Systematic literature review: xerostomia in advanced cancer patients.

PURPOSE: Dry mouth (xerostomia) is one of the commonest symptoms in cancer patients and can adversely affect quality of life. The aim of this review was to determine the effectiveness of pharmacological and non-pharmacological interventions in treating xerostomia in adult advanced cancer patients. METHODS: The literature search was performed in February 2014 using databases including EMBASE, MEDLINE, CINAHL, BNI and Cochrane library. The search was carried out using standard MeSH terms and was limited to adult population and English language. Studies investigating xerostomia secondary to head and neck cancer treatment and autoimmune disease were excluded. Titles and abstracts were screened and reviewed for eligibility. Only studies involving primary research were included in the analysis. RESULTS: Six studies met the eligibility criteria for review: three randomized controlled trials and three prospective studies. The quality assessment and reporting was performed using PRISMA, Jadad and STROBE. These studies compared acupuncture, pilocarpine, Saliva Orthana and chewing gum with each other or with placebo. All interventions were considered effective in treating xerostomia. However, effectiveness versus placebo could not be demonstrated for Saliva Orthana. Meta-analysis could not be performed due to heterogeneity of the study type and intervention. CONCLUSION: Limited published data exists reporting the effectiveness of measures in the treatment of xerostomia in cancer patients. Based on primary research of low quality, firm conclusions cannot be drawn. However, pilocarpine, artificial saliva, chewing gum and acupuncture can be tried based on the available data. This highlights the explicit need to improve our evidence base. Properly constructed randomized controlled trials demonstrating effectiveness of pharmacological and non-pharmacological interventions for dry mouth are required.

Opioids for chronic refractory breathlessness: patient predictors of beneficial response.

Chronic refractory breathlessness is common and distressing in advanced disease. Despite level I evidence to support the use of opioids for this symptom, not all patients benefit. This study aimed to discover which patient characteristics predict those most likely to gain improvement in breathlessness. This is an international, multicentre, retrospective analysis of 213 individual pooled datasets from four clinical trials of an opioid for chronic refractory breathlessness. "Response to opioid" was defined as 1) an absolute value of ≥ 10 mm improvement on the visual analogue scale (VAS) and 2) a relative value of ≥ 10% improvement from baseline VAS. We investigated baseline predictors using logistic regression. In the final model, higher baseline breathlessness intensity scores strongly predicted absolute and relative response (p<0.001). Younger age also predicted relative response (p = 0.025); functional status and dominant cause of breathlessness did not. Some evidence supported the descriptor "not enough air", but was not statistically significant (p = 0.052). A therapeutic trial of opioids is appropriate, irrespective of the cause of the breathlessness or functional status. Younger people or those with worse breathlessness are more likely to benefit. Opioids have a role in the management of chronic refractory breathlessness, but net benefit for individuals must be optimised.

Minimally clinically important difference in chronic breathlessness: every little helps.

OBJECTIVES: The aim of the study was to determine the minimally clinically important difference (MCID) for breathlessness due to chronic heart failure (CHF). BACKGROUND: The 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. METHODS: Measurements 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. RESULTS: Thirty-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. CONCLUSIONS: A 1-point change in NRS or mBorg score is a reasonable estimate of the MCID in average daily chronic breathlessness in CHF.

Transcutaneous electric nerve stimulation (TENS) for cancer pain in adults.

BACKGROUND: Cancer-related pain is complex and multi-dimensional but the mainstay of cancer pain management has predominantly used a biomedical approach. There is a need for non-pharmacological and innovative approaches. Transcutaneous Electric Nerve Stimulation (TENS) may have a role in pain management but the effectiveness of TENS is currently unknown. This is an update of the original review published in Issue 3, 2008. OBJECTIVES: The aim of this systematic review was to determine the effectiveness of TENS for cancer-related pain in adults. SEARCH METHODS: The initial review searched The Cochrane Library, MEDLINE, EMBASE, CINAHL, PsychINFO, AMED and PEDRO databases in April 2008. We performed an updated search of CENTRAL, MEDLINE, EMBASE, CINAHL and PEDRO databases in November 2011. SELECTION CRITERIA: We included only randomised controlled trials (RCTS) investigating the use of TENS for the management of cancer-related pain in adults. DATA COLLECTION AND ANALYSIS: The search strategy identified a further two studies for possible inclusion. One of the review authors screened each abstract using a study eligibility tool. Where eligibility could not be determined, a second author assessed the full paper. One author used a standardised data extraction sheet to collect information on the studies and independently assess the quality of the studies using the validated five-point Oxford Quality Scale. The small sample sizes and differences in patient study populations of the three included studies (two from the original review and a third included in this update) prevented meta-analysis. For the original review the search strategy identified 37 possible published studies; we divided these between two pairs of review authors who decided on study selection; all four review authors discussed and agreed final scores. MAIN RESULTS: Only one additional RCT met the eligibility criteria (24 participants) for this updated review. Although this was a feasibility study, not designed to investigate intervention effect, it suggested that TENS may improve bone pain on movement in a cancer population. The initial review identified two RCTs (64 participants) therefore this review now includes a total of three RCTs (88 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: Despite the one additional RCT, the results of this updated systematic review remain 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.

Attitudes to morphine in chronic heart failure patients.

OBJECTIVES: Low-dose opioids are used for the palliation of pain, breathlessness and cough in advanced chronic heart failure (CHF) patients. The authors wanted to determine any potential barriers or facilitators to opioid administration in patients with CHF by assessing their knowledge, concerns and attitudes to morphine therapy. METHODS: Semistructured interviews were held with a purposive sample of 10 men with symptoms of CHF. Data were analysed using a constant comparative approach until thematic saturation. RESULTS: Four key areas emerged: medication use; symptoms; prior morphine experience; and attitudes, concerns and anxieties regarding morphine use. Despite polypharmacy, participants said that morphine would be acceptable if it was monitored by a trusted healthcare professional. Many patients had experienced morphine before, often in life-threatening situations such as myocardial infarction, when it had helped greatly. Opioids were not strongly associated exclusively with death and dying (in contrast to patient reports in the cancer literature). CONCLUSIONS: Although some concerns about morphine were expressed, these did not appear to override a willingness to consider its use if recommended by a trusted clinician. However, some participants perceived that their doctor was concerned about its use, holding it as a last reserve. Morphine appears to be an acceptable breathlessness treatment option to these people with CHF. Prescribers may need education and reassurance if these medicines are to be used to their full potential and views may be different in other communities.

Prescribing in Chronic Severe Hepatic Impairment.

Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available via www.palliativedrugs.com. The series editors welcome feedback on the articles.

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

AIMS: Morphine is shown to relieve chronic breathlessness 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 AND RESULTS: Parallel group, double-blind, randomized, placebo-controlled, phase III trial of 20 mg daily oral modified release morphine was conducted in 13 sites in England and Scotland: hospital/community cardiology or palliative care outpatients. The primary analysis compared between-group numerical rating scale average breathlessness/24 hours at week 4 using a covariance pattern linear mixed model. Secondary outcomes included treatment-emergent harms (worse or new). The trial closed early due to slow recruitment, randomizing 45 participants [average age 72 (range 39-89) years; 84% men; 98% New York Heart Association class III]. For the primary analysis, the adjusted mean difference was 0.26 (95% confidence interval, -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 1 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.

Transcutaneous electric nerve stimulation (TENS) 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.

Ranitidine: forgotten drug of delayed gastric emptying.

Delayed gastric emptying in the presence or absence of mechanical bowel obstruction can cause distressing symptoms in palliative care patients. We present two patients, both with vomiting due to delayed gastric emptying and gastric outlet obstruction secondary to pancreatic cancer, treated with subcutaneous ranitidine resulting in a symptomatic response. We hypothesise that ranitidine is a useful adjunct to standard treatment with prokinetic agents or octreotide in such patients and potentially those with proximal mechanical bowel obstruction from other malignancies with associated delayed gastric emptying.

Spironolactone.

Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles (hq@palliativedrugs.com).

Furosemide.

Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles (hq@palliativedrugs.com).

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 was 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 men; 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; P < 0.001). There was also an inverse association between morphine preference and sedation (odds ratio = 0.77, 95% confidence interval 0.60-0.99; P < 0.05). An inverse association was also seen between nausea and morphine preference in the univariate model only (P < 0.05). No association was seen between morphine preference and breathlessness intensity, either at baseline or change from baseline. CONCLUSION: Participants preferred morphine over placebo for the relief of chronic refractory breathlessness. Morphine offers clinically important improvement, but net benefit can be easily outweighed by side effects, reducing net benefits. Side effects require aggressive management to allow more patients to realize benefits.

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; R(2) = 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.

Repeat dose opioids may be effective for breathlessness in chronic heart failure if given for long enough.

BACKGROUND: The longer-term effects of opioids for breathlessness are not known in people with chronic heart failure (CHF). OBJECTIVE: Our aim was to assess the longer-term effect of oral opioids on breathlessness due to CHF. METHODS: We conducted a 3-month open-label extension to a crossover randomized controlled trial (RCT) comparing 4 days of morphine, oxycodone, and placebo. Thirty-five participants from a tertiary cardiology clinic completed the RCT. Thirty-three were followed for 3 months, continuing open-label opioids if they wished. Thirteen participants continued an opioid; 20 did not. Four measures of breathlessness intensity (0-10 numerical rating scale [NRS] and modified Borg score, each recording worst and average breathlessness during 24 hours) were combined using principal component analysis to give a single measure for the primary analysis. Groups were compared using analysis of covariance. Secondary measures included quality of life (SF-12(®) Health Survey), cardiorespiratory, and global impression of change in breathlessness at 3 months. RESULTS: At 3 months, the composite breathlessness measure improved to a greater extent in the opioid group (p=0.017). The opioid group had an improvement in global impression of change (mean 2.62 [opioids] versus -0.65 [nonopioids]; p=0.0009). The SF-12 physical component improved more in the opioid group (p=0.014). Cardiorespiratory variables were unchanged. CONCLUSIONS: Opioids given for 3 months were well tolerated and safe. Opioid-related improvement in breathlessness in people with CHF might not be seen until longer-term administration. We cannot conclude from these data that they are effective and a longer-term RCT is needed.

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 (0-100mm 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 -18.2mm. The participant preference change in score was -9mm (95% CI, -15.8, -2.1) (P = 0.008). CONCLUSION: This larger dataset supports a clinically important difference of 10mm. Studies should be powered to detect this difference.

Attitudes to morphine in chronic heart failure patients.

OBJECTIVES: Low-dose opioids are used for the palliation of pain, breathlessness and cough in advanced chronic heart failure (CHF) patients. The authors wanted to determine any potential barriers or facilitators to opioid administration in patients with CHF by assessing their knowledge, concerns and attitudes to morphine therapy. METHODS: Semistructured interviews were held with a purposive sample of 10 men with symptoms of CHF. Data were analysed using a constant comparative approach until thematic saturation. RESULTS: Four key areas emerged: medication use; symptoms; prior morphine experience; and attitudes, concerns and anxieties regarding morphine use. Despite polypharmacy, participants said that morphine would be acceptable if it was monitored by a trusted healthcare professional. Many patients had experienced morphine before, often in life-threatening situations such as myocardial infarction, when it had helped greatly. Opioids were not strongly associated exclusively with death and dying (in contrast to patient reports in the cancer literature). CONCLUSIONS: Although some concerns about morphine were expressed, these did not appear to override a willingness to consider its use if recommended by a trusted clinician. However, some participants perceived that their doctor was concerned about its use, holding it as a last reserve. Morphine appears to be an acceptable breathlessness treatment option to these people with CHF. Prescribers may need education and reassurance if these medicines are to be used to their full potential and views may be different in other communities.

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. Trial registered prior to the recruitment of the first participant with Current Controlled Trials (www.controlled-trials.com; Trial number ISRCTN 85268059).