Can We Make More Accurate Prognoses During Last Days of Life?

Background: Life expectancy prediction is important for end-of-life planning. Established methods (Palliative Performance Scale [PPS], Palliative Prognostic Index [PPI]) have been validated for intermediate- to long-term prognoses, but last-weeks-of-life prognosis has not been well studied. Patients admitted to a palliative care facility often have a life expectancy of less than three weeks. Reliable last-weeks-of-life prognostic tools are needed. Objective: To improve short-term survival prediction in terminally ill patients. Method: This prospective study included all patients admitted to a palliative care facility in Montreal, Canada, over one year. PPS and PPI were assessed until patients' death. Seven prognostic clinical signs of impending death (Short-Term Prognosis Signs [SPS]) were documented daily. Results: The analyses included 273 patients (76% cancer). The median survival time for a PPS ≤20% was 2.5 days, while for a PPS ≥50% it was 44.5 days, for a PPI >8 the median survival was 3.5 days and for a PPI ≤4 it was 38.5 days. Receiver operating characteristic curves showed a high accuracy in predicting survival. Median survival after the first occurrence of any SPS was below one week. Conclusions: This study demonstrated that the PPS and PPI perform well between one week and three months extending their usefulness to shorter term survival prediction. SPS items provided survival information during the last week of life. Using SPS along with PPS and PPI during the last weeks of life could enable a more precise short-term survival prediction across various end-of-life diagnoses. The translation of this research into clinical practice could lead to a better adapted treatment, the identification of a most appropriate care setting for patients, and improved communication of prognosis with patients and families.

Population Pharmacokinetic/Pharmacodynamic Modeling of O-Desmethyltramadol in Young and Elderly Healthy Volunteers.

BACKGROUND: Age-related changes in the concentration-effect relationship of (+)-O-desmethyl-tramadol [(+)-ODM], tramadol's active metabolite, are not documented in the elderly. OBJECTIVE: The objective of this study was to characterize, in elderly and young subjects, the (+)-ODM pharmacokinetic and pharmacodynamic relationship to examine the effect of age after single-dose administration of tramadol 200 mg extended-release tablets. METHODS: A population analysis of a double-blind, randomized, placebo-controlled, two-period cross-over study including 13 elderly (aged ≥75 years) subjects with mild renal insufficiency and 16 young (aged 18-40 years) subjects was conducted. For 48 h post-dose, blood samples were collected and pain tolerance thresholds measured using an electrically stimulated pain model. A pharmacokinetic/pharmacodynamic model incorporating a one-compartment pharmacokinetic model for (+)-ODM parameterized with first-order formation rate, clearance (CL/fm), volume of distribution (V/fm) and a sigmoid maximum effect (Emax) model incorporating baseline (E0) and placebo effect was used. RESULTS: Maximum plasma concentrations of (+)-ODM occurred later and plasma concentrations declined more slowly in the elderly than in young subjects. In the elderly, V/fm was 76% larger and CL/fm 16% slower. Baseline (E0) and sensitivity (C50) for pain tolerance were similar between young and elderly subjects. However, the Emax parameter was 2.5 times higher in the elderly and maximum possible treatment-related effect was 169 (135-221) in the young and 194 (149-252) in the elderly; that is, 15% higher in the elderly. CONCLUSIONS: This exploratory analysis suggests that age-related differences exist in the distribution and elimination of (+)-ODM, including a 76% larger distribution outside the central compartment and 16% slower clearance of (+)-ODM. These pharmacokinetic changes are associated with a 15% higher maximum possible treatment-related effect and carry the potential for greater efficacy but also the potential for increased side effects at the same dose in elderly subjects. Clinicaltrials.gov identifier: NCT02329561.

Evaluation of an Experimental Pain Model by Noncompartmental Analysis of Results from a Randomized Placebo Controlled Trial.

BACKGROUND: Understanding analgesic pharmacodynamics (PD) in the elderly is key to optimising pain management. Electrically stimulated pain models (ESPM) permit assessment of pain responses in humans. C and A-delta sensory fibres convey pain and respond to low frequency electrical stimulus (5 and 250 Hz, respectively). Human research suggests pain tolerance threshold (PTT) is similar or decreases with age. OBJECTIVES: To determine whether an ESPM is able to detect a difference in PTT in elderly (>/= 75 years) and young (20-40 years) subjects after single dose administration of a placebo and tramadol, a low potency analgesic. STUDY DESIGN: Two-cohort, randomized, placebo-controlled, cross-over study. METHODS: A noncompartmental analysis of data at 17 timepoints on 5 Hz and 250 Hz PTT over 24 h. RESULTS: Young (16) and elderly (13) patients showed similar baseline (E0) PTT between active and placebo both overall and by age group in both frequencies. Net drug effect took into account negative and positive changes from E0. In the elderly, net peak effect on PTT produced by active treatment was significantly greater for both 5 Hz (34%) and 250 Hz (30%). Net area under the 24-h effect-time curve during active treatment was significantly higher for both 5 Hz (163 %) and 250 Hz (175%) stimulations in the elderly. No clinically significant difference was observed in the young. LIMITATIONS: High variability in young subjects, despite efforts to remove outliers limited our ability to draw conclusions in that age group. Generalizability of results obtained from an experimental pain model in volunteers to treatment of elderly patients may be limited. CONCLUSION: ESPM can detect a difference for pain tolerance threshold between placebo and tramadol administration in the elderly. Although both 5 Hz and 250 Hz stimulations can detect a difference, the effect size for 5 Hz is larger and seems more precise and reliable, particularly in the elderly. KEY WORDS: Electrical pain model, elderly, geriatric, tramadol, placebo, opioid, area under the effect curve, noncompartmental analysis.

Pharmacokinetics of Tramadol and O-Desmethyltramadol Enantiomers Following Administration of Extended-Release Tablets to Elderly and Young Subjects.

BACKGROUND: Tramadol is frequently used in geriatric patients; however, pharmacokinetic (PK) publications on tramadol and O-desmethyltramadol (ODM) in elderly patients are rare. OBJECTIVE: Our objective was to characterize the PK of tramadol and ODM, including absorption processes and covariates for tramadol, in elderly and young subjects after single-dose administration of 200-mg extended-release tablets. METHODS: We conducted a PK study in 15 elderly (aged ≥75 years) subjects with mild renal insufficiency and 20 young (18-40 years) subjects; blood and urine samples were collected for 48 h post-dose. Non-compartmental analysis (NCA) of each tramadol and ODM enantiomer included area under the concentration-time curve (AUC), terminal elimination rate (k el), total body clearance, volume of distribution (V area/ F), and renal clearance (Clr0-48). A one-compartment population model of total tramadol concentration was parameterized with clearance (CL/F), volume of distribution (V/F), and mixed order absorption (first-order and zero-order absorption rate constants with lag times). RESULTS: NCA demonstrated comparable maximum plasma concentration (C max) and AUC between age groups for tramadol enantiomers, but significant differences in V area/ F (mean 34% higher) and k el (mean 28% lower) in the elderly. PK of ODM were significantly different in the elderly for AUC0-inf (mean 35% higher), Clr0-48 (mean 29% lower), and k el (mean 33% lower). The population analysis identified age as a covariate of V/F (young 305 L; elderly 426 L), with a 50% longer mean elimination half-life in the elderly. No differences in absorption processes were observed. CONCLUSIONS: Tramadol exposure was similar between the age groups; exposure to ODM was higher in elderly subjects.

Extended-release tramadol/paracetamol in moderate-to-severe pain: a randomized, placebo-controlled study in patients with acute low back pain.

OBJECTIVE: Combinations of oral analgesics may offer several potential benefits compared with an individual agent. The objective of this study was to investigate the efficacy and safety of an extended-release, twice-daily fixed combination of 75 mg tramadol/650 mg paracetamol (DDS-06C) in the treatment of moderate-to-severe pain, using acute low back pain as a model. RESEARCH DESIGN AND METHODS: In this phase III study, 277 patients with moderate-to-severe acute low back pain were randomized to 1-2 tablets of DDS-06C or placebo every 10-12 h for 2.5 days during the double-blind phase. Following the double-blind phase, patients had the option to continue for a 2.5-day open-label phase. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov (Identifier: NCT00643383) MAIN OUTCOME MEASURES: The primary end point was the sum of pain intensity differences (SPID) over the 50-h double-blind phase (SPID50). Secondary end points included total pain relief score over the 50-h double-blind phase (TOTPAR50), patient's global impression of medication, and SPID over the first 4 h. RESULTS: A statistically significant (p = 0.038) greater decrease in pain intensity was observed in the DDS-06C group (median SPID50: -6.0) versus placebo (median SPID50: -4.0). Greater pain relief was also observed in patients randomized to DDS-06C: the median TOTPAR50 was 13.0 for the DDS-06C group and 11.0 for placebo (p = 0.026). DDS-06C demonstrated statistically significant superior efficacy compared with placebo for the majority of the other secondary end points. Overall, 38% of patients treated with DDS-06C experienced at least one adverse event; the intensity was mild-to-moderate in 81% of cases. The most commonly reported adverse events (>5% of patients receiving DDS-06C) were nausea, dizziness, vomiting, and somnolence. CONCLUSIONS: Using acute low back pain, a model with a high degree of heterogeneity and intrinsic variability, DDS-06C was superior to placebo on measures of pain intensity and relief, and was well-tolerated.

Onset of analgesic effect and plasma levels of controlled-release tramadol (Tramadol Contramid once-a-day) 200-mg tablets in patients with acute low back pain.

BACKGROUND AND AIMS: Tramadol hydrochloride, a centrally acting, synthetic analgesic, has been available in Europe since 1977 in a variety of formulations and in the United States since 1995. Its clinical efficacy was established in a variety of painful conditions (cance rpain, neuropathic pain, and osteoarthritis). Nonetheless, little published data exist regarding the relationship between analgesic onset and minimum therapeutic plasma levels. Tramadol Contramid once-a-day (OAD) demonstrates a pharmacokinetic profile with a sharp initial absorption slope similar to the pharmacokinetic profile of the immediate-release tramadol, suggesting that both the immediate-release and the once-daily (Contramid) formulation may produce a similar onset of analgesia. METHODS: This multicentre, open-label, single-dose study examined the pharmacokinetics/pharmacodynamics of Tramadol Contramid OAD in patients with acute low back pain. Patients who signed informed consent were screened and washed-out of prior analgesics. Patients received one dose of Tramadol Contramid OAD 200 mg. The patients indicated the time of onset of pain relief (stopwatch method). Ratings of pain intensity and pain relief and pharmacokinetic samples were taken prior to dosing, at the onset of pain relief and 3 and 6 hours postdose. No rescue medication was permitted until the end of the study (6-hour postdose). Adverse events were monitored throughout the study. RESULTS: Forty of the 47 patients enrolled completed the study. Onset of perceptible pain relief was achieved within 1 hour for the majority of patients and at plasma levels, suggesting a therapeutic threshold between 50 and 100 ng/mL. Two patients did not experience any pain relief CONCLUSIONS: The results of this exploratory study suggest that similar to immediate-release tramadol, onset of analgesia for this controlled-release formulation of tramadol (Tramadol Contramid OAD) occurs within 1 hour at a mean therapeutic threshold concentration of 56 +/- 38 ng/mL.

A comparison of the analgesic efficacy of Tramadol Contramid OAD versus placebo in patients with pain due to osteoarthritis.

One thousand twenty-eight (1,028) patients with pain due to osteoarthritis (OA) of the knee were enrolled in this multicenter, randomized, double-blind, parallel study designed to assess the analgesic efficacy and safety of Tramadol Contramid OAD compared to placebo. An open-label phase was followed by a double-blind phase, in which a total of 646 patients were randomized to double-blind treatment with placebo or Tramadol Contramid OAD. Patients were titrated to their optimal dose (200mg or 300 mg), which was maintained for 12 weeks. An absolute mean reduction of 3.0+/-2.1 on a Pain Intensity Numerical Rating Scale (PI-NRS) was noted in the Tramadol Contramid OAD treatment group. The difference between active and placebo groups regarding this absolute mean reduction was statistically significant (P<0.001) throughout the study. The responder analysis demonstrated that a significantly greater percentage of patients in the active treatment arm achieved a reduction of >or=1 and >or=2 points on the PI-NRS score by the end of the study (P=0.035). A significantly greater percentage of respondents in the Tramadol Contramid OAD group indicated improvement on both the Patient and Physician Global Impressions of Change (P=0.0002). Both the 200mg and 300 mg doses contributed to the overall superiority of Tramadol Contramid OAD. The most frequent adverse events were consistent with the known side effects of tramadol and were generally mild to moderate in intensity. These results confirm that Tramadol Contramid OAD given once daily is an efficacious and safe treatment for pain due to OA.

Efficacy and safety of 12 weeks of osteoarthritic pain therapy with once-daily tramadol (Tramadol Contramid OAD).

This placebo-controlled study examined the analgesic efficacy, safety, and clinical benefit of Tramadol Contramid OAD, a once-daily formulation with both immediate- and extended-release components. Five hundred and fifty-two patients with moderate to severe pain due to osteoarthritis (OA) of the knee were randomized into this multicenter, double-blind, parallel arm study. After randomization to Tramadol Contramid OAD 100, 200, or 300 mg, or to placebo, patients' dose was titrated to the fixed randomized dose and maintained for 12 weeks. Efficacy was evaluated with the Patients' Global Rating of Pain Relief (median ratings at maintenance visits), and the Western Ontario and McMaster University (WOMAC) Pain and Physical Function subscales (percent difference, baseline to end of study) as coprimary endpoints. A responder analysis was conducted (percentage of patients who achieved a 30 percent improvement on their baseline WOMAC pain score). The difference from placebo on the median Patient Global Rating of Pain Relief at the four maintenance visits was statistically significant (200 and 300 mg: p < or = 0.001). Treatment was rated effective or very effective by 75 percent and 80 percent of patients randomized to Tramadol Contramid OAD 200 mg and 300 mg, respectively. There was a 46 percent (300-mg dose; p = 0.016) and 43 percent (200-mg dose; p = 0.05) improvement on the WOMAC pain score (baseline to the end of the study) with Tramadol Contramid OAD compared with 32percent for placebo. The responder analysis demonstrated a statistically significant difference in the percentage of patients who achieved a 30 percent improvement in their baseline WOMAC pain score for both Tramadol Contramid OAD 200 mg (65 percent; p = 0.0095) and 300 mg (65 percent; p = 0.0104) compared with placebo (50 percent). The type and incidence of adverse events were typical of tramadol (nausea, dizziness/vertigo, vomiting, somnolence, and constipation) and the intensity was mild to moderate in 87percent of patients who experienced them regardless of dose. This study shows the efficacy and safety of Tramadol Contramid OAD 200 mg and 300 mg in patients with moderate or severe pain of the knee due to OA.

Efficacy and Safety Assessment of a Novel Once-Daily Tablet Formulation of Tramadol : A Randomised, Controlled Study versus Twice-Daily Tramadol in Patients with Osteoarthritis of the Knee.

OBJECTIVE: To compare the 24-hour sustained efficacy and safety of a new tramadol once-daily formulation (tramadol OAD) using Contramid((R)) controlled-release technology with a marketed twice-daily formulation (tramadol BID). PATIENTS, DESIGN AND SETTING: 431 patients with osteoarthritis of the knee were enrolled in this randomised, double-blind, multicentre, parallel study. After titration to optimum dose (range 100-400mg), patients received medication for 12 weeks. MAIN OUTCOME MEASURES AND RESULTS: Efficacy evaluations included: Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores (pain, stiffness, physical function and global), daily efficacy ratings (post-dose: tramadol OAD 24 hours; tramadol BID 12 hours), pain ratings over 24 hours, and patient and investigator overall ratings. Non-inferiority was demonstrated for the primary endpoint, mean percentage change in WOMAC pain score from baseline to week 12 (tramadol OAD 58%; tramadol BID 59%) [95% CI -7.67, 3.82]. The median optimum dose received was 200mg (both treatments). In 73% of patients, pain was mild to absent at the end of the dosing interval for both treatments (tramadol OAD 24 hours; tramadol BID 12 hours). Pain ratings over 24 hours were similar between groups, indicating 24-hour sustained efficacy for tramadol OAD. More tramadol BID patients reported dizziness/vertigo (37% vs 26%), vomiting (14% vs 8%) and headache (18% vs 13%) while tramadol OAD patients reported more somnolence (30% vs 21%). CONCLUSIONS: This study demonstrated that this novel tramadol OAD formulation provides sustained analgesic efficacy over the entire 24-hour dosing interval and a clinically favourable safety profile, both of which will provide a clear clinical benefit.