Model-Based Analysis of the Influence of Alcohol Use and Age on Pharmacokinetics-Pharmacodynamics of Oral Oxycodone in Middle-Age and Older Community-Dwelling Adults.

Little is known about how opioid responses vary by age and in the presence of alcohol consumption. This model-based pharmacokinetic (PK)-pharmacodynamic (PD) analysis quantified the impact of age and alcohol use on pupillometry and cold pressor test (CPT) PD based on data from an open-label study of a single, immediate-release 10-mg oral oxycodone in middle-age and older adults (aged 35-85) without severe functional limitations. PK and pupillometry assessments were obtained on 11 occasions over 8 hours. Cold pressor test was administered at 1.5, 5, and 8 hours after oxycodone dosing. The study population consisted of 62 older adults (aged ≥60) and 66 middle-aged adults (aged 35-59), with 82% meeting the unhealthy drinking criteria. Oral oxycodone PK were well described using a 1-compartment model with a sequential 0 to first-order absorption process. Inhibitory maximum effect and linear direct effect PD models described the respective pupillometry and cold pressor test data using simultaneous PK-PD analysis in MONOLIX. Recent alcohol use measures were selected a priori as covariates. This analysis demonstrated an influence of age on clearance and body weight on the distribution volume of oxycodone; alcohol consumption was not noted to alter oxycodone PK. Oxycodone pupillometry PD were influenced by the level of subject-reported alcohol consumption (Alcohol Use Disorders Identification Test for Consumption), alcohol use biomarker-blood phosphatidylethanol, previous cannabis use, and age. Over the opioid exposure range of the study, none of the covariables including alcohol and age were noted to affect cold pressor test pharmacodynamics. Additional clinical studies are needed to further investigate the clinical consequences of opioid-alcohol-age interaction.

Cognitive skill training improves memory, function, and use of cognitive strategies in cancer survivors.

BACKGROUND: Cancer survivors commonly report symptoms of impaired cognition. This project examined effectiveness of a behavioral skills training intervention to improve cognition and reduce cognitive dysfunction symptoms in cancer survivors. METHODS: Participants were randomly assigned to group-based workshops focused on learning new cognitive skills (skills treatment-TX) or an active control of education workshops (education control-EC) or a passive control of wait list (WL). Participants were evaluated pre- and post intervention with subjective mood and symptom questionnaires and objective neurocognitive tests. RESULTS: One hundred twenty-eight participants (mean age 59 years), average 4.6 years (+ / - 5.5 years) post cancer treatment with various cancer types (breast, bladder, prostate, colon, uterine), were enrolled. Analysis of all participants who attended workshop(s) revealed improvement in the TX workshop completers on all objective cognitive measures (attention, concentration, declarative, and working memory) save one test of selective attention, and improvement on a single measure (verbal memory) and decline (selective attention) in the EC group. TX workshop completers also improved on all symptom and mood measures, in contrast to EC group which improved on a single subscale of a symptom measure, but increased on an anxiety measure. TX group alone improved on a quantified measure of each participants' unique, "top three," self-described cognitive symptoms. CONCLUSION: Improvement from behavioral skills training was evident from objective cognitive tests, subjective symptom measures, and quantified, individual patient-specific symptoms. Behavioral skill training is an effective treatment for cognitive dysfunction in cancer survivors, and should be considered as a treatment option by health care providers.

Elevated customary alcohol consumption attenuates opioid effects.

BACKGROUND: Regular alcohol consumption is on the rise among older adults and has the potential of altering the subjective experience of pain and response to pain medications. This study examined the cognitive, analgesic and side effect response to oxycodone in middle age and older adults with elevated levels of customary alcohol consumption in a human laboratory setting. METHODS: After refraining from alcohol for one day, eligible participants underwent baseline assessment cognition and side effects by means of questionnaires that were repeated at three time points (90 min, 5 and 8 h) following administration of a 10 mg oral dose of oxycodone. Response to pain stimulus (Cold Pressor Test (CPT)), pupil size, and plasma oxycodone were also measured. RESULTS: One hundred twenty-eight adults (age 35-85) completed the study day. Compared to those with lower customary alcohol consumption, participants with elevated alcohol consumption showed attenuated opioid-induced pupil constriction and cognitive decline on objective measures of working memory, sustained attention, inhibitory control, coordination on a simulated driving task, and subjective dysphoric effects with enhanced subjective euphoric effects. Oxycodone pharmacokinetics, pain tolerance to CPT, and Berg balance were impacted comparably between alcohol consumption groups. Women endorsed greater negative drug effects, whereas men endorsed positive drug effects. CONCLUSION: Independent of subject's age, elevated customary alcohol consumption attenuates opioid central effects (i.e., pupil miosis, impaired cognition) and gender influences subjective drug effects. Clinicians should consider alcohol consumption and gender when prescribing opioid medications.

Relationship of Phosphatidylethanol Biomarker to Self-Reported Alcohol Drinking Patterns in Older and Middle-Age Adults.

BACKGROUND: Risky alcohol consumption is on the rise among older adults. Biomarkers such as phosphatidylethanol (PEth) have been used to evaluate the correspondence between an objective, laboratory-based biomarker and self-report of alcohol consumption. This study examined the relationship between PEth, self-report of alcohol consumption, and health indices in a sample of community-dwelling older to middle-age adults (aged 35 to 89) with healthy and risky levels of alcohol consumption. METHODS: Self-reports of alcohol consumption were collected using the Alcohol Use Disorders Identification Test (AUDIT) and Form 30. In addition, indices of health along with a blood sample to determine PEth values were collected (N = 183). RESULTS: PEth was correlated with age, AUDIT-C, AUDIT total, alcohol consumption, mood, and liver function measures but not with medical comorbidity or body mass index (J Gerontol B Psychol Sci Soc Sci 73, 2018, 633). Alcohol consumption over the past 30 days measured with Form 30 was the strongest predictor of PEth levels for both middle-age and older adults, with age a small contributing predictor. General alcohol consumption patterns for amount of alcohol consumed over a 30-day period revealed middle-age adults consumed larger amounts of alcohol compared with older adults, but older adults consumed alcohol on more days than middle-age adults. Middle-age participants evidenced higher PEth levels than older adults at comparable drinking rates. CONCLUSIONS: Overall, findings suggest a strong relationship between alcohol consumption and PEth levels with age a small but contributing factor to predicting PEth levels.

Impact of androgen deprivation therapy on mood, cognition, and risk for AD.

Prostate cancer is the most common form of cancer diagnosed in men. Androgen deprivation therapy (ADT) is commonly prescribed, with some estimates indicating over 50% of men with prostate cancer receive ADT at some point in their treatment. Men on ADT are typically otherwise healthy, with good long-term survival. However, consequences of androgen deprivation can include side effects that may include changes in cognition or onset of dementia. This review will describe what is known about ADT and changes in cognitive function, the possible connection with Alzheimer's disease, how to discuss this with patients about to start ADT, and what patients can do to potentially mitigate cognitive changes.

Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults.

OBJECTIVE: To examine potential disease-modifying effects of statin drugs, we conducted a 12-month randomized, placebo-controlled clinical trial of simvastatin in cognitively normal adults using change in CSF Alzheimer disease biomarkers as primary outcome measure. METHODS: Participants were 45-64 years old and statin-naive with normal cognition and normal or mildly elevated cholesterol. Forty-six participants completed the 1-year study per protocol (25 in the simvastatin and 21 in the placebo group). Simvastatin was titrated to 40 mg/d. CSF Aß42, total tau, and p-tau181 were measured at baseline and after 12 months of treatment using the INNO-BIA AlzBio3 assay. We used analysis of covariance to assess differences in biomarker change from baseline between treatment groups, adjusting for age, sex, and APOE ε4 status. RESULTS: Changes from baseline did not differ significantly between treatment groups for any CSF biomarker, with p values of 0.53, 0.36, and 0.25 for CSF Aß42, total tau, and p-tau181, respectively. There was no significant modifying effect of sex, APOE ε4, or baseline high-density lipoprotein or triglycerides on treatment group for any of the biomarkers (all p > 0.18). However, a significant interaction between treatment group and baseline low-density lipoprotein (LDL) was observed for p-tau181 (p = 0.003), where greater decreases from baseline in CSF p-tau181 concentrations were associated with higher baseline LDL level for the simvastatin group. CONCLUSIONS: Simvastatin-related reductions in CSF p-tau181 concentrations may be modulated by LDL cholesterol. The potential disease-modifying effects of simvastatin on CSF phospho-tau should be further investigated in persons with hypercholesterolemia.

Dementia and co-occurring chronic conditions: a systematic literature review to identify what is known and where are the gaps in the evidence?

OBJECTIVE: The challenges posed by people living with multiple chronic conditions are unique for people with dementia and other significant cognitive impairment. There have been recent calls to action to review the existing literature on co-occurring chronic conditions and dementia in order to better understand the effect of cognitive impairment on disease management, mobility, and mortality. METHODS: This systematic literature review searched PubMed databases through 2011 (updated in 2016) using key constructs of older adults, moderate-to-severe cognitive impairment (both diagnosed and undiagnosed dementia), and chronic conditions. Reviewers assessed papers for eligibility and extracted key data from each included manuscript. An independent expert panel rated the strength and quality of evidence and prioritized gaps for future study. RESULTS: Four thousand thirty-three articles were identified, of which 147 met criteria for review. We found that moderate-to-severe cognitive impairment increased risks of mortality, was associated with prolonged institutional stays, and decreased function in persons with multiple chronic conditions. There was no relationship between significant cognitive impairment and use of cardiovascular or hypertensive medications for persons with these comorbidities. Prioritized areas for future research include hospitalizations, disease-specific outcomes, diabetes, chronic pain, cardiovascular disease, depression, falls, stroke, and multiple chronic conditions. CONCLUSIONS: This review summarizes that living with significant cognitive impairment or dementia negatively impacts mortality, institutionalization, and functional outcomes for people living with multiple chronic conditions. Our findings suggest that chronic-disease management interventions will need to address co-occurring cognitive impairment. Copyright © 2017 John Wiley & Sons, Ltd.

Cognitive problems in patients on androgen deprivation therapy: a qualitative pilot study.

OBJECTIVES: Androgen deprivation therapy (ADT; also known as hormone therapy) is a well-established treatment for prostate cancer patients with rising prostate-specific antigen levels after localized treatment, and for those with metastatic disease. The neurological impact of ADT has been likened to that of aging and is therefore theorized to impair cognitive functioning in prostate cancer patients. We briefly summarize the research that has examined cognitive functioning of ADT patients primarily through neuropsychological assessment. A qualitative pilot study is presented with the aim of describing ADT patients' experiences of cognitive changes since starting ADT. MATERIALS AND METHODS: Semistructured telephone interviews were undertaken with 11 community-dwelling prostate cancer patients undergoing ADT following definitive localized treatment. Participants were recruited via online prostate cancer support forums. Content analyses were conducted to establish relevant themes, which in this case were the cognitive domains of impairment. RESULTS: Eight of the 11 participants reported impairments in the domains of concentration, information processing, verbal fluency, visual information processing/visuospatial function, memory, and executive dysfunction. Neurobehavioral problems, including neurofatigue and apathy were also reported. CONCLUSIONS: The interviews illustrate the potential negative effects of ADT on cognitive and neurobehavioral functions, and their impact on patients' work and in their daily lives. We describe how the field of cognitive rehabilitation offers promising tools to assist ADT patients with cognitive problems.

Cognitive response to estradiol in postmenopausal women is modified by high cortisol.

Estradiol has potent favorable effects on brain function and behavior in animals while in human trials, the results are inconsistent. A number of potential mediating variables influencing response to estradiol have been proposed to account for this variability, 1 of which includes stress. We conducted a placebo-controlled study to examine joint and independent effects of estradiol and elevated levels of the stress hormone cortisol on cognition and biomarkers of aging and neurodegenerative disease. Thirty-nine healthy postmenopausal women (56-84 years) received 0.10 mg/dL of transdermal 17ß-estradiol (E2) or placebo for 8 weeks. During the last 4 days of the trial, subjects also received 90 mg/day (30 mg 3×/day) of oral hydrocortisone (CORT) to induce stress-level elevations in cortisol, or a matched placebo. The 4 groups thus included placebo (placebo patch/placebo pill), CORT-alone (placebo patch/hydrocortisone), E2-alone (estradiol patch/placebo pill), and E2+CORT (estradiol patch/hydrocortisone). Eight weeks of E2 increased plasma estradiol by 167%, and 4 days of CORT increased plasma cortisol by 119%. Overall, E2 had favorable effects on verbal memory (p = 0.03), working memory (p = 0.02), and selective attention (p = 0.04), and the magnitude of these effects was attenuated for E2+CORT. E2-alone and E2+CORT had opposing effects on plasma levels of the amyloid-ß (Aß) biomarker (Aß40/42 ratio, p < 0.05), with the more favorable response observed for E2-alone. CORT-induced increases in insulin-like growth factor-1 were blunted by E2 coadministration. Our findings indicate that cognitive and physiological responses to estradiol are adversely affected by elevated stress hormone levels of cortisol in healthy postmenopausal women.

Changes in neuronal activation patterns in response to androgen deprivation therapy: a pilot study.

BACKGROUND: A common treatment option for men with prostate cancer is androgen deprivation therapy (ADT). However, men undergoing ADT may experience physical side effects, changes in quality of life and sometimes psychiatric and cognitive side effects. METHODS: In this study, hormone naïve patients without evidence of metastases with a rising PSA were treated with nine months of ADT. Functional magnetic resonance imaging (fMRI) of the brain during three visuospatial tasks was performed at baseline prior to treatment and after nine months of ADT in five subjects. Seven healthy control patients, underwent neuroimaging at the same time intervals. RESULTS: ADT patients showed reduced, task-related BOLD-fMRI activation during treatment that was not observed in control subjects. Reduction in activation in right parietal-occipital regions from baseline was observed during recall of the spatial location of objects and mental rotation. CONCLUSIONS: Findings, while preliminary, suggest that ADT reduces task-related neural activation in brain regions that are involved in mental rotation and accurate recall of spatial information.

Comparative cognitive and subjective side effects of immediate-release oxycodone in healthy middle-aged and older adults.

UNLABELLED: This study measured the objective and subjective neurocognitive effects of a single 10-mg dose of immediate-release oxycodone in healthy, older (> 65 years), and middle-aged (35 to 55 years) adults who were not suffering from chronic or significant daily pain. Seventy-one participants completed 2 separate study days and were blind to medication condition (placebo, 10-mg oxycodone). Plasma oxycodone concentration peaked between 60 and 90 minutes postdose (P < .01) and pupil size, an indication of physiological effects of the medication, peaked at approximately 90 to 120 minutes postdose (P < .01). Significant declines in simple and sustained attention, working memory, and verbal memory were observed at 1 hour postdose compared to baseline for both age groups with a trend toward return to baseline by 5 hours postdose. For almost all cognitive measures, there were no medication by age-interaction effects, which indicates that the 2 age groups exhibited similar responses to the medication challenge. This study suggests that for healthy older adults who are not suffering from chronic pain, neurocognitive and pharmacodynamic changes in response to a 10-mg dose of immediate-release oxycodone are similar to those observed for middle-aged adults. PERSPECTIVE: Study findings indicate that the metabolism, neurocognitive effects, and physical side effects of oral oxycodone are similar for healthy middle-aged and older adults. Therefore, clinicians should not avoid prescribing oral opioids to older adults based on the belief that older adults are at higher risk for side effects than younger adults.

Effects of insulin and octreotide on memory and growth hormone in Alzheimer's disease.

Both insulin alone and the somatostatin analogue octreotide alone facilitate memory in patients with Alzheimer's disease (AD). Since octreotide inhibits endogenous insulin secretion, the cognitive effects of insulin and octreotide may not be independent. This study tested the individual and interactive effects of insulin and octreotide on memory and plasma growth hormone (GH) levels in older adults. Participants were 16 memory-impaired (AD = 7, amnestic mild cognitive impairment = 9; apolipoprotein E [APOE] epsilon4- [no epsilon4 alleles] = 9, epsilon4+ [1-2 epsilon4 alleles] = 7), and 19 cognitively-intact older adults (APOE epsilon4- = 17, epsilon4+ = 1). On separate days, fasting participants received counterbalanced infusions of: 1) insulin (1 mU.kg(-1).min(-1)) and dextrose to maintain euglycemia; 2) octreotide (150 microg/h); 3) insulin, dextrose, and octreotide; or 4) saline. Story recall was the principal endpoint. Insulin alone facilitated delayed recall for epsilon4- patients, relative to epsilon4+ patients (P = 0.0012). Furthermore, epsilon4- patients with higher Mattis Dementia Rating Scale (DRS) scores had greater octreotide-induced memory facilitation (P = 0.0298). For healthy adults, octreotide facilitated memory (P = 0.0122). Unexpectedly, hyperinsulinemia with euglycemia increased GH levels in healthy controls (P = 0.0299). Thus, insulin and octreotide appear to regulate memory in older adults. APOE epsilon4 genotype modulates responses to insulin and octreotide. Finally, insulin may regulate GH levels during euglycemia.

Open trial of injectable risperidone for methamphetamine dependence.

We tested acceptability and tolerability of long-acting injectable risperidone for methamphetamine (MA) dependence in an open trial with the hypothesis that participants would reduce MA use. Participants were also evaluated for changes in neurocognitive function and psychiatric symptomology. Participants with MA dependence (n = 34) entered a 7-day open-label run-in with oral risperidone. Participants who tolerated oral risperidone (n = 22) were begun on long-acting injectable risperidone 25 mg intramuscular medication with subsequent injections q 2 weeks to a total of 4 injections. Participants remained on oral risperidone during the first 3 weeks after initial injection. Participants were offered 8 weekly individual sessions of relapse prevention counseling. At baseline, participants reported using MA an average of 4.1 days per week (SD = 1.9). Estimated mean days of MA use per week while on injections was 1.0 (95% confidence interval = 0.6-1.4), with days of use decreasing significantly from baseline through week 8 (ß = -0.27; 95% confidence interval: - 0.38--0.16; P < 0.001). Mean week 6 risperidone + 9-OH risperidone plasma levels for participants abstinent from MA from weeks 5 to 8 (n = 7, 63.6%) were 18.8 ng/mL (SD = 6.6) compared with 12.3 (SD = 4.0) for those not abstinent (n = 4; P = 0.075). No serious adverse events occurred. Verbal memory improved at week 4 compared with baseline (P < 0.05). Participation in this trial of injectable risperidone was associated with reductions in MA use as well as some positive benefits on verbal memory. However, these results are limited by the use of an open trial design with a high dropout rate. Risperidone deserves further study in controlled trials as a pharmacotherapy for MA dependence.

Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults.

Intranasal insulin administration raises central nervous system (CNS) insulin levels in humans and acutely facilitates verbal memory in patients with Alzheimer's disease (AD), an effect that may differ by APOE genotype. The purpose of this study was to examine the cognitive dose response curves for intranasal insulin administration, and determine whether the effects of insulin differ between participants with (epsilon4+) and without (epsilon4-) the APOE- epsilon4 allele. On separate mornings, 33 memory-impaired adults with AD or amnestic mild cognitive impairment and 59 normal adults each underwent five intranasal treatment conditions consisting of insulin (10, 20, 40, or 60 IU) or placebo. Cognition was tested 15-minutes post-treatment, and blood was acquired at baseline and 45-minutes post-treatment. Plasma insulin and glucose levels were unaffected by treatment. Insulin administration facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults, with performance generally peaking at 20 IU. In contrast, memory-impaired epsilon4+ subjects demonstrated a relative decline in verbal memory. Insulin also differentially modulated plasma amyloid-beta for memory-impaired subjects and normal controls, effects that again differed by APOE genotype. These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration.

Altered medial temporal lobe responses during visuospatial encoding in healthy APOE*4 carriers.

The apolipoprotein varepsilon4 allele (APOE*4) is a major genetic risk factor for Alzheimer's disease (AD) and has been associated with altered cortical activation as assessed by functional neuroimaging in cognitively normal younger and older carriers. We chose to evaluate medial temporal lobe (MTL) activation during encoding and recognition using a perspective-dependent (route or survey) visuospatial memory task by monitoring the blood-oxygen-level-dependent (BOLD) fMRI response in older, non-demented APOE*4 carriers (APOE*4+) and non-carriers (APOE*4-). During encoding, the APOE*4- group had greater average task-associated BOLD responses in ventral visual pathways, including the MTLs, as compared to the APOE*4+ group. Furthermore, MTL activation was greater during route encoding than survey encoding on average in APOE*4-, but not APOE*4+, subjects. During recognition, both groups performed similarly and no BOLD signal differences were found. Finally, within-group analysis revealed MTL activation during encoding was correlated with recognition performance in APOE*4-, but not APOE*4+ subjects. Reduced task-associated MTL activation that does not correlate with either visuospatial perspective or task performance suggests that MTL dysregulation occurs prior to clinical symptoms of dementia in APOE*4 carriers.

An open-label pilot study of risperidone in the treatment of methamphetamine dependence.

Psychopharmacological treatments for methamphetamine (MA) dependence have questionable efficacy. Open-label risperidone was evaluated in veterans seeking MA dependence treatment. Participants (N = 11) received four weeks of risperidone. They provided weekly self-reports of substance use, urine drug screens, and adverse effects. Neuropsychological assessments and psychiatric symptomatology (Brief Symptom Inventory; BSI) were measured at baseline and follow-up. The eight completers had an average risperidone dose of 3.6 mg/day and decreased days of MA use during the trial from a mean of 13.0 (SD = 6.5) in the 30 days prior to starting risperidone to a mean of 0.125 (SD = 0.4; t = 5.7, p = .001), When measured over time, fine motor function (Grooved Peg Board Dominant Hand) was the only neuropsychological domain to improve significantly. No other domain changed significantly from baseline to follow-up among study completers. BSI data were converted to demographically corrected T-scores utilizing appropriate normative data (mean = 50, SD = 10). BSI somatization T-scores declined from a mean of 59.0 (SD = 8.4) to 51.8 (SD = 8.3; t = 2.7, p <.05), and positive symptom distress declined from a mean of 52.8 (SD =8.0) to 41.7 (SD = 8.6; t= 3.0, p <.05). Risperidone was well tolerated and associated with decreased MA use.

Salivary cortisol and memory function in human aging.

OBJECTIVE: To examine the association of salivary cortisol with cognitive changes in a 3 year longitudinal study. Previous studies have suggested that elevated glucocorticoid concentrations alter hippocampal neuronal morphology, inhibit neurogenesis, and impair cognition. METHODS: Salivary cortisol samples were collected at home by 79 cognitively intact older persons (mean age 78+/-7 years) at 08:00, 15:00 and 23:00h, and collections were repeated annually for 3 years. Cognitive function was also assessed annually. RESULTS: The mean cortisol level of samples taken at three times of day and the cortisol concentration at 23:00h were significantly associated with poorer performance on tasks of declarative memory and executive function. Of 46 subjects who completed the entire 3 year study, higher initial cortisol concentration at 23:00h predicted a decline in performance of delayed paragraph recall. CONCLUSION: These results partially confirm previous findings that high cortisol is associated with impaired declarative memory function in non-demented older persons. In addition, our data show that high salivary cortisol concentrations predict a decline in memory function over the next 3 years.

A comparison of methamphetamine-dependent inpatients childhood attention deficit hyperactivity disorder symptomatology.

Methamphetamine-dependent inpatients (N = 51) were screened for childhood attention deficit hyperactivity disorder (ADHD) using the Wender Utah Rating Scale upon admission to 30-day inpatient treatment. Baseline assessments included neuropsychological tests of executive function, memory, information processing, verbal fluency, attention, motor skills, and the Brief Symptom Inventory (BSI), a measure of psychiatric symptomatology. The thirty-six participants (70.6%) screening positive for ADHD reported significantly more frequent methamphetamine use prior to baseline. Baseline cognitive functioning was similar between groups, but the presumptive ADHD participants exhibited significantly worse psychiatric symptomatology. At three-week follow- up, 41 participants (80.4%) repeated the neuropsychological battery and BSI. All 10 non-completers screened positive for ADHD. The entire sample improved with abstinence in most neuropsychological domains except memory. The presumptive ADHD group failed to improve on tests of attention. All participants demonstrated significant reductions in psychiatric symptoms with abstinence. Methamphetamine-dependent individuals with ADHD symptoms are common and pose a significant treatment challenge.

The cognitive effects of opioids.

Successful opioid therapy often depends on achieving a balance between analgesic effectiveness and side effects. The risk of opioid-induced cognitive impairment often hinders clinicians and patients from initiating or optimizing opioid therapy. Despite subjective experiences of mental dullness and sedation, objective tests of cognitive functioning do not always demonstrate marked changes following opioid administration. To guide clinical practice, as well as patient and family teaching, pain management nurses should be familiar with literature regarding this topic. The purpose of this article is to review the empiric literature on opioids and cognitive functioning, including the relationships among pain, cognition, delirium, and opioids. In general, research reflects minimal to no significant impairments in cognitive functioning. If impairment does occur, it is most often associated with parenteral opioids administered to opioid-naive individuals. Some evidence suggests that opioids may actually enhance cognitive function and decrease delirium in some patient populations. This article describes this research and explores the clinical implications of the research in this area.