To determine whether changes in motor function and reaction time are present in presymptomatic in... more To determine whether changes in motor function and reaction time are present in presymptomatic individuals carrying the Huntington disease (HD) allele. A case-control, double-blind study comparing asymptomatic at-risk subjects, with or without the HD allele, and subjects clinically determined to have early manifest HD. The Department of Medical and Molecular Genetics at Indiana University School of Medicine, Indianapolis. We studied 383 patients at risk for HD. Each subject was asymptomatic by self-report. Genotype for the HD allele was determined by polymerase chain reaction testing. A battery of 8 physiological tests measuring speed of movement and reaction time was performed with a computer-driven system. Following neurologic examination, 17 of the 120 gene carriers (GCs) had symptoms sufficient for a clinical diagnosis of manifest HD. The remaining 103 GCs were designated presymptomatic GCs. When the non-GCs were compared with the presymptomatic GCs (1-way analysis of covariance and the Fisher protected t test), results on 3 of the 8 physiological tests--movement time, movement time with decision, and auditory reaction time--were different. Additionally, the number of trinucleotide (CAG) repeats significantly correlated with test performance for movement time with decision and visual reaction time with decision when both the entire group of GCs and the presymptomatic GCs alone were considered. These results suggest that subtle subclinical changes in motor function are present in presymptomatic individuals who have inherited the HD allele.
This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of mo... more This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of modafinil, for the treatment of excessive sleepiness in patients with narcolepsy. This was a multicenter double-blind study with 196 patients (aged 18-65 years) randomized to receive armodafinil 150 mg (n = 65), armodafinil 250 mg (n = 67), or placebo (n = 64) once daily for 12 weeks. Efficacy was assessed using the Maintenance of Wakefulness Test (MWT) (six 20-min subtests across the day), the Clinical Global Impression of Change (CGI-C), subjective measures of sleepiness (Epworth Sleepiness Scale), patient diaries, and evaluations of cognitive performance (Cognitive Drug Research) and fatigue (Brief Fatigue Inventory). Armodafinil significantly increased MWT mean sleep latency (at 0900-1500) compared with placebo. The mean change from baseline at final visit for armodafinil was an increase of 1.3, 2.6, and 1.9 min in the 150-mg, 250-mg, and combined groups, respectively, compared with a decrease of 1.9 min for placebo (p < 0.01 for all three comparisons). Mean late-day MWT latency (1500-1900) was also significantly improved (difference of armodafinil combined group relative to placebo at final visit: 2.8 min, p = 0.0358). The proportions of patients who showed at least minimal improvement in the CGIC rating from baseline to final visit in the armodafinil 150-mg, 250-mg, and combined groups were 69%, 73%, and 71%, respectively, compared with 33% for placebo (p < 0.0001). Both doses were associated with statistically significant improvements in memory, attention, and fatigue (p < 0.05). The most common adverse events in patients receiving armodafinil were headache, nausea, and dizziness. Armodafinil significantly improved ability to sustain wakefulness throughout the day in patients with narcolepsy. Armodafinil also significantly improved overall clinical condition, memory, attention, and fatigue when compared with placebo.
The authors describe the MR imaging characteristics and clinical course of a 22-year-old man with... more The authors describe the MR imaging characteristics and clinical course of a 22-year-old man with acute disseminated demyelinating disease, either Marburg multiple sclerosis or recurrent (relapsing) acute disseminated perivenous encephalomyelitis
8567 Background: Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and... more 8567 Background: Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa. Results reported here represent a pre-specified interim analysis of an open-label safety and efficacy study of FEBT in opioid-tolerant patients with cancer-related breakthrough pain (BTP). METHODS Patients with cancer-related BTP receiving around-the-clock and supplemental opioids were eligible to enroll. Patients who had participated in a previous dose-titration study of FEBT enrolled directly into the 1-year phase; new patients entered a titration phase to determine an effective FEBT dose before entering the 1-year phase. An effective FEBT dose was defined as the dose needed to provide adequate analgesia for BTP. By October 3, 2005, 170 patients (aged 24 to 95 years) received FEBT (100-800 μg) and had documented safety data. RESULTS Of the 112 new patients, 70.5% identified an effective FEBT dose and were eligible for enroll...
18521 Background: Standard recommendations for short-acting oral opioid doses to manage breakthro... more 18521 Background: Standard recommendations for short-acting oral opioid doses to manage breakthrough pain (BTP) assume some relation with the stable opioid dose used to treat persistent pain. Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the efficiency of fentanyl absorption through the buccal mucosa. They may provide rapid-onset analgesia. This pooled analysis of data from 3 studies examined the relationship between effective FEBT dose and around-the-clock (ATC) dose in patients who completed open-label titration to an effective FEBT dose. Methods: Patients were 18–80 years of age with cancer, persistent pain, and BTP. Eligible patients experienced an average of 1–4 episodes of BTP per day and were receiving stable doses of opioids (≥60 mg/day of morphine or equivalent) for persistent pain. Titration guidelines were uniform across studies; the maximum allowed dose of FEBT was 800 μg. Results: Of 304 patients enrolled, 208 completed titration to an effective FE...
To determine whether changes in motor function and reaction time are present in presymptomatic in... more To determine whether changes in motor function and reaction time are present in presymptomatic individuals carrying the Huntington disease (HD) allele. A case-control, double-blind study comparing asymptomatic at-risk subjects, with or without the HD allele, and subjects clinically determined to have early manifest HD. The Department of Medical and Molecular Genetics at Indiana University School of Medicine, Indianapolis. We studied 383 patients at risk for HD. Each subject was asymptomatic by self-report. Genotype for the HD allele was determined by polymerase chain reaction testing. A battery of 8 physiological tests measuring speed of movement and reaction time was performed with a computer-driven system. Following neurologic examination, 17 of the 120 gene carriers (GCs) had symptoms sufficient for a clinical diagnosis of manifest HD. The remaining 103 GCs were designated presymptomatic GCs. When the non-GCs were compared with the presymptomatic GCs (1-way analysis of covariance and the Fisher protected t test), results on 3 of the 8 physiological tests--movement time, movement time with decision, and auditory reaction time--were different. Additionally, the number of trinucleotide (CAG) repeats significantly correlated with test performance for movement time with decision and visual reaction time with decision when both the entire group of GCs and the presymptomatic GCs alone were considered. These results suggest that subtle subclinical changes in motor function are present in presymptomatic individuals who have inherited the HD allele.
Objective: The purpose of this retrospective, observational pilot study was to explore change in ... more Objective: The purpose of this retrospective, observational pilot study was to explore change in route of administration (RoA) and motivation for changing RoA during the course of opioid abuse.Design: This retrospective pilot study involved collecting and analyzing semistructured interview data.Setting: Interviews were conducted with patients undergoing outpatient substance abuse treatment at a buprenorphine clinic.Participants: Twenty adult patients (50 percent male) participated in the interviews.Main outcome measures: Interview data were qualitatively and quantitatively analyzed to evaluate trends and motivations for changing RoA.Results: In this sample, RoA varied over time. Most patients (75.0 percent) began abusing prescription opioids by swallowing intact pills, and 53.3 percent of patients eventually progressed to chewing. All patients who initiated abuse through chewing or insufflation (ie, intranasal use) progressed to injection. However, several patients (20.0 percent) di...
Objective: To characterize the pharmacokinetics (PK) and in vitro alcohol dissolution characteris... more Objective: To characterize the pharmacokinetics (PK) and in vitro alcohol dissolution characteristics of extended-release (ER), injection-molded (IM) morphine tablets with abuse-deterrent (AD) features (morphine-ADER-IMT).Design: In vivo, in vitro, and in silico studies were conducted. A randomized, two-cohort study evaluated the bioequivalence of morphine-ADER-IMT (60 mg) to morphine ER (60 mg; MS Contin®; Purdue Pharma LP, Stamford, CT) and characterized the effect of food on the PK profile of morphine-ADER-IMT. A three-treatment, three-period crossover study assessed the bioequivalence of morphine-ADERIMT (30 and 2 × 15 mg) to morphine ER (30 mg). Bioequivalence studies were performed in healthy male and female subjects (18-55 y of age) in the presence of naltrexone blockade. PK modeling was performed to assess steady-state bioequivalence for morphine-ADER-IMT 60 mg compared with morphine ER 60 mg. In vitro alcohol dissolution studies were performed with morphine-ADER-IMT (15 and...
Prescription opioid misuse and abuse in the United States (US) is epidemic and is a major burden ... more Prescription opioid misuse and abuse in the United States (US) is epidemic and is a major burden on health-care resources and costs to society. The need to significantly reduce the risks of prescription opioid misuse and abuse must be balanced with the important needs of patients with chronic pain who may benefit from treatment with opioids. The use of abuse-deterrent formulations (ADFs) of prescription opioids is one approach that could reduce the risk of prescription opioid abuse and misuse while maintaining access to opioids. ADF opioids have properties that make their abuse more difficult, less attractive, or less rewarding. In 2015, the US Food and Drug Administration issued final guidance to industry for the development of ADF opioids that recommended specific studies be conducted to demonstrate the abuse-deterrent properties of new opioid formulations. The technologies and the preclinical and clinical development of ADF opioids are rapidly evolving. This review provides an ov...
To determine whether changes in motor function and reaction time are present in presymptomatic in... more To determine whether changes in motor function and reaction time are present in presymptomatic individuals carrying the Huntington disease (HD) allele. A case-control, double-blind study comparing asymptomatic at-risk subjects, with or without the HD allele, and subjects clinically determined to have early manifest HD. The Department of Medical and Molecular Genetics at Indiana University School of Medicine, Indianapolis. We studied 383 patients at risk for HD. Each subject was asymptomatic by self-report. Genotype for the HD allele was determined by polymerase chain reaction testing. A battery of 8 physiological tests measuring speed of movement and reaction time was performed with a computer-driven system. Following neurologic examination, 17 of the 120 gene carriers (GCs) had symptoms sufficient for a clinical diagnosis of manifest HD. The remaining 103 GCs were designated presymptomatic GCs. When the non-GCs were compared with the presymptomatic GCs (1-way analysis of covariance and the Fisher protected t test), results on 3 of the 8 physiological tests--movement time, movement time with decision, and auditory reaction time--were different. Additionally, the number of trinucleotide (CAG) repeats significantly correlated with test performance for movement time with decision and visual reaction time with decision when both the entire group of GCs and the presymptomatic GCs alone were considered. These results suggest that subtle subclinical changes in motor function are present in presymptomatic individuals who have inherited the HD allele.
This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of mo... more This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of modafinil, for the treatment of excessive sleepiness in patients with narcolepsy. This was a multicenter double-blind study with 196 patients (aged 18-65 years) randomized to receive armodafinil 150 mg (n = 65), armodafinil 250 mg (n = 67), or placebo (n = 64) once daily for 12 weeks. Efficacy was assessed using the Maintenance of Wakefulness Test (MWT) (six 20-min subtests across the day), the Clinical Global Impression of Change (CGI-C), subjective measures of sleepiness (Epworth Sleepiness Scale), patient diaries, and evaluations of cognitive performance (Cognitive Drug Research) and fatigue (Brief Fatigue Inventory). Armodafinil significantly increased MWT mean sleep latency (at 0900-1500) compared with placebo. The mean change from baseline at final visit for armodafinil was an increase of 1.3, 2.6, and 1.9 min in the 150-mg, 250-mg, and combined groups, respectively, compared with a decrease of 1.9 min for placebo (p < 0.01 for all three comparisons). Mean late-day MWT latency (1500-1900) was also significantly improved (difference of armodafinil combined group relative to placebo at final visit: 2.8 min, p = 0.0358). The proportions of patients who showed at least minimal improvement in the CGIC rating from baseline to final visit in the armodafinil 150-mg, 250-mg, and combined groups were 69%, 73%, and 71%, respectively, compared with 33% for placebo (p < 0.0001). Both doses were associated with statistically significant improvements in memory, attention, and fatigue (p < 0.05). The most common adverse events in patients receiving armodafinil were headache, nausea, and dizziness. Armodafinil significantly improved ability to sustain wakefulness throughout the day in patients with narcolepsy. Armodafinil also significantly improved overall clinical condition, memory, attention, and fatigue when compared with placebo.
The authors describe the MR imaging characteristics and clinical course of a 22-year-old man with... more The authors describe the MR imaging characteristics and clinical course of a 22-year-old man with acute disseminated demyelinating disease, either Marburg multiple sclerosis or recurrent (relapsing) acute disseminated perivenous encephalomyelitis
8567 Background: Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and... more 8567 Background: Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa. Results reported here represent a pre-specified interim analysis of an open-label safety and efficacy study of FEBT in opioid-tolerant patients with cancer-related breakthrough pain (BTP). METHODS Patients with cancer-related BTP receiving around-the-clock and supplemental opioids were eligible to enroll. Patients who had participated in a previous dose-titration study of FEBT enrolled directly into the 1-year phase; new patients entered a titration phase to determine an effective FEBT dose before entering the 1-year phase. An effective FEBT dose was defined as the dose needed to provide adequate analgesia for BTP. By October 3, 2005, 170 patients (aged 24 to 95 years) received FEBT (100-800 μg) and had documented safety data. RESULTS Of the 112 new patients, 70.5% identified an effective FEBT dose and were eligible for enroll...
18521 Background: Standard recommendations for short-acting oral opioid doses to manage breakthro... more 18521 Background: Standard recommendations for short-acting oral opioid doses to manage breakthrough pain (BTP) assume some relation with the stable opioid dose used to treat persistent pain. Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the efficiency of fentanyl absorption through the buccal mucosa. They may provide rapid-onset analgesia. This pooled analysis of data from 3 studies examined the relationship between effective FEBT dose and around-the-clock (ATC) dose in patients who completed open-label titration to an effective FEBT dose. Methods: Patients were 18–80 years of age with cancer, persistent pain, and BTP. Eligible patients experienced an average of 1–4 episodes of BTP per day and were receiving stable doses of opioids (≥60 mg/day of morphine or equivalent) for persistent pain. Titration guidelines were uniform across studies; the maximum allowed dose of FEBT was 800 μg. Results: Of 304 patients enrolled, 208 completed titration to an effective FE...
To determine whether changes in motor function and reaction time are present in presymptomatic in... more To determine whether changes in motor function and reaction time are present in presymptomatic individuals carrying the Huntington disease (HD) allele. A case-control, double-blind study comparing asymptomatic at-risk subjects, with or without the HD allele, and subjects clinically determined to have early manifest HD. The Department of Medical and Molecular Genetics at Indiana University School of Medicine, Indianapolis. We studied 383 patients at risk for HD. Each subject was asymptomatic by self-report. Genotype for the HD allele was determined by polymerase chain reaction testing. A battery of 8 physiological tests measuring speed of movement and reaction time was performed with a computer-driven system. Following neurologic examination, 17 of the 120 gene carriers (GCs) had symptoms sufficient for a clinical diagnosis of manifest HD. The remaining 103 GCs were designated presymptomatic GCs. When the non-GCs were compared with the presymptomatic GCs (1-way analysis of covariance and the Fisher protected t test), results on 3 of the 8 physiological tests--movement time, movement time with decision, and auditory reaction time--were different. Additionally, the number of trinucleotide (CAG) repeats significantly correlated with test performance for movement time with decision and visual reaction time with decision when both the entire group of GCs and the presymptomatic GCs alone were considered. These results suggest that subtle subclinical changes in motor function are present in presymptomatic individuals who have inherited the HD allele.
Objective: The purpose of this retrospective, observational pilot study was to explore change in ... more Objective: The purpose of this retrospective, observational pilot study was to explore change in route of administration (RoA) and motivation for changing RoA during the course of opioid abuse.Design: This retrospective pilot study involved collecting and analyzing semistructured interview data.Setting: Interviews were conducted with patients undergoing outpatient substance abuse treatment at a buprenorphine clinic.Participants: Twenty adult patients (50 percent male) participated in the interviews.Main outcome measures: Interview data were qualitatively and quantitatively analyzed to evaluate trends and motivations for changing RoA.Results: In this sample, RoA varied over time. Most patients (75.0 percent) began abusing prescription opioids by swallowing intact pills, and 53.3 percent of patients eventually progressed to chewing. All patients who initiated abuse through chewing or insufflation (ie, intranasal use) progressed to injection. However, several patients (20.0 percent) di...
Objective: To characterize the pharmacokinetics (PK) and in vitro alcohol dissolution characteris... more Objective: To characterize the pharmacokinetics (PK) and in vitro alcohol dissolution characteristics of extended-release (ER), injection-molded (IM) morphine tablets with abuse-deterrent (AD) features (morphine-ADER-IMT).Design: In vivo, in vitro, and in silico studies were conducted. A randomized, two-cohort study evaluated the bioequivalence of morphine-ADER-IMT (60 mg) to morphine ER (60 mg; MS Contin®; Purdue Pharma LP, Stamford, CT) and characterized the effect of food on the PK profile of morphine-ADER-IMT. A three-treatment, three-period crossover study assessed the bioequivalence of morphine-ADERIMT (30 and 2 × 15 mg) to morphine ER (30 mg). Bioequivalence studies were performed in healthy male and female subjects (18-55 y of age) in the presence of naltrexone blockade. PK modeling was performed to assess steady-state bioequivalence for morphine-ADER-IMT 60 mg compared with morphine ER 60 mg. In vitro alcohol dissolution studies were performed with morphine-ADER-IMT (15 and...
Prescription opioid misuse and abuse in the United States (US) is epidemic and is a major burden ... more Prescription opioid misuse and abuse in the United States (US) is epidemic and is a major burden on health-care resources and costs to society. The need to significantly reduce the risks of prescription opioid misuse and abuse must be balanced with the important needs of patients with chronic pain who may benefit from treatment with opioids. The use of abuse-deterrent formulations (ADFs) of prescription opioids is one approach that could reduce the risk of prescription opioid abuse and misuse while maintaining access to opioids. ADF opioids have properties that make their abuse more difficult, less attractive, or less rewarding. In 2015, the US Food and Drug Administration issued final guidance to industry for the development of ADF opioids that recommended specific studies be conducted to demonstrate the abuse-deterrent properties of new opioid formulations. The technologies and the preclinical and clinical development of ADF opioids are rapidly evolving. This review provides an ov...
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