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.

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.

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.

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.

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.

Neural correlates of action understanding in infants: influence of motor experience.

Mirror neurons are recognized as a crucial aspect of motor and social learning yet we know little about their origins and development. Two competing hypotheses are highlighted in the literature. One suggests that mirror neurons may be innate and are an adaptation for action understanding. The alternative, proposes that mirror neurons develop through sensorimotor experience. To date, there has been little direct evidence from infant studies to support either argument. In the present study, we explored the temporal dynamics and spatial distribution of electroencephalography (EEG) brain responses in young infants during the observation of three distinct types of actions: (a) actions that are within the motor repertoire of infants, (b) actions that are not within the motor repertoire of infants, and (c) object motion. We show that young infants had significant motor resonance to all types of actions in the sensorimotor regions. Only observation of human goal-directed actions led to significant responses in the parietal regions. Importantly, there was no significant mu desychronization observed in the temporal regions under any observation condition. In addition, the onset of mu desychronization occurred earliest in response to object motion, followed by reaching, and finally walking. Our results suggest that the infants may have a basic, experience-independent sensorimotor mechanism optimized to detect all coherent motion that is modulated by experience.

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.

Magnetoencephalographic analysis of cortical activity in adults with and without Down syndrome.

BACKGROUND: This preliminary study served as a pilot for an ongoing analysis of spectral power in adults with Down syndrome (DS) using a 151 channel whole head magnetoencephalography (MEG). The present study is the first step for examining and comparing cortical responses during spontaneous and task related activity in DS. METHOD: Cortical responses were recorded with a 151 channel whole head MEG system in three adults with DS and three age-matched adults without DS. MEG data were obtained at rest with eyes open and during observation of point-light displays of human motion and object motion. Data from both groups were evaluated by spectral analysis. RESULTS: The preliminary results showed greater alpha (8-14 Hz) power particularly in the occipital and parietal areas during the eyes open condition in the adults with DS in relation to a normal comparison group. The visual task had little effect on alpha power in the comparison group. Engaging in the visual task reduced power in alpha across all regions in the DS group to the level observed in comparisons. In the gamma band (30-50 Hz), power values were similar across both groups for the eyes open condition. In the comparison group, large reductions in gamma were observed in the occipital and bilateral temporal areas during the visual task. This change was not observed in the DS group. CONCLUSIONS: The results from this pilot study suggest that MEG may be useful in characterizing task-specific changes in cortical activity in individuals with DS. Future studies with a larger group of individuals will further contribute to our understanding of the neurophysiology of Down syndrome.

Stiffness and postural stability in adults with Down syndrome.

The purpose of this study was to characterize postural sway in quiet standing under eyes-open and eyes-closed conditions, and to obtain a measure of postural stiffness during quiet standing in adults with Down syndrome (DS) versus control subjects. We obtained descriptive measures from centre-of-pressure (COP) data and analysed and compared COP trajectories and postural stiffness estimates from two stochastic models, the "pinned polymer" (PP) and "inverted pendulum" (IP) models. These estimates were correlated with clinical measures of muscle tone. Our results showed that overall, estimated values for postural stiffness from both models were larger for the DS group than for normal controls. In addition, average stiffness measures were greater under the eyes-closed condition than under the eyes-open condition for the DS group. The IP model detected significant trends over trials whereas the PP model did not. Clinical assessment of muscle tone for the DS group ranged from low to high-normal and there was no significant correlation with the postural stiffness measures obtained from either model. These results suggest that individuals with DS have the ability to modulate their underlying "stiffness" under conditions of quiet standing. Furthermore, there appears to be no strong relationship between clinical measures of muscle tone and postural stiffness measures under dynamic conditions.

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.

Double blind randomized placebo control trial of controlled release codeine in the treatment of osteoarthritis of the hip or knee.

OBJECTIVE: Pain is the cardinal feature of osteoarthritis (OA), and with advancing disease there is loss of function and increasing pain even at times of joint rest. Few studies have evaluated the role of opioid analgesics in treating the pain of OA. METHODS: This randomized, double blind, parallel group study compared the efficacy and safety of a 12 hourly controlled release codeine formulation (Codeine Contin) with placebo in patients with chronic pain due to OA of the hips and/or knees. The 4 week treatment period, following an analgesic washout phase of 2-7 days, included weekly clinic evaluations, at which the dose was escalated as appropriate, and daily patient diary completion. Pain (daily), stiffness, and physical function (weekly) were assessed using the multidimensional, self-administered WOMAC (visual analog scale version) questionnaire. RESULTS: Sixty-six eligible patients completed the study. The mean initial and final daily doses of controlled release codeine were 50 mg every 12 h at baseline and 159 mg every 12 h at the final assessment. All variables in the efficacy analysis indicated superiority of controlled release codeine over placebo. The WOMAC pain scale showed an improvement of 44.8% over baseline in the controlled release codeine group compared with 12.3% taking placebo (p = 0.0004). For the WOMAC stiffness and physical function scales the improvements over baseline on controlled release codeine were 47.7% and 49.3%, respectively compared with 17.0% and 17.0%, respectively, with placebo (p = 0.003; p = 0.0007). Controlled release codeine was also significantly better than placebo on measures of sleep quality and requirement for supplemental acetaminophen. CONCLUSION: Single entity controlled release codeine is an effective treatment for pain due to OA of the hip or knee.

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.

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.

Randomised trial of oral morphine for painful episodes of sickle-cell disease in children.

BACKGROUND: Oral controlled-release morphine can provide effective analgesia through a non-invasive route and may facilitate outpatient management of severe episodes of sickle-cell pain. We compared the clinical efficacy and safety of oral morphine with continuous intravenous morphine in children with severe episodes of sickle-cell pain, by a double-blind, randomised, parallel-group design. METHODS: 56 children aged 5-17 years received loading doses of intravenous morphine of up to 0.15 mg/kg, followed by randomly assigned oral morphine 1.9 mg/kg every 12 h plus intravenous placebo (saline), or intravenous morphine 0.04 mg kg-1 h-1, plus placebo tablet. Breakthrough pain was treated with oral, immediate-release morphine 0.4 mg/kg every 2-3 h as required. Pain was assessed daily at 0900 h, 1300 h, 1700 h, and 2100 h with a picture face scale, a pictorial scale (Oucher), a behavioural-observational scale (CHEOPS), and by an investigator. FINDINGS: 50 children completed the study (28 boys, 22 girls; mean age 11.2 years [SD 3.5]; mean oral morphine dose 2.99 mg/kg daily [0.75]; mean intravenous morphine dose, 0.81 mg/kg daily [0.30]). Mean overall pain scores were similar for oral and intravenous morphine (CHEOPS, 6.3 [1.5] vs 6.4 [1.4], p = 0.8; Oucher, 31.5 [25.4] vs 39.2 [21.7], p = 0.3; Faces, 2.2 [1.4] vs 2.4 [1.3], p = 0.6; clinical rating, 1.7 [0.7] vs 1.9 [0.5], p = 0.3). Opioid analgesia was required for a mean of 4.2 days (1.7) and 5.4 days (2.6), respectively (p = 0.0591). Pain scores from all scales correlated significantly (r = 0.5865-0.8980, p = 0.0001). Frequency of rescue analgesia did not differ significantly between the oral and intravenous morphine groups (0.7 [0.8] vs 0.9 [0.7] doses daily, p = 0.2). Frequency and severity of adverse events did not differ significantly. INTERPRETATION: Oral, controlled-release morphine is a reliable, non-invasive alternative to continuous intravenous morphine for the management of painful episodes of sickle-cell disease in children.

Comparative clinical efficacy and safety of a novel controlled-release oxycodone formulation and controlled-release hydromorphone in the treatment of cancer pain.

BACKGROUND: The use of oxycodone to treat chronic cancer pain has been hampered by its short elimination half-life, which necessitates administration every 4 hours. This study compared the clinical efficacy and safety of a novel oxycodone formulation with that of hydromorphone in the treatment of cancer pain. METHODS: In a double-blind crossover study, 44 patients with stable cancer pain were randomized to controlled-release oxycodone or controlled-release hydromorphone, each given every 12 hours for 7 days. Pain intensity, nausea, and sedation were assessed by patients four times daily, and breakthrough analgesia was recorded. RESULTS: Thirty-one patients completed the study (18 women, 13 men; mean age, 56 +/- 3 years) and received a final controlled-release oxycodone dose of 124 +/- 22 mg per day and a final controlled-release hydromorphone dose of 30 +/- 6 mg per day. There were no significant differences between treatments in overall Visual Analogue Scale (VAS) pain intensity (VAS 28 +/- 4 mm vs. 31 +/- 4 mm), categorical pain intensity (1.4 +/- 0.1 vs. 1.5 +/- 0.1), daily rescue analgesic consumption (1.4 +/- 0.3 vs. 1.6 +/- 0.3), sedation scores (24 +/- 4 mm vs. 18 +/- 3 mm), nausea scores (15 +/- 3 mm vs. 13 +/- 3 mm), or patient preference. Two patients experienced hallucinations on controlled-release hydromorphone, but none did while receiving controlled-release oxycodone. CONCLUSIONS: Controlled-release oxycodone demonstrated excellent pharmacodynamic characteristics, analgesic efficacy, and safety as compared with controlled-release hydromorphone and represents an important new therapeutic option for cancer pain management.

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.

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.