Development of the Sports Organization Concussion Risk Assessment Tool (SOCRAT).

OBJECTIVE: In this paper, we describe the development of a novel tool-the Sports Organization Concussion Risk Assessment Tool (SOCRAT)-to assist sport organizations in assessing the overall risk of concussion at a team level by identifying key risk factors. METHODS: We first conducted a literature review to identify risk factors of concussion using ice hockey as a model. We then developed an algorithm by combining the severity and the probability of occurrence of concussions of the identified risk factors by adapting a risk assessment tool commonly used in engineering applications. RESULTS: The following risk factors for ice hockey were identified: age, history of previous concussions, previous body checking experience, allowance of body checking, type of helmet worn and the game or practice environment. These risk factors were incorporated into the algorithm, resulting in an individual risk priority number (RPN) for each risk factor and an overall RPN that provides an estimate of the risk in the given circumstances. CONCLUSION: The SOCRAT can be used to analyse how different risk factors contribute to the overall risk of concussion. The tool may be tailored to organizations to provide: (1) an RPN for each risk factor and (2) an overall RPN that takes into account all the risk factors. Further work is needed to validate the tool based on real data.

A variational Bayes spatiotemporal model for electromagnetic brain mapping.

In this article, we present a new variational Bayes approach for solving the neuroelectromagnetic inverse problem arising in studies involving electroencephalography (EEG) and magnetoencephalography (MEG). This high-dimensional spatiotemporal estimation problem involves the recovery of time-varying neural activity at a large number of locations within the brain, from electromagnetic signals recorded at a relatively small number of external locations on or near the scalp. Framing this problem within the context of spatial variable selection for an underdetermined functional linear model, we propose a spatial mixture formulation where the profile of electrical activity within the brain is represented through location-specific spike-and-slab priors based on a spatial logistic specification. The prior specification accommodates spatial clustering in brain activation, while also allowing for the inclusion of auxiliary information derived from alternative imaging modalities, such as functional magnetic resonance imaging (fMRI). We develop a variational Bayes approach for computing estimates of neural source activity, and incorporate a nonparametric bootstrap for interval estimation. The proposed methodology is compared with several alternative approaches through simulation studies, and is applied to the analysis of a multimodal neuroimaging study examining the neural response to face perception using EEG, MEG, and fMRI.

Neural correlates of music recognition in Down syndrome.

The brain mechanisms that subserve music recognition remain unclear despite increasing interest in this process. Here we report the results of a magnetoencephalography experiment to determine the temporal dynamics and spatial distribution of brain regions activated during listening to a familiar and unfamiliar instrumental melody in control adults and adults with Down syndrome (DS). In the control group, listening to the familiar melody relative to the unfamiliar melody, revealed early and significant activations in the left primary auditory cortex, followed by activity in the limbic and sensory-motor regions and finally, activation in the motor related areas. In the DS group, listening to the familiar melody relative to the unfamiliar melody revealed increased significant activations in only three regions. Activity began in the left primary auditory cortex and the superior temporal gyrus and was followed by enhanced activity in the right precentral gyrus. These data suggest that familiar music is associated with auditory-motor coupling but does not activate brain areas involved in emotional processing in DS. These findings reveal new insights on the neural basis of music perception in DS as well as the temporal course of neural activity in control adults.

Prenatal exposure to maternal depression is related to the functional connectivity organization underlying emotion perception in 8-10-month-old infants - Preliminary findings.

Emotion perception is critical for infant's social development. Mother's mood during pregnancy has been associated with infants' emotional developmental risks. Graphtheory analysis was applied on EEG data recorded from 35, 8-to-10-month-old-infants prenatally exposed to high or low depressed symptoms, while viewing happy and sad faces. We found an interaction between group and emotion such that infants exposed to high-depressed-symptoms showed higher modularity - reflecting reduced perceptual-dynamics - for viewing happy emotions compared to sad. The opposite was observed for infants exposed to low-depressive-symptoms. These preliminary findings suggest that prenatal depressive mood may shape early functional organization for viewing emotional faces.

The perception of friendship in adults with Down syndrome.

BACKGROUND: Measuring the perception of friendship in adults with Down syndrome (DS) has long been a research challenge. While there have been studies investigating the number of friends children with DS have in, the study of how adults with DS view the concept of friendship has been relatively unexplored. The aim of this study was to evaluate the perception of friendship in adults with DS using a visually based scale. METHODS: Sixty-six individuals participated in this study: 22 adults with DS, 22 typical mental age (MA) matched children and 22 typical adults matched for chronological age (CA). We administered a visually based Friendship scale made up of photographs depicting social interactions between individuals or groups. The scale was composed of two parts. In Part 1 participants were shown two photographs and asked to select the photograph that best depicted friends. In Part 2 participants were asked to view one photograph and asked, 'Is it okay for friends to do this?' RESULTS: Adults with DS scored lower on the Friendship scale in comparison with the CA and MA matched groups. Adults with DS made more errors in identifying 'friends' from 'non-friends' but were equally able to distinguish friendly behaviours and actions from non-friendly behaviours as their CA and MA matched peers. Individuals with DS were more likely to incorrectly identify photographs depicting a teacher, or a mother with a child as friends. Actions or behaviours that depicted subtle negative emotions were also incorrectly identified. CONCLUSIONS: These results are an important first step in understanding the perception of friendship and social behaviours related to friendship in adults with DS.

Infants and adults have similar regional functional brain organization for the perception of emotions.

An infant's ability to perceive emotional facial expressions is critical for developing social skills. Infants are tuned to faces from early in life, however the functional organization of the brain that supports the processing of emotional faces in infants is still not well understood. We recorded electroencephalography (EEG) brain responses in 8-10 month old infants and adults and applied graph theory analysis on the functional connections to compare the network organization at the global and the regional levels underlying the perception of negative and positive dynamic facial expressions (happiness and sadness). We first show that processing of dynamic emotional faces occurs across multiple brain regions in both infants and adults. Across all brain regions, at the global level, network density was higher in the infant group in comparison with adults suggesting that the overall brain organization in relation to emotion perception is still immature in infancy. In contrast, at the regional levels, the functional characteristics of the frontal and parietal nodes were similar between infants and adults, suggesting that functional regional specialization for emotion perception is already established at this age. In addition, in both groups the occipital, parietal and temporal nodes appear to have the strongest influence on information flow within the network. These results suggest that while the global organization for the emotion perception of sad and happy emotions is still under development, the basic functional network organization at the regional level is already in place early in infancy.

Changes in brain-behavior relationships following a 3-month pilot cognitive intervention program for adults with traumatic brain injury.

Facilitating functional recovery following brain injury is a key goal of neurorehabilitation. Direct, objective measures of changes in the brain are critical to understanding how and when meaningful changes occur, however, assessing neuroplasticity using brain based results remains a significant challenge. Little is known about the underlying changes in functional brain networks that correlate with cognitive outcomes in traumatic brain injury (TBI). The purpose of this pilot study was to assess the feasibility of an intensive three month cognitive intervention program in individuals with chronic TBI and to evaluate the effects of this intervention on brain-behavioral relationships. We used tools from graph theory to evaluate changes in global and local brain network features prior to and following cognitive intervention. Network metrics were calculated from resting state electroencephalographic (EEG) recordings from 10 adult participants with mild to severe brain injury and 11 age and gender matched healthy controls. Local graph metrics showed hyper-connectivity in the right inferior frontal gyrus and hypo-connectivity in the left inferior frontal gyrus in the TBI group at baseline in comparison with the control group. Following the intervention, there was a statistically significant increase in the composite cognitive score in the TBI participants and a statistically significant decrease in functional connectivity in the right inferior frontal gyrus. In addition, there was evidence of changes in the brain-behavior relationships following intervention. The results from this pilot study provide preliminary evidence for functional network reorganization that parallels cognitive improvements after cognitive rehabilitation in individuals with chronic TBI.

Clinical efficacy and safety of a novel controlled-release morphine suppository and subcutaneous morphine in cancer pain: a randomized evaluation.

PURPOSE: A significant number of cancer patients will require an alternate route of morphine administration at some point during their illness. This study compared the clinical efficacy and safety of a novel morphine sulfate controlled-release suppository (MS-CRS) and subcutaneous (SC) morphine in patients with cancer pain. METHODS: Thirty patients with cancer pain were randomized in a double-blind crossover study to MS-CRS every 12 hours or SC morphine every 4 hours for 4 days each, using a 2.5:1 analgesic equivalence ratio. Pain intensity was assessed using a visual analog scale (VAS) and the Present Pain Intensity Index of the McGill Pain Questionnaire. Nausea and sedation were also assessed with a VAS. Evaluations were made by the patient at 8 AM, noon, 4 PM, and 8 PM and rescue morphine consumption recorded. RESULTS: Twenty-three patients completed the study (13 men and 10 women; mean age, 64.0 +/- 2.0 years) and were treated with mean daily MS-CRS and SC morphine doses of 326 +/- 69 mg and 138 +/- 28 mg, respectively. There was a small but significant difference in overall ordinal pain-intensity scores in favor of MS-CRS (0.7 +/- 0.1 v 0.9 +/- 0.1, P = .0459). There were no significant differences between MS-CRS and SC morphine in overall VAS scores for pain intensity (13 +/- 3 v 13 +/- 3 mm), sedation (23 +/- 3 v 25 +/- 4 mm), and nausea (8 +/- 2 v 9 +/- 2 mm). The mean daily rescue analgesic consumption during MS-CRS and SC morphine did not differ significantly (1.2 +/- 0.4 v 1.2 +/- 0.4 doses/d). CONCLUSION: MS-CRS, administered every 12 hours, provides analgesia comparable to SC morphine and represents a reliable, noninvasive alternative method of pain control for patients unable to take oral morphine.

Randomized, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain.

PURPOSE: Use of oxycodone for chronic cancer pain has been hampered by its short elimination half-life. This study was designed to compare the efficacy and safety of controlled-release formulations of oxycodone and morphine for cancer pain. PATIENTS AND METHODS: Thirty-two adult patients with cancer pain and a > or = 3-day history of stable analgesia with oral opioids provided written informed consent and were randomized to controlled-release oxycodone or controlled-release morphine for 7 days. To blind the study using available tablet strengths, the dose ratio of oxycodone to morphine was set at 1:1.5. On day 8, patients were crossed over to the alternate drug for 7 days. Pain intensity was assessed using a visual analog scale (VAS 0 to 100 mm) and a categorical scale (CAT 0 to 4). Side effects were assessed using a checklist (four-point categorical severity) and a nondirected questionnaire. Patients and investigators made blinded global ratings of efficacy and treatment preference. RESULTS: Twenty-three patients completed the study (10 men, 13 women). The VAS and CAT scores were (mean+/-SD) 23+/-21 and 1.2+/-0.8 on controlled-release oxycodone, and 24+/-20 (P=.43) and 1.3+/-0.7 (P=.36) on controlled-release morphine. No period or carryover effect was detected. There were no significant differences in adverse effects (P=.40) or ratings of efficacy and preference. The median oxycodone/morphine dose ratio was 1.5 and the maximum was 2.3. CONCLUSION: Controlled-release oxycodone is as safe and effective as controlled-release morphine in the treatment of cancer pain.

Disposition of morphine and its glucuronide metabolites after oral and rectal administration: evidence of route specificity.

Morphine-6-glucuronide is a metabolite of morphine that shows significant analgesic effects in animals and humans. To evaluate route-specific differences in the potential contribution of morphine-6-glucuronide to morphine analgesia, we studied the pharmacokinetics of morphine, morphine-6-glucuronide, and morphine-3-glucuronide after oral and rectal administration of morphine sulfate in a six-subject randomized, single-dose, two-way crossover evaluation. The mean area under the plasma concentration-time curve (AUC) molar ratios of morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) to morphine (M) were greater after oral morphine administration compared with rectal morphine administration (M6G/M ratio, 2.7:1 versus 1.3:1, p = 0.025; M3G/M ratio, 18.3:1 versus 9.3:1, p = 0.002). Systemic bioavailability and peak plasma concentrations of morphine-6-glucuronide and morphine-3-glucuronide were significantly greater after oral morphine administration compared with the rectal route (AUC: M6G, 377.1 +/- 124.2 versus 236.2 +/- 133.7 nmol.hr/L, p = 0.05; M3G, 2610.1 +/- 446.4 versus 1650.2 +/- 309.0 nmol.hr/L, p = 0.004; maximum concentrations: M6G, 110.9 +/- 37.5 versus 64.6 +/- 28.8 nmol/L, p = 0.002; M3G, 576.9 +/- 155.8 versus 266.8 +/- 110.5 nmol/L, p = 0.007). Conversely, the systemic availability of morphine was lower after oral administration, although this difference failed to achieve statistical significance (142.3 +/- 17.1 versus 176.6 +/- 69.4 nmol.hr/L, p = 0.14). These data suggest that rectal administration of morphine is associated with significant avoidance of hepatic biotransformation, and they provide a convincing argument for the evaluation of morphine-6-glucuronide concentrations in pharmacokinetic and pharmacodynamic comparisons involving different routes of morphine administration.

Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia.

OBJECTIVE: Although opioid analgesics are used in the management of neuropathic pain syndromes, evidence of their efficacy remains to be established. We evaluated the clinical efficacy and safety of oxycodone in neuropathic pain using postherpetic neuralgia as a model. METHODS: Patients with postherpetic neuralgia of at least moderate intensity were randomized to controlled-release oxycodone 10 mg or placebo every 12 hours, each for 4 weeks, using a double-blind, crossover design. The dose was increased weekly up to a possible maximum of 30 mg every 12 hours. Pain intensity and pain relief were assessed daily, and steady (ongoing) pain, brief (paroxysmal) pain, skin pain (allodynia), and pain relief were recorded at weekly visits. Clinical effectiveness, disability, and treatment preference were also assessed. RESULTS: Fifty patients were enrolled and 38 completed the study (16 men, 22 women, age 70+/-11 years, onset of postherpetic neuralgia 31+/-29 months, duration of pain 18+/-5 hours per day). The oxycodone dose during the final week was 45+/-17 mg per day. Compared with placebo, oxycodone resulted in pain relief (2.9+/-1.2 versus 1.8+/-1.1, p=0.0001) and reductions in steady pain (34+/-26 versus 55+/-27 mm, p=0.0001), allodynia (32+/-26 versus 50+/-30 mm, p=0.0004), and paroxysmal spontaneous pain (22+/-24 versus 42+/-32 mm, p=0.0001). Global effectiveness, disability, and masked patient preference all showed superior scores with oxycodone relative to placebo (1.8+/-1.1 versus 0.7+/-1.0, p=0.0001; 0.3+/-0.8 versus 0.7+/-1.0, p=0.041; 67% versus 11%, p=0.001, respectively). CONCLUSIONS: Controlled-release oxycodone is an effective analgesic for the management of steady pain, paroxysmal spontaneous pain, and allodynia, which frequently characterize postherpetic neuralgia.

Comparative efficacy and safety of controlled-release morphine suppositories and tablets in cancer pain.

Although the oral route is the preferred method of opioid therapy in patients with cancer pain, many patients will require an alternate route of analgesic administration at some point during the trajectory of their illness. This study compared the efficacy and safety of a novel, controlled-release suppository of morphine (MSC-R) and controlled-release morphine tablets (MSC-T) in patients with cancer pain. In a double-blind crossover study, 27 patients with cancer pain were randomized to receive MSC-R or MSC-T every 12 hours for 7 days each, using a 1:1 analgesic equivalence ratio. Pain intensity was assessed using a visual analog scale (VAS) and the Present Pain Intensity Index of the McGill Pain Questionnaire. Nausea and sedation were also assessed with a VAS. Pharmacodynamic assessments were made by the patient at 8:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM and rescue morphine use recorded in a daily diary. There were no significant differences between MSC-R and MSC-T in overall scores for pain intensity VAS, ordinal pain intensity, and sedation. There was a small but significant difference in overall nausea VAS score in favor of MSC-R. Mean daily rescue analgesic use did not differ significantly during between treatment with MSC-R and MSC-T. MSC-R provides pain control comparable to that provided by MSC-T when given every 12 hours at a 1:1 dose ratio, and represents a reliable alternative method of pain control for patients unable to take oral opioid agents.

Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone.

Although the pharmacokinetics of oral hydromorphone has been evaluated in healthy volunteers after small single oral doses, data are not available regarding the disposition of hydromorphone and its principal metabolite, hydromorphone-3-glucuronide (H3G), at steady-state and after large oral doses. The authors studied the pharmacokinetics of hydromorphone and H3G after oral administration of an immediate-release (IR) and controlled-release (CR) formulation of hydromorphone at a daily dose of 48 +/- 11 mg (range 6-216 mg) in a randomized, double-blind, steady-state, two-way crossover evaluation in 18 patients with chronic cancer pain. Controlled-release hydromorphone demonstrated equivalent bioavailability and acceptable CR characteristics, when compared with IR hydromorphone (CR vs. IR: AUC0-12 123.10 +/- 20.38 vs. 118.98 +/- 20.92 ng.hr.mL-1, P = NS, Cmax 17.76 +/- 3.07 vs. 19.70 +/- 4.04 ng.mL-1, P = NS, Cmin 6.04 +/- 1.01 vs. 5.28 +/- 1.000 ng.mL-1, P = NS, and Tmax 4.78 +/- 0.78 vs. 1.47 +/- 0.22 hr, P = 0.0008). A significant linear relationship existed between hydromorphone dose and hydromorphone AUC (r = 0.8315, P = 0.0001) and between hydromorphone AUC and H3G AUC (r = 0.8048, P = 0.0001) over a wide dose range. The steady-state molar ratio of H3G to hydromorphone was 27:1. The authors conclude that CR hydromorphone provides a pharmacokinetic profile consistent with 12 hourly dosing and that at steady state, oral hydromorphone is extensively metabolized to H3G, although the pharmacologic activity of this metabolite remains unknown.

Steady-state pharmacokinetic evaluation of a novel, controlled-release morphine suppository and subcutaneous morphine in cancer pain.

Although the oral route is the preferred method for morphine administration for cancer pain, many patients will require an alternate route of administration at some point during their illness. The authors studied the steady-state pharmacokinetics of morphine after administration of a novel, controlled-release suppository (MS-CRS) and subcutaneous morphine in a randomized, double-blind, two-way crossover evaluation in 10 patients with cancer pain. When administered at a 2.5:1 analgesic ratio, MS-CRS given every 12 hours showed an equivalent extent of absorption compared with subcutaneous morphine given every 4 hours (AUC0-12, 132.5 +/- 30.1 versus 123.8 +/- 27.3 ng.h.mL-1, P = not significant [NS]). Peak morphine concentrations were lower, time of peak was later, and percent fluctuation less after MS-CRS than after subcutaneous morphine (Cmax, 14.7 +/- 2.9 versus 29.9 +/- 5.4 ng/mL, P = .0110; tmax, 3.33 +/- 0.75 versus 2.22 +/- 0.15 hours, P = .0160; fluctuation, 122 +/- 71 versus 356 +/- 123%, P = .00160). Relative bioavailability of MS-CRS using the 2.5:1 analgesic ratio was 105%, and bioavailability from data dose normalized without regard to route specificity in metabolism was 42%. For both routes of administration there was a significant linear relationship between morphine dose and AUC (MS-CRS, r = .8568, P = .0032; subcutaneous morphine, r = .8314, P = .0055). MS-CRS morphine provides a pharmacokinetic profile consistent with dosing every 12 hours; at steady state, the extent of absorption is comparable with that of subcutaneous morphine when administered at a 2.5:1 dose ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum theophylline profile with once-daily theophylline (Uniphyl) following conversion from intravenous theophylline in adult asthmatic patients.

Although guidelines are available for conversion from intravenous (IV) theophylline to twice-daily, oral, controlled-release theophylline, the optimal method for conversion to Uniphyl, a chronotherapeutically formulated, once-daily theophylline preparation, has not been previously evaluated. The present study was designed to prospectively evaluate a method for converting patients from IV theophylline to Uniphyl, to formulate simple, practical dosage recommendations for use in clinical practice. Ten patients with acute exacerbation of asthma receiving IV theophylline for > or = 48 hours and with steady state serum theophylline concentrations (STCs) between 4.5 and 15.5 mg/L (25 and 86 mumol/L) were enrolled into the study. Patients with STCs > or = 4.5 and < 12 mg/L (> or = 25 and < 66 mumol/L) and those with STCs > or = 12 and < or = 15.5 mg/L (> or = 66 and < or = 86 mumol/L) received their first Uniphyl dose immediately following termination of IV theophylline (No Time Lapse [NTL] group) and after a 4-hour delay (Time Lapse [TL] group), respectively. The differences in the area under the curve values between Uniphyl dosing and IV theophylline were 11% in the NTL group (1214.6 +/- 247.9 mumol/h.L-1 vs 1370.4 +/- 148.1 mumol/h.L-1, 95% confidence interval, 74% to 103%; P = 0.068) and 10% in the TL group (1959.4 +/- 165.1 mumol/h.L-1 vs 1784.6 +/- 119.4 mumol/h.L-1, 95% confidence interval, 103% to 117%; P = 0.013).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of cimetidine and ranitidine on the pharmacokinetics of a chronotherapeutically formulated once-daily theophylline preparation (Uniphyl).

The effects of cimetidine and ranitidine on the steady-state pharmacokinetics, safety, and efficacy of a chronotherapeutically formulated (CTF), once-daily theophylline preparation (Uniphyl) were evaluated in 12 adult patients with asthma. In this randomized, double-blind, three-way crossover study, patients received a fixed dose of CTF-theophylline and concurrent cimetidine, ranitidine, or placebo for a period of 7 days each. Asthma symptoms, drug side effects, and beta 2-agonist inhaler use were recorded daily. Venous blood sampling for pharmacokinetic assessment was done over a complete dosing interval on day 7 of each phase. Coadministration of cimetidine, but not ranitidine, was associated with a significant decrease in the apparent oral clearance of theophylline (2.47 +/- 0.91 vs 1.85 +/- 0.63 L/hr; P = 0.004) and increases in the theophylline area under the curve (233.48 +/- 58.99 vs 307.43 +/- 79.07 mg/L/hr; P = 0.003), peak concentration (13.2 +/- 2.8 vs 16.7 +/- 3.7 mg/L; P = 0.002), and trough concentration (6.4 +/- 2.5 vs 9.0 +/- 3.0 mg/L; P = 0.008). Despite the changes in theophylline pharmacokinetic parameters during cimetidine treatment, no significant differences in asthma symptom scores or side effects were seen when once-daily CTF-theophylline was administered concomitantly with cimetidine, ranitidine, or placebo.

Pharmacokinetics of two novel rectal controlled-release morphine formulations.

Administration of morphine by the oral route is not possible in cancer patients who are unable to swallow or are intolerant of oral morphine. Thus, there is a need for reliable alternate routes of drug administration. We compared the bioavailability of two prototype 30-mg morphine sulfate controlled-release suppository formulations (high and low viscosity) with 30-mg oral controlled-release morphine sulfate tablets in a 14-subject single-dose randomized, three-way crossover study. Venous blood samples were obtained immediately prior to and for 24 hr following each dose. Morphine concentrations were determined by radioimmunoassay. Compared with oral controlled-release morphine, the high- and low-viscosity suppository formulations had significantly greater bioavailability (AUC0-24 72.7 +/- 13.2 for the oral preparation versus 98.6 +/- 35.7 and 105.8 +/- 37.3 ng.hr/mL for the suppositories, respectively, P < 0.05), later peak concentration (tmax 2.3 +/- 0.8 versus 3.1 +/- 2.3 and 5.0 +/- 1.5 hr, respectively, P < 0.05), and longer half-value duration (4.3 +/- 1.6 versus 10.4 +/- 5.5 and 9.5 +/- 4.3 hr, respectively, P < 0.05). Peak concentration for the high-viscosity suppository formulation (Cmax 7.75 +/- 2.66 ng/mL) was significantly lower than the low-viscosity suppository (Cmax 9.23 +/- 2.85 ng/mL) and the oral tablet (Cmax 10.4 +/- 2.78 ng/mL) formulations (P < 0.05). The increased bioavailability observed with the two controlled-release suppositories may be the result of partial avoidance of hepatic biotransformation with rectal administration.

Chronic nausea in advanced cancer patients: a retrospective assessment of a metoclopramide-based antiemetic regimen.

The purpose of this retrospective study is to assess the frequency and intensity of chronic nausea in patients admitted to the Palliative Care Unit and the results of a metoclopramide-based treatment regimen. We reviewed the medical records of 100 consecutive patients admitted to the Palliative Care Unit at the Edmonton General Hospital until death during 1992-1993. All patients had terminal cancer and normal cognitive function. All patients completed the Functional Analogue Scale for appetite, nausea, pain, activity, shortness of breath, and sensation of well-being at 1000 and 1600 hours every day. Patients who complained of nausea initially received metoclopramide 10 mg every 4 hr orally or subcutaneously (Step 1). If nausea persisted, dexamethasone 10 mg twice daily was added (Step 2). Step 3 consisted of a continuous subcutaneous infusion of metoclopramide of 60-120 mg/day plus dexamethasone. If no response was observed, other antiemetics were administered (Step 4). Upon admission to the unit, 32 patients (32%) presented with nausea. During the average admission of 25 +/- 13 days, 98 patients (98%) developed nausea. Twenty-five patients (25%) required other antiemetics because of bowel obstruction (18), extrapyramidal side effects (3), or other reasons (4). Most patients without bowel obstruction achieved excellent control of nausea using the metoclopramide-based regimen. During the first 5 days and last 5 days of admission, nausea had significantly lower intensity than the rest of the symptoms that were monitored. Our results suggest that, although nausea is very frequent, it can be well controlled in the majority of patients using safe and simple antiemetic regimens.

A double-blind, crossover study of controlled-release metoclopramide and placebo for the chronic nausea and dyspepsia of advanced cancer.

To compare a novel controlled-release formulation of metoclopramide with placebo in patients with cancer-associated dyspepsia syndrome, 26 adult patients with a >/=1 month history of cancer-associated dyspepsia syndrome were randomized to receive either controlled-release metoclopramide 40 mg every 12 hours or matching placebo for a period of 4 days. On day 5, patients crossed over to the alternate treatment for a further period of 4 days. Dose adjustments and rescue antiemetics were permitted during both phases. Nausea, anorexia, bloating, vomiting/retching, and drowsiness were assessed on a 100-mm VAS scale in a daily diary. On the last day of treatment of each phase, nausea was significantly lower in the controlled-release metoclopramide group compared to placebo (17 +/- 12 mm versus 12 +/- 10 mm). Nausea scores tended to increase across days during the placebo phase and to decrease during the controlled-release metoclopramide phase. There was a trend for improvement in the intensity of all symptoms on controlled-release metoclopramide with the exception of appetite, but this trend only reached statistical significance for nausea. The frequency and severity of elicited adverse events did not differ significantly between treatments, although drowsiness, dizziness, and poor sleep were somewhat higher in the placebo group. In no case was it necessary to discontinue controlled-release metoclopramide because of toxicity. These results indicate that controlled-release metoclopramide reduces gastrointestinal symptoms in this population of advanced cancer patients.

Randomized evaluation of controlled-release codeine and placebo in chronic cancer pain.

Codeine is widely used in combination with acetaminophen and aspirin for the management of mild to moderate pain. However, there are few controlled clinical trials of single-entity codeine in chronic cancer pain. The purpose of this study was to evaluate the clinical efficacy and safety of controlled-release codeine given every 12 hr in patients with cancer pain. Thirty-five patients with chronic cancer pain were randomized in a double-blind crossover study to controlled-release (CR) codeine or placebo, for 7 days each. Pain intensity was assessed at 0800 hr and 2000 hr using a visual analogue scale (VAS) and a five-point categorical scale, and the use of "rescue" acetaminophen-plus-codeine (300 mg/30 mg every 4 hr as needed) was recorded. Thirty patients completed the study (17 male, 13 female; mean age, 64.4 +/- 9.8 years) with a mean daily CR codeine dose of 277 +/- 77 mg (range, 200-400 mg). CR codeine treatment resulted in significantly lower overall VAS pain intensity scores (22 +/- 18 mm versus 36 +/- 20 mm, P = 0.0001), categorical pain intensity scores (1.2 +/- 0.8 versus 1.8 +/- 0.8, P = 0.0001), and pain scores when assessed by day of treatment and by time of day. Daily "rescue" analgesic consumption was significantly lower on CR codeine, compared to placebo treatment (2.2 +/- 2.3 versus 4.6 +/- 2.8 tablets per day, P = 0.0001). Both patients and investigators preferred CR codeine to placebo (80% versus 3%, P = 0.0014 and 73% versus 7%, P = 0.0160, respectively). These data indicate that CR codeine, given every 12 hr results in significant reductions in pain intensity and the use of "rescue" acetaminophen-plus-codeine in patients with cancer pain. CR codeine provides the benefits of a flexible single entity codeine formulation and the convenience of 12-hr duration of action, which allows patients uninterrupted sleep and improved compliance.