < 0.0001) and agreement between observed and predicted KPS (kappa coefficient = 0.52) was shown. Conclusion: We suggest that the NYHA discriminates poorly between clinically important performance states in people with advanced disease (NYHA III and IV; KPS <50%). The KPS, used in conjunction, would provide useful additional information in research and clinical practice

Short-term opioids for breathlessness in stable chronic heart failure: A randomized controlled trial

Aims To assess the effect of oral opioids vs. placebo on breathlessness in patients with chronic heart failure (CHF). Methods and results Oral morphine (Oramorph), oral oxycodone (Oxynorm), and placebo were studied in an outpatient setting. Once randomized, participants received all three interventions in a controlled double-blind crossover trial for 4 days each, with a 3-day washout between interventions. Patients known to the Hull and East Yorkshire Academic Cardiology department with CHF (New York Heart Association Grade III–IV) were invited to participate. Participants were eligible if they were on standard medical therapy with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and diuretics. Participant-rated change in 11-point numerical rating scale (NRS) (average over previous 24 h) breathlessness severity score from baseline (Day 1) to Day 4 of treatment was the primary outcome measure. The study was powered to detect a one-point change in severity.Thirty-nine patients were randomized and 35 completed all three study arms. Breathlessness severity was reduced from baseline with all three interventions. There was no statistically significant difference between active intervention and placebo or between the two types of opioid for the primary endpoint [-1.37 in NRS score for placebo group vs. -0.41 in morphine group (P = 0.13) and -1.29 for oxycodone group (P = 0.90)]. The response to treatment was not affected by aetiology, severity of CHF, or concurrent drug therapy. Opioid administration did not cause detrimental changes in clinical observations and was well tolerated. Conclusion We demonstrated no benefit over placebo for the relief of breathlessness with short-term low-dose oral opioids for CHF patients

Oral modified release morphine for breathlessness in chronic heart failure : a randomised placebo-controlled trial

Aims: Morphine is shown to relieve chronic breathless in chronic obstructive pulmonary disease. There are no definitive data in people with heart failure. We aimed to determine the effectiveness and cost-effectiveness of 12 weeks’ morphine therapy for the relief of chronic breathlessness in people with chronic heart failure compared with placebo. Methods: Parallel-group, double-blind, randomised, placebo-controlled, phase III trial of 20mg daily oral modified-release morphine conducted in 13 sites in England and Scotland; hospital/community cardiology or palliative care out-patients. The primary analysis compared between-group numerical rating scale average breathlessness at week 4 using a covariance pattern linear mixed model. Secondary outcomes included treatment-emergent harms (worse, or new). Results: The trial closed early, randomising 45 participants (average age 72 [range 39 to 89] years; 84% men; 98% New York Heart Association class III). For the primary analysis, the adjusted mean difference was 0.26 (95% CI -0.86 to 1.37) in favour of placebo. All other breathlessness measures improved in both groups (week 4 change-from-baseline), but by more in those assigned to morphine. Neither group was excessively drowsy at baseline or week 4. There were no between-group differences in quality of life (Kansas) or cognition (Montreal) at any time point. There was no exercise-related desaturation and no change between baseline and week 4 in either group. There was no change in vital signs at week 4. The natriuretic peptide measures fell in both groups, but by more in the morphine group (morphine 2169 [1092, 3851] pg/mL vs placebo 2851 [1694, 5437]) pg/mL. There was no excess serious adverse events in the morphine group. Treatment-emergent harms during the first week were more common in the morphine group; all apart from one were ≤ grade 2. Conclusions: We could not answer our primary objectives due to inadequate power. However, we provide novel placebo-controlled medium-term benefit and safety data useful for clinical practice and future trial design. Morphine should only be prescribed in this population when other measures are unhelpful, and with early management of side-effects. KEY WORDS: Heart failure; randomized controlled trial; morphine; breathlessness; dyspne