Wael Lasheen

Respiratory function during parenteral opioid titration for cancer pain

Background: Respiratory depression is the most feared opioid-related side-effect yet research on the topic is sparse. We evaluated changes in respiratory parameters during parenteral opioid titration for cancer pain to determine if opioid titration was associated with evidence of hypoventilation. The primary outcome measure was to measure changes in end-tidal CO2 (ET-CO2) during opioid titration to pain control. Methods: Subjects with severe cancer pain admitted for parenteral opioid titration for poorly controlled pain were eligible. Those who were oxygen dependent were excluded. ET-CO2, O2 saturation, respiratory rate (RR), and vital signs were monitored daily until pain control was achieved. Results: 30 patients completed the study of which 29 are reported. The mean ET-CO2 at initial evaluation was 33.39 ∓ 5.0 and 34.79 ∓ 5.7 mmHg at pain control (P =0.14, 95% CI -0.5 to 3.3). None had an ET-CO2 ≥50 mmHg. All maintained O2 saturation ≥92%. RR dropped transiently below 10/minute in two subjects. Conclusions: Parenteral opioid titration for relief of cancer pain was not associated with respiratory depression as demonstrated by significant changes in ET-CO2 or oxygen saturation in non-oxygen dependent cancer patients.

The cancer anorexia-cachexia syndrome: myth or reality?

BackgroundControversy exists as what constitutes the cancer anorexia-cachexia syndrome (CACS), and whether it truly is a distinct clinical disorder. In this study, we aimed to: (1) assess if CACS is a distinct clinical disorder, (2) identify the symptoms characteristic of CACS, (3) evaluate CACS impact on patient outcomes (symptom burden and survival time from referral).MethodsConsecutive patients referred to palliative medicine were assessed by 38-symptom questionnaire. Demographics, Eastern Cooperative Oncology Group (ECOG), disease and extent, and survival were recorded. CACS, defined as anorexia plus weight loss (>10% of pre-illness weight). For analysis, patients were divided into four groups: (1) group CACS; (2) group A (only anorexia, NO >10% pre-illness weight loss); (3) group WL (weight loss >10% pre-illness weight only but NO anorexia); and (4) group N (NO weight loss >10% pre-illness weight and NO anorexia). Symptoms present in ≥5%, and patients with complete data were analyzed.ResultsFour hundred eighty-four patients had complete data, metastatic cancer, and 26 symptoms present in ≥5%. Groups had significantly different ECOG, symptom burden, and survival. Significantly different symptom prevalence between groups: dry mouth,*early satiety,*constipation,*nausea,*taste changes,*vomiting,*dysphagia,*fatigue,*weak,*lack of energy, insomnia, dyspnea, depression, hoarseness, and anxiety. The nine symptoms with asterisk were CACS specific. Symptom Burden: CACS independently predicted greatest burden. Survival: Group N had significantly longer survival.ConclusionsCACS appeared to be a distinct disorder with unique clinical characteristics in our advanced cancer population. Nine other symptoms constituted CACS. CACS independently predicted higher symptom burden. CACS absence predicted longer survival. More evidence is needed to better characterize this syndrome and generate a valid CACS consensus. A comprehensive validated CACS assessment instrument is required.

Bioelectrical Impedance Phase Angle Changes During Hydration and Prognosis in Advanced Cancer

Introduction. We wished to determine bioelectrical impedance (BIA) correlates before hydration or changes during hydration and determine if these changes were prognostically important. Methods and Materials. Fifty eligible patients underwent BIA measurements 3 consecutive days. Laboratory studies (electrolytes, creatinine, and hemoglobin) on day 1; weights and vital signs were recorded. Kaplan-Meier survival estimates were made at 30 and 60 days. Hazard ratios (HRs) based on Cox proportional hazards model were calculated. Results. Weight loss was associated with shorter survival. A higher phase angle (PA) on day 1 predicted longer survival. Increased PA during hydration predicted shorter survival: increased weight during hydration predicted longer survival. Discussion. Higher phase angle before hydration predicts poorer survival and, paradoxically, an increase in phase angle during hydration predicted poorer survival and preexisting intracellular dehydration, cachexia, or poor membrane function. Conclusions. Phase angle and weight during hydration predict survival in cancer.

A Phase II Dose Titration Study of Thalidomide for Cancer-Associated Anorexia

CONTEXT Sixty-five percent of people with advanced cancer suffers from loss of appetite. Several inflammatory cytokines appear to cause appetite loss in animal models. Thalidomide is an immunomodulatory drug that has been associated with improved appetite in those with HIV infections and cancer. OBJECTIVES We completed a two-stage Phase II dose titration study of thalidomide, the primary purpose of which was to assess appetite response to thalidomide in cancer-associated anorexia. METHODS Individuals older than 18 years of age with active cancer, loss of appetite by numerical rating scale (NRS), life expectancy of at least four weeks, and Eastern Cooperative Oncology Group performance status of 0-3 were entered into the study. Pretreatment screening included medical history, neurologic examination, and symptoms by NRS and categorical scale (CAT). Patients received 50mg of thalidomide by mouth at bedtime for two weeks. Individuals who did not respond were dose escalated to 100mg at night for two weeks. Assessment of appetite, early satiety, fatigue, insomnia, night sweats, pain, and quality of life (QOL) occurred at two-week intervals. Toxicity also was assessed. The primary outcome was appetite response defined as a two-point reduction in the NRS or a one-point improvement in the CAT. RESULTS Thirty-five patients entered the study; 33 completed 14 days of therapy and were analyzed for efficacy and toxicity. Sixty-four percent who completed at least two weeks of thalidomide had improved appetite. The CAT scores for appetite, insomnia, and QOL improved significantly. The 95% confidence intervals did not overlap. Five participants dropped out because of toxicity: two before two weeks and three later. CONCLUSION Thalidomide reduced multiple symptoms commonly associated with cancer-related anorexia and improved QOL. Our findings confirmed and validated a previously published single-arm trial. A recent randomized trial demonstrated greater benefits when thalidomide is used combined with other agents to treat cancer-associated anorexia and cachexia. Thalidomide helped cancer-associated anorexia in most patients. It also improved insomnia and QOL in advanced cancer.

METHYLPHENIDATE SIDE EFFECTS IN ADVANCED CANCER: A RETROSPECTIVE ANALYSIS

Introduction: Methylphenidate (MP) is often recommended for symptom control in advanced cancer. Little is known about its side effects in frail adults. Objectives: To evaluate MP-associated symptoms or side effects (S/E). Methods: Data was collected from 2 published prospective cohort series and a phase 2 study of MP for symptom control in advanced cancer. All 3 reports had identical dosing schedules and symptom assessments. Initial MP doses were 10 mg/d (5 mg at 8 AM and at 12 noon) titrated up to a maximum of 30 mg/d. Depression, fatigue, and symptoms identified as possible MP S/E were evaluated for presence (prevalence) and for severity (using categorical scales) before MP (day 0) and on days 3, 5, and 7 thereafter. The categorical scale used was none, mild, moderate, and severe. Results: 62 patients were enrolled. Fifty completed 7 days of MP with a median age of 69 (range 30-90) years. Thirty-five received MP 10 mg/day. Most (96%) had improvement in depression and/or fatigue. Among the 62 patients, new symptom prevalence throughout the study was agitation (16%), insomnia (16%), dry mouth (15%), nausea (10%), tremors (6%), anorexia (5%), headache (3%), palpitations (2%), and vomiting (2%). Patients could have more than 1 symptom simultaneously. Seven (11%) withdrew due to MP S/E. Some symptoms present before MP showed significant improvement during MP therapy. Conclusions: (1) Treatment with MP (10-20 mg/d) in advanced cancer is well tolerated. (2) S/E symptoms with MP appeared to improve spontaneously despite continued MP therapy. (3) Depression and fatigue improved at doses lower than those recommended in other clinical conditions. (4) MP improved depression and fatigue, and some secondary symptoms associated with them. Methylphenidate (MP) appears safe when used in the treatment of depression and fatigue in advanced cancer.

Symptom Assessment in Palliative Medicine: Complexities and Challenges

Symptoms are important patient-reported outcomes (PRO), which help to evaluate the impact of diseases and treatments and assess quality of care. Thorough symptom assessment is a challenge, as patients in palliative settings are often polysymptomatic and easily fatigued. There is no consensus about standardization of symptom assessment in palliative medicine. The available research provides some methodological guidance, but the psychometric properties of structured multisymptom assessments are largely understudied. New approaches may improve the efficacy of clinical assessment and create instruments with greater clinical utility. In this article, we discuss current methodological concepts of symptom assessment in clinical practice, specifically with reference to symptom questionnaires appropriate for palliative medicine.

Symptom Variability During Repeated Measurement Among Hospice Patients With Advanced Cancer

Aim: In this prospective study, we explored symptom variability in patients with cancer during repeated measurements. Methods: Patients with cancer admitted to an inpatient hospice completed a daily questionnaire throughout their admission. The questionnaire consisted of 5 visual analogue scales (VAS) for anxiety, depression, nausea, pain, and sedation and 3 verbal rating scales (VRS) for depression, pain, and vomiting. Data from those who completed 5 consecutive days were used for the primary analysis. We used all available data points to compare VAS and VRS. An index was developed to assess for daily symptom variability. Results/Discussion: A total of 125 hospice inpatients were enrolled; 46 (38%) completed 3 consecutive daily questionnaires and 30 (24%), 5 days. We found (1) a statistically significant decrease in severity of symptoms present on admission, (2) new symptoms developed, (3) consequently overall symptom prevalence on days 1 and 5 appeared unchanged, (4) high daily symptom variability as demonstrated by the variability index and also changing daily symptom interrelationships, (5) demographic characteristics influenced symptom patterns on admission and subsequently, (6) severe pain predicted more frequent and severe symptom burden only on admission, (7) severe depression predicted more frequent and severe symptom burden on admission and thereafter, (8) VAS scores for depression and pain did not correspond with discrete VRS categories (mild, moderate, severe). Conclusions: (1) Symptom studies in advanced disease while difficult to conduct yield valuable information, (2) symptom relationships changed daily; strict timing of data collection is crucial for data analysis, (3) symptom monitoring following admission is an overlooked measure of risk assessment, (4) symptom prevalence studies alone for treatment follow-up may be misleading, (5) depression is an important predictor of symptoms and need to be more aggressively assessed and treated, (6) demographic characteristics may help identify symptom patterns and better direct treatment, (7) VRS rather than VAS was more reliable for assessing symptoms in hospice cancer patients.

Intermittent Cancer Pain: Clinical Importance and an Updated Cancer Pain Classification

Aim: We report the characteristics of intermittent cancer pain. In addition, we propose a new clinically based classification. Methods: Consecutive patients with cancer referred to our palliative medicine service were consented and underwent a comprehensive pain evaluation including available laboratory and radiological studies, at the time of initial contact. Results and discussion: In total, 100 consecutive patients reported 158 different pain sites. Pain temporal pattern observed was 60% of patients had continuous (CP) plus intermittent pain (IP); 29% IP alone; and 11% CP alone. The etiology of IP was somatic (58%), visceral (24%), neuropathic (7%), and mixed (11%). Median duration of IP was 4 months with a median daily frequency of 4 episodes. Consequently, we propose that IP be classified into IP alone or nonbreakthrough pain (NBP; because there is no underlying CP or around-the-clock [ATC] opioids used) and breakthrough pain (BP; because there is underlying CP or/and ATC opioids used). We propose that both BP and NBP be each subclassified into 3 categories: (1) incident, (2) non-incident, and (3) mixed. In addition, a 4th category exclusive to BP: end-of-dose failure. Incident pains made up (N = 42, 47%) nearly half of all IP. According to our classification, incident pain was part of BP in 41% (N = 25) or NBP in 58% (N = 17). Incident NBP received less treatment than incident BP, and it was less controlled. Conclusion: (1) Intermittent pain is a major problem in patients with cancer, (2) NBP is a common but under-recognized form of cancer pain, (3) NBP is less defined and controlled than BP, (4) incident NBP accounts for 40% of all incident cancer pain, and (5) variable IP definitions and classifications make comparisons between studies difficult.

The intravenous to oral relative milligram potency ratio of morphine during chronic dosing in cancer pain

Morphine (M) is the opioid analgesic of choice for severe cancer pain. The IV to PO M equipotent switch ratio (CR) is controversial. We designed this prospective observational cohort to confirm the efficacy and safety of M IV to PO CR of 1:3. Consecutive cancer patients admitted to an inpatient palliative medicine unit were screened for inclusion. Pain was managed by palliative medicine specialists. They were blinded to the patient data collected, and the calculated CR. The switch was considered successful if the following criteria were met: (1) Pain adequately controlled: pain rated as none or mild (2) Number of RD less than 4 (for non incident pain) per 24 hours (3) No limiting side effects. We used Day 3 ATC M dose for CR calculations. The major outcome measures were the IV : PO CR ratio, morphine doses (mg/day), pain severity, number of PRN doses, and day 1 and day 3side effects. Descriptive statistics were used to report mean, median, standard deviation and range of different variables. Two hundred and fifty six consecutive admissions were screened, and 106 were eligible for the study. Sixty two underwent a successful M route switch and were included in this analysis. A ratio of 1:3 was safely implemented over a wide M dose range. About 80% were successfully switched with a calculated CR of 1:3. 20% required an oral M dose adjustment after route switch either to better pain control or reduce side effects with a resultant higher (e.g. 1:4) or lower (e.g. 1:2) calculated potency ratios respectively. A potency ratio of 1:3 was safe as evaluated by common M side-effects, the dose also easy to calculate. The 1: 3 M IV to PO relative milligram potency ratio appears correct and practical for most patients over a wide M dose range.

A comparative study of 2 sustained-release morphine preparations for pain in advanced cancer

Purpose: Several sustained-release morphine (SRM) formulations are available internationally. This study compared 2 such products available in the United States, SR1 and SR2. Patients and Methods: In an open-label study, patients with advanced cancer pain were randomized to receive SR1 or SR2 every 12 hours around-the-clock (ATC) for 5 days, with immediate release (IR) liquid morphine for rescue dosing (RD). Efficacy, safety, and patient acceptability were determined. Results: A total of 32 patients were evaluable for efficacy and toxicity. Pain scores, RD dosage, RD frequency over 5 days, RD within 3 hours before and after the scheduled SRM, and 8 of the 11 evaluated side effects were higher in the SR1 group. At presumed morphine steady state (day 3), pain scores (P = .05), RD dosage (P = .07), RD frequency (P = .07), and number of RD ±3 hours from scheduled SRM dose (P = .05) were consistently greater in the SR1 group (despite a higher median morphine dose in that group). There was a clinically important and directionally consistent trend that favored SR2, although not all were statistically significant. Patient preference favored SR2 (P < .05). Neither group had difficulty swallowing SR1 or SR2. Conclusions: This is the first study that directly compared two 12-hour SRM formulations. The data suggested, by multiple clinically important measures, that SR2 may provide superior analgesic efficacy and less toxicity compared to SR1. It also supports the concept that it cannot be assumed that different SR formulations of a given opioid are clinically equivalent. A larger study is needed to confirm our findings.