Illicit drug use correlates with negative urine drug test results for prescribed hydrocodone, oxycodone, and morphine.

BACKGROUND: A number of studies indicate that 10.8%-34% of patients with chronic pain use illicit drugs. One hypothesis for this occurrence is that some patients may be supplementing their prescription medications with illicit drugs. OBJECTIVE: The primary purpose of this retrospective data analysis was to test the hypothesis that people whose urine specimens are positive for the medications that have been listed as being prescribed to them are positive for fewer illicit substances than those whose specimens were negative for their prescribed medications. The secondary purpose of the study was to correlate the use of illicit drugs and the amount of prescribed medications excreted in urine. STUDY DESIGN: A retrospective study of the incidence of patients using illicit drugs versus their consistency with reported medications. METHODS: Using urine specimens from a cohort of nearly 400,000 patients whose identities had been redacted, and who were being treated for chronic pain with opioid therapy, this study was performed to correlate the patients' positivity with their prescribed medication to the prevalence of illicit substance use. A secondary study was conducted to correlate the amount of prescribed medication excreted in urine (measured in ng/mL) with the incidence of illicit drug use. The specific prescription medications analyzed were hydrocodone, morphine, and oxycodone. RESULTS: Specimens defined as negative for prescribed hydrocodone (27.3%), morphine (11.5%) or oxycodone (19%) were more likely to contain illicit drugs than those found to be positive for the prescribed medication. The illicit drug prevalence among the inconsistent specimens was 15.3% for hydrocodone, 23.8% for morphine, and 24.4% for oxycodone. The secondary study showed no statistically significant difference in the excretion level of prescribed medication between those patients using and not using illicit drugs. LIMITATIONS: The study is limited in that no data was obtained to determine the causal relationships of illicit drug use. CONCLUSIONS: This work supports the hypothesis that people who are positive for their prescribed medications use fewer illicit drugs than those who do not take their medications. It may be beneficial for physicians to test more thoroughly for illicit drugs when patients' drug tests are negative for their prescribed medications.

Therapeutic monitoring of benzodiazepines in the management of pain: current limitations of point of care immunoassays suggest testing by mass spectrometry to assure accuracy and improve patient safety.

BACKGROUND: Concomitant use of opioids and benzodiazepines can result in significant untoward effects. Point of care (POC) urine testing devices are commonly used tools to monitor patient use of medications. These useful devices are relatively inexpensive and yield immediate results that can be acted upon at the time of the appointment, although numerous limitations have been identified for specific medications or medication classes. We established the diagnostic accuracy of a commonly used POC testing method for benzodiazepines. METHODS: One thousand patients, from a single interventional pain practice receiving opioid therapy provided urine specimens as part of the usual practice of monitoring consistency with prescribed medications. These de-identified urine specimens were tested using LC-MS/MS and the results were compared using the standard calculations for sensitivity, specificity, and predicted value. Five specimens were excluded from the study because the prescribed flurazepam could not be confirmed by LC-MS/MS (the LC-MS/MS instrumentation was not set to identify flurazepam), resulting in 995 specimens. RESULTS: Point of care assays yielded false negative results for patients prescribed benzodiazepines nearly 20% of the time (98 out of 498 patients). The point of care cup often failed to produce positive results for persons who were shown by LC-MS/MS to be taking lorazepam or clonazepam. Although only 26 out of 498 patients (5%) were prescribed ≥2 benzodiazepines, 73 out of 498 patients (15%) were found to be positive for that drug class. CONCLUSIONS: POC immunoassay for benzodiazepines could fail to provide accurate information regarding patient specific medication use. The false positive and false negative rates of the immunoassay were particularly high for clonazepam and lorazepam. Further testing of patient specimens using more accurate methods such as LC-MS/MS is necessary to provide definitive data that can assist in clinical decision making, and potentially protect these patients from untoward effects, morbidity and mortality.

Determination of illicit drug cutoff values in a pain patient population.

BACKGROUND: When properly selected, cutoff levels minimize the reporting of false negative and false positive test results and allow the laboratory to accurately determine the prevalence of marijuana, cocaine and methamphetamine use. Selecting the ideal cutoff requires the collection of drug excretion data for a large patient population to determine the expected range of drug concentrations. The cutoff can then be set to capture a high percentage of positives at a concentration within the dynamic range of the method. We used quantitative urine drug excretion data to calculate cutoffs needed to best determine the presence of these illicit drugs in urine. METHODS: This study used liquid chromatography tandem mass spectrometry (LC-MS/MS) as the analytical method. The study group was the pain patient population which is well-known to have a significant incidence of use of these illicit drugs. Frequency distributions were plotted for the creatinine normalized and raw data for all positive specimens with values greater than or equal to the method limit of quantitation. A non-parametric 2.5% estimator was applied to each data set to establish the cutoff for each drug. RESULTS: The urinary excretion data for the three drugs studied suggest cutoffs of approximately 30 ng/ml (benzoylecgonine), 10 ng/ml (carboxy-THC), and 50 ng/ml (methamphetamine) to identify 97.5% of the users of these drugs in this population. CONCLUSIONS: Evaluation of urinary excretion data provides an objective method to validate the selection of cutoffs. These data provide additional support for the revised SAMHSA cutoffs which could increase the positivity rates for both benzoylecgonine and methamphetamine by 7%.

Determination of medication cutoff values in a pain patient population.

BACKGROUND: Clinical laboratories are required to establish reference intervals for all the analytes tested, and these are provided along with the test results. In contrast, laboratories testing for pain medications use cutoffs established by the manufacturers of immunoassay reagents. These cutoffs may be inappropriate for monitoring patients being treated for chronic pain with opioid therapy because the cutoffs are set too high. PURPOSE OF THE STUDY: To use quantitative urine drug excretion data determined by liquid chromatography-tandem mass spectrometry analysis to calculate cutoffs needed to best determine patient compliance with prescribed medications. METHODS: Two methods of calculation were used to estimate cutoffs. First, all positive results for each drug or drug metabolite were ranked from highest to lowest. The lowest value was one-half of the lower limit of quantitation. A nonparametric 2.5 percent estimator was used to establish each cutoff Second, positive results were normalized using creatinine values, resulting in the excretion being expressed as nanograms of excreted drug per gram of creatinine. A nonparametric 2.5 percent estimator was used to establish the cutoff. RESULTS: Cutoffs established using these calculations included at least 97.5 percent of the data for the drugs: 7-aminoclonazepam, alpha-hydroxalprazolam, buprenorphine, carisoprodol, hydrocodone, hydromorphone, meperidine, meprobamate, methadone, morphine, oxycodone, oxymorphone, propoxyphene, and tramadol gave cutoffs near the lower limit of quantitation. One exception was with the drug codeine, where the lower limit could not be identified. CONCLUSIONS: These cutoffs were significantly lower than those suggested by many immunoassay manufacturers and better identify patient compliance in a representative population of pain patients. The limitation of the study is that only values one-half of our lowest calibrator were used. By using population values, laboratories can establish appropriate cutoffs for best monitoring pain patient medication compliance.

Illicit drug use in the pain patient population decreases with continued drug testing.

BACKGROUND: A major concern of physicians treating pain patients with chronic opioid therapy and similar drugs is determining whether the patients are also using illicit drugs. This is commonly determined by urine drug testing (UDT). However, there are few studies on whether or not monitoring patients by this technique decreases illicit drug use. OBJECTIVE: To determine if the presence of illicit drugs decreases over a number of physician visits where UDT was performed. METHOD: The method involved a retrospective study of tests for the illicit drugs marijuana, cocaine, methamphetamine, ecstacy (MDMA) phencyclidine (PCP) and the heroin metabolite, 6-acetylmorphine as confirmed by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). A database of 150,000 patient visits was examined for the presence of any of these 6 drugs. RESULTS: A total of 87,000 patients were initially tested. The number of patients who were repeatedly tested decreased over time. The percentage of patients positive for any of these illicit drugs decreased from 23% to 9% after 14 visits where UDT was performed. When graphed there was a trend to decreasing use. The Spearman correlation = -0.88, p < 0.0001. The major illicit drug was marijuana. When this was removed from the analysis, there was an even greater correlation with decreased illicit drug use. Spearman correlation = -0.92 (p < 0.0001) using a weighted correlation. LIMITATION: Patients continuing to use illicit drugs might be dismissed from practices thus biasing the study towards illicit drug avoidance. CONCLUSION: Continued UDT might decrease illicit drug use among pain patients.

An improved method of determining ethanol use in a chronic pain population.

BACKGROUND: Determination of ethanol use in the pain patient population being treated with chronic opioid therapy is critically important to the treating physician. Urinary ethanol, ethyl glucuronide (EtG), and ethyl sulfate (EtS) have been used to identify alcohol use. Because urine samples are shipped to reference laboratories, the possibility of glucose fermentation during transit producing ethanol complicates interpretation. The purpose of this study was to establish whether ethanol-positive urine samples were due to ingestion or fermentation during shipping. METHODS: The authors obtained 94 ethanol-positive urine samples from pain patients, which were further tested for EtG, EtS, and glucose. RESULTS: Only 62 of the 94 samples contained EtS or EtS. Of the 94 samples, 63 samples had glucose values above 10 mg/dL. Four of the 32 EtG-negative patients had ethanol levels that were nonphysiologic. Limitations of the study include the lack of demographic data beyond treatment with opioids for chronic pain. CONCLUSIONS: Roughly one-third of the time, ethanol-positive urine samples that have been shipped were positive because of fermentation and not because of patient alcohol consumption. This method is a combination of urinary ethanol measurement and liquid chromatography tandem mass spectrometry quantitation of both EtG and EtS. In the absence of these metabolites, the presence of urinary ethanol is attributed to fermentation. The improvement is a better definition of the source of the ethanol. Confirmatory testing showing the presence of the ethanol metabolites EtG and EtS is needed to validate that the ethanol is due to consumption. The presence of glucose, while common in the ethanol-positive samples, is not an absolute indicator that the ethanol was due to fermentation.

An innovative method for determining lipemia interference in blood specimens.

BACKGROUND: Lipemia interference in blood samples is usually determined by adding exogenous substances that cause turbidity or by using ultracentrifugation to clarify the sample. However, there are a number of problems associated with these methods, which make it difficult to ascertain with certainty that lipemia is the cause of interference. We assessed a novel method for evaluating lipemia interference. METHODS: Lipemic and non-lipemic serum samples, with similar HDL cholesterol concentrations, were mixed in various proportions (5 concentrations) and assayed for HDL and triglycerides. Thus, matched HDL samples with increasing triglycerides concentrations were tested. We then calculated the percent recovery for HDL for each mixture. RESULTS: Six matched sets of samples had HDL recoveries ranging from 95.9% to 101.1% (n=6 sets, 5 concentrations per set, total of 30 concentrations), with HDL concentrations ranging from 0.78 to 2.16 mmol/l. Triglycerides concentrations in these samples ranged from 1.06 to 9.78 mmol/l for the 30 concentrations. CONCLUSIONS: We determined that there was no triglycerides interference on the HDL method performed on the Hitachi S40 Clinical Analyzer up to a triglycerides concentration of 9.78 mmol/l. This matching method is simple to perform and proved useful in evaluating interference due to lipemia.

Anomalous observations of hydrocodone in patients on oxycodone.

BACKGROUND: Urine drug monitoring is used by physicians treating chronic pain patients with opioid therapy. Patients are tested in part to insure that they are not taking other drugs. Therefore, the finding of hydrocodone in a patient who is only prescribed oxycodone has clinical implications. Oxycodone preparations are known to have small amounts of hydrocodone as an impurity estimated to be < 0.1%. We established the concentration of unexpected hydrocodone in patients taking oxycodone. METHODS: Urine drug testing specimens from a population of 30,000 pain patients prescribed oxycodone in various formulations were quantitatively measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The frequency and concentration of hydrocodone as a function of oxycodone concentration were determined. RESULTS: There were 187 specimens with > 100,000 ng/ml of oxycodone. Of these, 72% were positive for hydrocodone. Of the 311 specimens with oxycodone concentrations > 50,000-100,000 ng/ml, 33% were positive for hydrocodone. Of the 1067 specimens with oxycodone > 20,000-50,000 ng/ml, 16% were positive for hydrocodone. Of the 8508 specimens with oxycodone > 1000-20,000 ng/ml, 16% were positive for hydrocodone. CONCLUSIONS: The high frequency of hydrocodone in samples containing high concentrations of oxycodone was ascribed to the manufacturing process of the oxycodone medications. However, a significant number of patients also took hydrocodone that was not listed on their prescribed medications. When oxycodone is > 100,000 ng/ml, hydrocodone should be <1500 ng/ml. When oxycodone is < 100,000 ng/ml then hydrocodone should be <500 ng/ml. Values greater than these indicate non-prescribed hydrocodone use. Clinicians and laboratories testing urine for drugs should be aware of the possibility of low concentrations of hydrocodone in the urine of patients taking high doses of oxycodone.

Improvement of pain physicians' practices of opioid management: population-based urinary excretion data.

BACKGROUND: Physicians treating patients for chronic pain have limited means of determining whether a person is taking their medications as prescribed and are not taking extra medication. Complicating patient treatment regimens is the fact that pain physicians' prescribing practices may come under scrutiny by the Drug Enforcement Agency and other licensing agencies. If questioned, doctors can be hard-pressed to substantiate that their particular practices meet the established standard of care. It would be helpful to establish that their patients adhere to medications when compared with other practices. Previous studies show that urinary excretion data transformed by mathematical models can produce a reliable range of expected values for pain medications and may be useful to help resolve the aforementioned issues. PURPOSE OF THE STUDY: To provide comparative urinary excretion information data on three commonly prescribed opioid medications (morphine, hydrocodone, and oxycodone). METHODS: This retrospective study involved quantitative analysis of300, 000 urine specimens for three test drugs using previously described methods. The results were analyzed as percent frequency distributions and logarithmic functions. RESULTS: The authors established a creatinine-normalized range of urinary concentration values for each drug. Results for two practices were compared with the meta-findings, providing quantitative evidence of overall standard of care prescription practice by that physician. CONCLUSIONS: Expected urinary drug excretion values for morphine, hydrocodone, and oxycodone can potentially benefit pain physicians by showing that they are within the expected standard of care, helping to establish patient compliance, and identifying patients whose metabolism of these drugs may put them at risk.

Reference intervals: a novel approach to detect drug abuse in a pain patient population.

BACKGROUND: pain physicians have few objective ways of determining which of their patients are drug abusers. Traditionally, these include psychological tests, physical examination, patient history, and urine drug testing. The traditional urine drug testing information provided to pain physicians mainly identifies patient compliance or drug diversion with qualitative information, that is, the patient is positive or negative for the presence of the drug in excreted urine. Although this information is useful for establishing compliance and identifying diversion, it is incomplete because it does not identify drug abuse. OBJECTIVE: The authors endeavored to determine whether quantitative urine drug testing and mathematical estimators of the upper limits of excretion could be used to identify possible drug abusers. STUDY DESIGN: analysis of quantitative urine drug tests and application of mathematical models for reference interval estimation of common analytes to determine whether they could be used to define upper 9 7.5 percentile limits of excretion in the pain patient population. METHODS: the authors analyzed 8,971 consecutive urines from patients on chronic opioid therapy using nonparametric, parametric, robust, and transformed estimators to derive the upper 97.5 percentile concentration values of 31 drugs and their metabolites. RESULTS: the authors showed that the mathematical models used to define reference intervals could be applied to urinary drug excretion. As an example, an upper limit of excretion of approximately 100, 000 ng/mL was established for morphine. Limitations of the study included lack of information on medication history, time of last dose before urine collection, age, sex, and complete medical history. Better estimates of the upper limits of excretion can be obtained by physicians applying their knowledge of dosage and collection times. CONCLUSIONS: application of a reference interval model allows identification of a patient population that excretes extremely high amounts of drug or its metabolite when compared with the rest of the population. Explanations for this high excretion include high dosage medication by prescription and drug abuse, determination of which can be done by the treating physician. The authors suggest that this patent-applied-for analytical model can become a potential tool to alert physicians to patients who may be abusing drugs.

Observations of medication compliance by measurement of urinary drug concentrations in a pain management population.

BACKGROUND: One of the major concerns of physicians treating pain patients with opioids is to determine whether the patients are compliant, and this is commonly determined by urine drug testing. There is limited information on which drugs these patients are most compliant with. There is also limited information as to how compliance is defined in terms of cutoffs. OBJECTIVE: To compare reported patient medication use with the presence of the drug in the patients' urine with defined cutoffs. METHOD: A retrospective study of the medications listed by the physicians' offices and the confirmed drug test findings. A Millennium Laboratories database of 20, 457 patient results was examined for the presence of the listed medications and was matched for the presence of the drugs above the analytical cutoffs. RESULTS: For oxycodone and hydrocodone, the authors observed 23 and 24 percent noncompliance, respectively. For carisoprodol, they observed 33 percent noncompliance. For morphine, they observed 14 percent noncompliance. For methadone, they observed 9 percent noncompliance. CONCLUSIONS: Noncompliance is prevalent in this patient population and varies with the prescribed drug.

An evaluation of the diagnostic accuracy of liquid chromatography-tandem mass spectrometry versus immunoassay drug testing in pain patients.

BACKGROUND: Immunoassay screening is used by pain physicians to determine compliance with controlled substances. Because clinical use of pain medications is different from illicit drug use, there is a need to evaluate the level of diagnostic accuracy of this procedure for the pain patient. OBJECTIVE: To compare the results of automated screening by immunoassay with analysis by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) in identifying pain patients using illicit drugs and pain patients excreting low concentrations of their prescribed medications. STUDY DESIGN: A diagnostic accuracy study. METHODS: Urine samples from 4,200 pain patients were tested by immunoassay and LC-MS/MS for the following drugs and metabolites: Amphetamine, Methamphetamine, Alpha-hydroxyalprazolam, Lorazepam, Nordiazepam, Oxazepam, Temazepam, Cannabinoids, Cocaine, Methadone, Methadone Metabolite, Codeine, Hydrocodone, Hydromorphone, Morphine, Propoxyphene, and Norpropoxyphene. RESULTS: In a number of patients negative immunoassay findings were superseded by positive results on analysis by Mass Spectrometry. These were termed false negative results. The greatest failures were for the benzodiazepines (28%) and for cocaine (50%). LIMITATIONS: The study was limited by the lack of complete demographics for the cohort and because only one immunoassay diagnostic product was used. It was also limited because not all drugs react the same in the immunoassay. CONCLUSIONS: We show that in general, immunoassay screening results are accurate, although as shown in this study there are many false negative observations. The use of LC-MS/MS technology significantly decreases the number of false negative results.

Marijuana correlates with use of other illicit drugs in a pain patient population.

BACKGROUND: A significant number of chronic pain patients may use marijuana. Physicians treating those patients can benefit by knowing whether their patients using marijuana are at higher risk for using other illicit drugs such as cocaine and/or methamphetamine. OBJECTIVE: Our objective was to determine whether marijuana-using chronic pain patients have a higher incidence of cocaine and/or methamphetamine use. STUDY DESIGN: A retrospective study of the incidence of pain patients using marijuana and/or other illicit drugs such as methamphetamine and cocaine versus the incidence of pain patients not using marijuana but using methamphetamine and/or cocaine. METHODS: Urine specimens from chronic pain patients were analyzed by LC-MS/MS to determine the co-occurrence of these abused substances. RESULTS: In this study 21,746 urine specimens were obtained from chronic pain patients. We found a 13.0% incidence of patients positive for the acid form of Tetrahydrocannabinol (THCA). The percentage of those positive for cocaine was 4.6%, those positive for methamphetamine totaled 1.07%. Using both chi-square and a Logistic Regression analysis, we determined that there was a correlation between marijuana use and the use of other illicit drugs. The odds ratio was > 3.7 for other illicit drug use. LIMITATIONS: The study is limited in that we obtained no data as to the causal relationships of this type of drug use. CONCLUSIONS: Pain physicians should be aware that this relationship exists and marijuana-using patients are at greater risk for use of other illicit drugs although no causal relationship is implied. Increased monitoring of these patients may help minimize potential morbidity due to drug interactions as well as identify patients who may be diverting prescriptions in order to pay for illicit drugs.

Comparison of clonazepam compliance by measurement of urinary concentration by immunoassay and LC-MS/MS in pain management population.

BACKGROUND: Physicians determine patient compliance with their medications by use of urine drug testing. It is known that measurement of benzodiazepines is limited by immunoassay specificity and cutoff limits and therefore does not offer physicians an accurate picture of their patients' compliance with these medications. A few studies have used lower cutoffs to demonstrate patient compliance. OBJECTIVES: To define more appropriate cutoffs for compliance monitoring of patients prescribed clonazepam as determined using immunoassay and liquid chromatography-tandem mass spectrometry (LC-MS/MS). STUDY DESIGN: A diagnostic accuracy study of the urinary excretion of clonazepam. METHODS: Millennium Laboratories performed measurements on the urinary excretion of pain patients prescribed clonazepam as the indicator test. This benzodiazepine was chosen because it forms one major metabolite, 7-aminoclonazepam which is specific for that drug. Patients whose only benzodiazepine medication was clonazepam were selected as the test population. The Millennium Laboratories test database was filtered first to select patients on clonazepam, then a second filter was used to eliminate patients with any other listed benzodiazepine medications. Samples were tested using the Microgenics DRI benzodiazepine assay with a 200 ng/mL cutoff. The same samples were quantitatively assessed for 7-aminoclonazepam by LC-MS/MS with a cutoff of 40 ng/mL. The results from the immunoassay were scored as positive or negative while the quantitative results from the LC-MS/MS were also scored as positive or negative depending upon their concentration. RESULTS: Samples from 180 patients met these medication criteria. The positivity rates were 21% (38 samples) by immunoassay. The positivity rate was 70% (126 samples) if the LC-MS/MS cutoff was set at 200 ng/mL. However, the positivity rate was 87% (157 samples) if the LC-MS/MS was set at 40 ng/mL. Concentration distributions revealed a significant fraction (7%) in the 40 - 100 ng/mL range. LIMITATIONS: A limitation of the study was the inability to measure lower than 40 ng/mL. There may be another fraction of the population that was positive below the cutoff value. CONCLUSIONS: The difference in positivity rate between the immunoassay and the LC-MS/MS result showed that the nominal 200 ng/mL cutoff of the immunoassay did not apply to 7-aminoclonazepam. This low immunoassay positivity rate is inconsistent with the manufacturer's published cross reactivity data for clonazepam and 7-aminoclonazepam. These data illustrate the limitations of using a 200 ng/mL cutoff to monitor clonazepam compliance and suggest that a cutoff of 40 ng/mL or less is needed to reliably monitor use of this drug.

Effect of ramelteon on middle-of-the-night balance in older adults with chronic insomnia.

STUDY OBJECTIVES: To evaluate the effect of ramelteon on middle-of-the-night balance, mobility, and memory in older insomniacs. METHODS: Thirty-three older adults (age > or = 65 years) with insomnia were enrolled in a single-dose, 3-way crossover study of balance after bedtime administration of ramelteon, 8 mg; zolpidem, 10 mg (positive control); or placebo. Subjects were administered study medication 30 minutes before bedtime and were awakened 2 hours after dosing to evaluate balance (Sensory Organization Test), turning speed and stability, memory (immediate and delayed word recall), and adverse events. There was a 4- to 10-day washout between treatments. RESULTS: Ramelteon or zolpidem (positive control) was compared with placebo. There were no differences between placebo and ramelteon on the Sensory Organization Test (p = 0.837), turn time (p = 0.776), or turn sway (p = 0.982). The positive control (zolpidem) did reveal significant impairments on the Sensory Organization Test, turn time, and turn sway (p < 0.001, all). Immediate and delayed memory recall were not significantly different with ramelteon (p = 0.683 and p = 0.650, respectively). Immediate recall declined significantly with zolpidem (p = 0.002). Adverse events were infrequent (ramelteon, n = 7; placebo, n = 7; zolpidem, n = 13); none were serious. CONCLUSION: In older adults, ramelteon did not impair middle-of-the night balance, mobility, or memory relative to placebo.

A comparison of urban school- and community-based dental clinics.

BACKGROUND: The objective of the study was to quantitatively compare school- and community-based dental clinics in New York City that provide dental services to children in need. It was hypothesized that the school-based clinics would perform better in terms of several measures. METHODS: We reviewed billing and visit data derived from encounter forms and expense reports from 4 school- and 3 community-based clinics during 12 months in 2004-2005. The health clinics, administered by the Children's Aid Society, provided dental services to children regardless of ability to pay. The assessments were based on 8 performance indicators, including some based on relative value units, and profile of service indicators was used for assessment. Descriptive statistics and results from hypothesis tests are reported. RESULTS: Based on significant and large differences on the indicators, the school-based health clinics appear to have definite advantages over community-based dental clinics. Results were consistent across many indicators. CONCLUSIONS: The results support increasing the number of school-based dental clinics in urban areas that serve children in need. Being based in schools, factors such as transportation issues, parent availability, and missed appointments are greatly reduced. This has great public dental health implications for children in underserved areas. Schools provide a natural location to provide preventive and responsive dental care. Similar advantages could be expected in rural areas and other areas of need.

Sleep improves when patients with chronic OA pain are managed with morning dosing of once a day extended-release morphine sulfate (AVINZA): findings from a pilot study.

STUDY OBJECTIVE: To investigate the effect of once-a-day extended release of morphine sulfate AVINZA (A-MQD) on polysomnographic measures of sleep in a population of chronic osteoarthritic pain patients with sleep difficulties. DESIGN: Single-center, single-blind, placebo-lead-in, 30 mg or 60 mg. Patients' sleep and neurocognition were objectively measured at a sleep laboratory, and patients self-rated their pain, sleep, and other functions. PARTICIPANTS: Thirty-four participants (26 to 75 years old) complaining of sleep difficulties and chronic, stable pain secondary to hip or knee osteoarthritis. INTERVENTIONS: Participants had a screening visit on current pain medication and then, following a single-blind placebo run-in period, received 30 mg/d of A-MQD for six days. At day 6, doses for participants with incomplete pain relief on the Brief-Pain-Inventory (BPI) pain scale were increased to 60 mg/d. Treatment continued for another eight days at the new dose level (14 days for a subgroup at 60 mg/d). Sleep was objectively measured by all-night polysomnography (PSG) at screening while on the participants' current pain therapy, at baseline following a placebo run-in and at the end of treatment while on A-MQD. OUTCOME MEASURES: PSG parameters evaluated included Total-Sleep-Time (TST), Wake-timeafter-Sleep-Onset (WASO), Sleep-Efficiency (SE), Latency-to-Persistent Sleep (LPS), Latency-to-REM-sleep, the Number-of-Awakenings (NAW), the time spent in each stage of sleep, and REM-sleep-latency. Subjective evaluations included participants' estimations of sleep time and sleep quality, the Epworth-Sleepiness-Scale (ESS), the BPI, and participant acceptance of and relief due to current therapy. Assessments of neurocognitive function were also made. RESULTS: Sleep initiation and maintenance tended to improve with A-MQD as demonstrated by the increases in TST and SE and decreases in WASO and NAW as compared with placebo-baseline values. Sleep architecture was preserved by the study drug and some increases in stage 2 and 3/4 sleep were seen compared with placebo baseline. Subjective ratings of sleep quality and sleep time were significantly improved with treatment, as were BPI scores and ratings of medication acceptance and pain relief. A-MQD was generally well tolerated. CONCLUSIONS: A-MQD was an effective treatment for pain, and this study treatment was associated with improvement of both objective and subjective sleep parameters in participants with chronic osteoarthritic pain.

Tiagabine increases slow-wave sleep in a dose-dependent fashion without affecting traditional efficacy measures in adults with primary insomnia.

INTRODUCTION: This study evaluated dose-response effects of tiagabine on sleep in adults with primary insomnia. METHODS: Men and women with primary insomnia (DSM-IV-TR) were randomly assigned to receive tiagabine 4, 6, 8, 10 mg or placebo in a randomized, double-blind, parallel-group study. Efficacy was assessed using polysomnography and self-report measures. Safety analyses included measures of residual sedation and adverse events. RESULTS: A total of 232 patients (31% men; mean age 44.3 years) received study drug. No significant differences were observed between tiagabine and placebo in wake after sleep onset, latency to persistent sleep, or total sleep time. Significantly greater increases from baseline in slow-wave sleep (stages 3 and 4) were found with the 3 highest doses of tiagabine compared with placebo (p < .01). Stage 1 sleep showed a significantly greater decrease from baseline for all doses of tiagabine than for placebo (p < .01). Self-report measures of sleep and daytime function did not differ from placebo, except for poorer ratings on the 10-mg dose. Similarly, psychomotor performance on the 10-mg dose was worsened compared with placebo. Tiagabine was generally well tolerated; dizziness and nausea were the most common adverse events, particularly at the 2 higher doses. CONCLUSIONS: In adults with primary insomnia, tiagabine significantly increased slow-wave sleep in a dose-dependent manner with a corresponding significant decrease in Stage 1 sleep, whereas no significant differences were observed in wake after sleep onset, latency to persistent sleep, or total sleep time compared with placebo.

Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic medications.

OBJECTIVE: To assess the effects of modafinil on fatigue, symptoms, attention, working memory, and executive functioning in schizophrenia patients treated with psychotropic medications. METHOD: Twenty-four patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder (10 men and 14 women) were randomly assigned to modafinil up to 200 mg a day (N = 13) or placebo (N = 11) as an adjunct therapy in an 8-week, double-blind, placebo-controlled study. Data were collected from May 18, 2001 to September 11, 2003. RESULTS: Four subjects terminated the study early, including one because of worsening of psychosis during the first week taking modafinil. In the modafinil (N = 10) and placebo (N = 10) groups, fatigue improved significantly over time (p < .01), but there were no differences between groups on changes in fatigue, positive and negative symptoms, or cognition. CONCLUSION: Fatigue improved in both groups, and there were no differences between groups on changes in fatigue, symptoms, attention, working memory, or executive functioning. Lack of differences between groups may be due to small sample size or possible regression to the mean in the placebo group.

Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia.

Patients with schizophrenia experience cognitive impairments associated with hypofunctioning of the frontal cortex. Modafinil, a novel wake-promoting agent, works through the sleep-wake centers of the brain to activate the cortex. This 4-week, open-label, pilot study evaluated adjunct modafinil in patients with schizophrenia or schizoaffective disorder. Eleven patients received once-daily oral doses of modafinil (100 mg/day, days 1-14; 100 or 200 mg/day, days 15-28) in addition to antipsychotic therapy. Modafinil significantly improved patients' global functioning as assessed by a blinded clinician (week 2, P = 0.026; week 4, P = 0.012) and the investigator (week 3, P = 0.035). Modafinil significantly improved overall clinical condition, with 64% and 82% of patients rated as clinically improved at week 4 by a blinded clinician and the investigator respectively. Eighty-nine percent of patients considered themselves to be clinically improved. Modafinil significantly improved fatigue (P = 0.025, week 3) and tended to improve cognitive functioning scores. Control of positive symptoms was well maintained. Treatment-emergent adverse events included dry mouth (n = 2) and hallucinations (n = 2). One patient discontinued the study because of hallucinations that were considered to be possibly related to inadequate antipsychotic therapy. Although preliminary, these results suggest modafinil may be an effective and well-tolerated adjunct treatment that improves global functioning and clinical condition, and reduces fatigue in patients with schizophrenia or schizoaffective disorder. Additional controlled studies are warranted.