Abuse liability assessment of atomoxetine in a drug-abusing population.

BACKGROUND: Atomoxetine is a non-amphetamine medication approved to treat ADHD in children, adolescents, and adults. Previous studies demonstrated low abuse potential for atomoxetine in recreational drug users. This study assessed the abuse potential of atomoxetine in stimulant-preferring drug abusers compared to methylphenidate and phentermine as positive controls and desipramine and placebo as negative controls. METHODS: Forty male and female, 32-53 years old stimulant-preferring drug abusers completed this balanced Latin-square designed study. Subjects received acute, double-blind doses of placebo, desipramine (100 and 200 mg), methylphenidate (90 mg), phentermine (60 mg), and atomoxetine (45, 90, and 180 mg). Subjective and physiological effects were collected for 24 h following each drug treatment. RESULTS: Methylphenidate and phentermine were liked significantly more than placebo, atomoxetine, or desipramine. No atomoxetine dose was liked significantly more than placebo and liking scores for atomoxetine were similar to, or significantly lower than, desipramine, as assessed by the Drug Rating Questionnaire-Subject. While atomoxetine 45 and 180 mg did not significantly change any Addiction Research Center Inventory (ARCI) scores, atomoxetine 90 mg significantly increased A and BG stimulant scores of the ARCI and both methylphenidate and phentermine produced greater A and BG increases than any atomoxetine dose and also increased MBG (euphoria) scores relative to placebo. CONCLUSIONS: Atomoxetine has significantly less abuse liability than methylphenidate or phentermine and no greater abuse liability than desipramine.

Challenges in the development of prescription opioid abuse-deterrent formulations.

Opioid analgesics remain the cornerstone of effective management for moderate-to-severe pain. In the face of persistent lack of access to opioids by patients with legitimate pain problems, the rate of prescription opioid abuse in the United States has escalated over the past 15 years. Abuse-deterrent opioid products can play a central role in optimizing the risk-benefit ratio of opioid analgesics--if these products can be developed cost-effectively without compromising efficacy or creating new safety issues for the target treatment population. The development of scientific methods for assessing prescription opioid abuse potential remains a critical and challenging step in determining whether a claim of abuse deterrence for a new opioid product is indeed valid and will thus be accepted by the medical, regulatory, and reimbursement communities. To explore this and other potential impediments to the development of prescription opioid abuse-deterrent formulations, a panel of experts on opioid abuse and diversion from academia, industry, and governmental agencies participated in a Tufts Health Care Institute-supported symposium held on October 27 and 28, 2005, in Boston, MA. This manuscript captures the main consensus opinions of those experts, and also information gleaned from a review of the relevant published literature, to identify major impediments to the development of opioid abuse-deterrent formulations and offer strategies that may accelerate their commercialization.

Increased occupancy of dopamine receptors in human striatum during cue-elicited cocaine craving.

In all, 19 research subjects, with current histories of frequent cocaine use, were exposed to cocaine-related cues to elicit drug craving. We measured the change of occupancy of dopamine at D2-like receptors with positron emission tomography (PET) and inferred a change of intrasynaptic dopamine (endogenous dopamine release), based on the displacement of radiotracer [(11)C]raclopride. Receptor occupancy by dopamine increased significantly in putamen of participants who reported cue-elicited craving compared to those who did not. Further, the intensity of craving was positively correlated with the increase in dopamine receptor occupancy in the putamen. These results provide direct evidence that occupancy of dopamine receptors in human dorsal striatum increased in proportion to subjective craving, presumably because of increased release of intrasynaptic dopamine.

Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol.

Assessment of abuse potential of opioid analgesics has a long history in both laboratory animals and humans. This article reviews the methods used in animals and in humans and then presents the data collected in the evaluation of tramadol, an atypical centrally acting opioid analgesic approved for marketing in the United States in 1998. Finally, data on the abuse of tramadol from postmarketing surveillance and case reports are presented. The consistency between animal and human study results and the predictive value of both are discussed. Overall, there was substantial agreement between animal and human data, with each having predictive value. Nonetheless, it is suggested that abuse-potential screening of new medications would benefit from an organized, integrated cross-species program.

Five year outcomes of a cohort of HIV-infected injection drug users in a primary care practice.

Overall mortality related to HIV infection has declined with the advent of highly active anti-retroviral therapy (HAART). The purpose of this study was to examine the five-year outcomes of a cohort of 175 consecutive patients with HIV infection and injection drug use followed at a primary care practice. Patients were seen for their first visit between June 1994 and May 1998. At five years from their initial visit, 53 patients (30.3%) had died, while 47 (26.9%) were still active patients in our primary care practice. Of those who died, HIV was the cause of death in a little over half of patients (55%) followed by liver disease (15%) and drug overdose (11%). Only 80 patients ever received highly active anti-retroviral therapy (HAART) and 52 (65%) of these achieved an undetectable viral load. Patients who never received HAART had a five-year mortality of 34.8%, compared to 25.0% in patients who ever received HAART, p < .001. Our data underscore the high burden of morbidity and mortality associated with HIV infection among IDUs despite the availability of effective treatment.

Randomized controlled study transitioning opioid-dependent pregnant women from short-acting morphine to buprenorphine or methadone.

This study compared the safety and withdrawal discomfort associated with transitioning pregnant opioid-dependent women from short-acting morphine onto buprenorphine or methadone under well-controlled double-blind conditions. Participants (n=18) were patients in a comprehensive treatment setting and were part of a larger randomized controlled trial comparing the neonatal abstinence syndrome in mothers treated with individualized doses of sublingual buprenorphine or oral methadone. Methadone was first given to all patients within 24h of treatment admission. After written informed consent was signed (3-5 days post-admission), methadone was discontinued and Immediate Release Morphine (IRM) was initiated. The initial total daily dose of IRM was six times the last daily methadone dose. The daily dose of IRM was divided in four daily doses. Induction onto double-blind, double dummy (i.e., two medications were administered with only one being active) methadone or buprenorphine was accomplished over 3 days (i.e., induction). Withdrawal scores during the IRM and induction onto randomized medication were judged mild and not statistically different for both methadone (mean dose 53.5 mg) and buprenorphine (mean dose 10.9 mg). No significant differences between medication groups were observed when individual withdrawal items were examined. No observed differences in safety measures including fetal movement, maternal physiological parameters of body temperature, heart rate and blood pressure were observed between groups. Transitioning opioid-dependent pregnant women from IRM to methadone or buprenorphine during the second trimester of pregnancy can be conducted with similar comfort and safety.

Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome.

This study was designed to compare the neonatal abstinence syndrome (NAS) in neonates of methadone and buprenorphine maintained pregnant opioid-dependent women and to provide preliminary safety and efficacy data for a larger multi-center trial. This randomized, double-blind, double-dummy, flexible dosing, parallel-group controlled trial was conducted in a comprehensive drug-treatment facility that included residential and ambulatory care. Participants were opioid-dependent pregnant women and their neonates. Treatment involved daily administration of either sublingual buprenorphine or oral methadone using flexible dosing of 4-24 mg or 20-100 mg, respectively. Primary a priori outcome measures were: (1) number of neonates treated for NAS; (2) amount of opioid agonist medication used to treat NAS; (3) length of neonatal hospitalization; and (4) peak NAS score. Two of 10 (20%) buprenorphine-exposed and 5 of 11 (45.5%) methadone-exposed neonates were treated for NAS (p=.23). Total amount of opioid-agonist medication administered to treat NAS in methadone-exposed neonates was three times greater than for buprenorphine-exposed neonates (93.1 versus 23.6; p=.13). Length of hospitalization was shorter for buprenorphine-exposed than for methadone-exposed neonates (p=.021). Peak NAS total scores did not significantly differ between groups (p=.25). Results suggest that buprenorphine is not inferior to methadone on outcome measures assessing NAS and maternal and neonatal safety when administered starting in the second trimester of pregnancy.

Abstinence incentive effects in a short-term outpatient detoxification program.

Despite being widely available, outpatient detoxification has limited efficacy as a stand-alone treatment. This study examined whether abstinence-contingent incentives would improve outcomes for patients entering outpatient opiate detoxification. Participants (N = 211) received a 100 US dollars voucher on the last day of detoxification either contingent on opiate and cocaine abstinence or noncontingently. Urine samples were collected at intake, on Wednesday, Friday (the last day of detoxification), and the following Monday. Among contingent-voucher participants, 31% were drug-free on Friday compared with 18% of noncontingent controls (Z = 2.4, p < .05). Few (12-13%) participants tested negative on Monday. Results support the ability of vouchers to produce modest improvements in abstinence initiation rates during brief detoxification but suggest that additional interventions are needed to sustain improvements.

A Comparison of Clonidine and Buprenorphine in the Outpatient Treatment of Opiate Withdrawal.

The opiate withdrawal syndrome, although not life threatening, is a major obstacle in the treatment of opiate dependence. Over a 12 week period, 124 patients (63% female, 66% African American and mean age 32.6 years) underwent 5 day treatment for opiate withdrawal. Patients treated in the first 6 weeks (n = 69) received clonidine based treatment (0.1 mg every 6 h with one dose received on-site each day and the others taken home), while patients treated in the latter 6 weeks (n = 65) received buprenorphine 0.3 mg IM daily. Both groups received supportive medications for diarrhea, cramps, aches, and nausea, had clonidine patches placed on day 4, and were offered naltrexone upon completion. Based on age, gender, and race the two treatment groups were similar. The completion rate was 75.4% for buprenorphine group and 47.5% for the clonidine group, (p =.001). In conclusion, buprenorphine was superior to clonidine in enabling opiate dependent patients to successfully complete an outpatient detoxification program.

A multisite, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of vigabatrin for treating cocaine dependence.

IMPORTANCE: Cocaine dependence is a significant public health problem, yet no validated pharmacological treatment exists. The potent γ-aminobutyric acid (GABA)ergic medication vigabatrin has previously been shown to be effective in a double-blind single-site study conducted in Mexico. OBJECTIVE: To evaluate the safety and efficacy of vigabatrin for the treatment of cocaine dependence in a U.S. sample. DESIGN AND SETTING: Multisite, randomized, double-blind, placebo-controlled, 12-week clinical trial with follow-up visits at weeks 13, 16, 20, and 24 in 11 U.S. sites. PARTICIPANTS: In total, 186 treatment-seeking participants with cocaine dependence (mean age, 45 years). Approximately 67% were male, and about 60% were of African American race/ethnicity. INTERVENTIONS: Participants received twice-daily doses of vigabatrin (total dosage, 3.0 g/d) or matched placebo, plus weekly computerized cognitive behavioral therapy and biweekly individual counseling for 13 weeks. Contingency management encouraged the provision of urine samples. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the proportion of participants with cocaine abstinence during the last 2 weeks of the 12-week treatment phase as assessed by self-reports and quantitative urine drug screens. The weekly fraction of cocaine use days and the number of drug-free urine samples during weeks 1 through 13 were key secondary measures. RESULTS: No significant differences were observed between the vigabatrin group and the placebo group on the primary outcome measure (P = .67), key secondary measures (P > .99), or other outcome measures. However, while pill counts and self-reports indicated that more than 66% of all participants (and >63% of the vigabatrin group) took more than 70% of their medication, post hoc vigabatrin urine concentration levels suggested that approximately 40% to 60% of patients taking vigabatrin may not have been adherent. This lack of adherence may have obscured any evidence of vigabatrin efficacy. No visual acuity or visual field deterioration occurred in any of the participants. CONCLUSIONS AND RELEVANCE: No protocol-defined differences in efficacy between vigabatrin treatment and placebo were detected for any outcome variable. This may have been due to medication nonadherence or, alternatively, due to the weak efficacy of vigabatrin. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00611130.

Long-term opioid therapy, aberrant behaviors, and substance misuse: comparison of patients treated by resident and attending physicians in a general medical clinic.

OBJECTIVE: To compare rates of opioid prescribing, aberrant behaviors, and indicators of substance misuse in patients prescribed long-term opioids by resident physicians or attending physicians in a general internal medicine practice. DESIGN: Medical records of 333 patients who were prescribed opioids for at least three consecutive months were reviewed. Aberrant behaviors over a 2-year period were documented, including reporting lost or stolen medications or receiving opioids from more than one provider. Indicators of substance misuse were also recorded, including positive urine drug testing for illicit substances, addiction treatment, overdose, and altering prescriptions. RESULTS: An estimated 13.6 percent of the patients followed by residents had been prescribed opioids for three or more months; this was significantly higher than the rate for attendings (5.9 percent, p < 0.001). Patients followed by residents were more likely to have reported lost or stolen prescriptions or medication (25.7 percent vs 12.2 percent, p = 0.03) or to have received opioids from another provider (17.8 percent vs 7.6 percent, p = 0.008); they were also more likely to exhibit an indicator of substance misuse (24.8 percent vs 7.6 percent, p < 0.001). However, in multivariate analyses, aberrant behaviors and indicators of substance misuse were not significantly associated with having a resident physician. CONCLUSIONS: Resident physicians at our institution are following a disproportionate number of patients on long-term opioids, many of whom exhibit aberrant behaviors and indicators of substance misuse. This underscores a need for better resident training and supervision to provide effective and safe care for patients with chronic pain.

Core outcome measures for opioid abuse liability laboratory assessment studies in humans: IMMPACT recommendations.

A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.

Buprenorphine maintenance treatment in a primary care setting: outcomes at 1 year.

The purposes of this study were to assess outcomes of patients prescribed buprenorphine at a primary care practice and to identify factors associated with favorable outcomes. All 255 patients given at least one prescription for buprenorphine between August 2003 and September 1, 2007, at a primary care practice in Baltimore were included. Data regarding demographics and comorbidities were collected retrospectively. Patients were classified as "opioid-positive" or "opioid-negative" each month based on patient report, urine toxicology, and provider assessment. After 12 months, 145 (56.9%) patients remained in treatment, and 64.7% of their months were opioid-negative. Patients using heroin were less likely to be opioid-negative, whereas those using prescription opioids were more likely to be opioid-negative. Polysubstance use was associated with increased treatment retention. The prescription of buprenorphine for opioid dependence treatment can be incorporated into primary care practice, and many patients, including polysubstance users, benefit from this treatment.

Dosing adjustments in postpartum patients maintained on buprenorphine or methadone.

Scant scientific attention has been given to examining the need for agonist medication dose changes in the postpartum period. Study objectives were: 1) to determine the need for medication dose adjustments in participants stabilized on buprenorphine or methadone 3 weeks before and 4 weeks after delivery, and 2) to evaluate the need for methadone dose adjustments during the first 7 days in participants transferred from buprenorphine to methadone at 5 weeks postpartum. Participants were opioid-dependent pregnant women who had completed a randomized, double-blind, double-dummy, flexible dosing comparison of buprenorphine to methadone. Participants received a stable dose of methadone (N = 10) or buprenorphine (N = 8) before and 4 weeks after delivery. Buprenorphine-maintained participants were transferred to methadone at 5 weeks postpartum. There were no significant differences predelivery and/or postdelivery between the buprenorphine and methadone conditions in the mean ratings of dose adequacy, "liking," "hooked," and "craving" of heroin or cocaine. Patient response to the conversion from buprenorphine to methadone seems variable. Buprenorphine-maintained participants required dose changes postpartum only after they transferred to methadone. Regardless of type of medication, postpartum patients should be monitored for signs of overmedication.

Buprenorphine and norbuprenorphine in hair of pregnant women and their infants after controlled buprenorphine administration.

BACKGROUND: Buprenorphine is under investigation as a pharmacotherapeutic agent for treating opioid dependence in pregnant women. We hypothesized that there would be a relationship between the cumulative maternal dose of buprenorphine during pregnancy and the concentration of buprenorphine and norbuprenorphine in maternal and infant hair. METHODS: This study examined buprenorphine and norbuprenorphine concentrations in hair obtained from 9 buprenorphine-maintained pregnant women and 4 of their infants. Specimens were analyzed by liquid chromatography-tandem mass spectrometry with limits of quantification of 3.0 pg/mg. All maternal hair specimens were washed with methylene chloride before analysis, and when sufficient amounts of maternal hair were available, specimens also were analyzed without washing. Infant hair specimens were not washed. RESULTS: Buprenorphine concentrations were significantly greater in unwashed hair than washed hair (P = 0.031). Norbuprenorphine concentrations were significantly greater than buprenorphine concentrations in both maternal (P = 0.0097) and infant hair (P = 0.0033). There were statistically significant associations between the cumulative maternal dose of buprenorphine administered and the concentrations of buprenorphine (washed, P <0.0001; unwashed, P = 0.0004), norbuprenorphine (washed, P <0.0001; unwashed, P = 0.0005), and buprenorphine plus norbuprenorphine (washed, P <0.0001; unwashed, P = 0.0005) for both washed and unwashed maternal hair specimens. There was a significant positive association between concentrations of buprenorphine and norbuprenorphine in maternal hair (washed, P <0.0001; unwashed, P = 0.0003), a trend for this association in infant hair (P = 0.08), and an association between buprenorphine concentrations in maternal unwashed hair and infant hair (P = 0.0002). The buprenorphine:norbuprenorphine ratio increased in distal segments. CONCLUSION: Buprenorphine treatment during gestation provides an opportunity for monitoring drug disposition in maternal and fetal tissues under controlled conditions.

Transferring methadone-stabilized pregnant patients to buprenorphine using an immediate release morphine transition: an open-label exploratory study.

A transition from methadone to buprenorphine without intervening withdrawal symptoms is critical for advancing the treatment of opioid-dependent patients. Four pregnant inpatients were transferred from methadone (65-85 mg) to five days of immediate release morphine (IRM) and then to buprenorphine (12-28 mg). Withdrawal scores decreased during the five days of IRM and subsequently increased over the first three days on buprenorphine. The transitional use of IRM appears safe for both mother and fetus. Withdrawal symptoms appeared during buprenorphine induction; however, these data suggest that the intensity of withdrawal symptoms may be lessened by the dose and frequency of buprenorphine administration.

A resident clerkship that combines inpatient and outpatient training in substance abuse and HIV care.

Substance abuse and HIV infection are important medical problems that receive comparatively little attention in residency training programs and residents often feel unprepared to deal with them. We developed a month-long rotation that combined outpatient care for patients with HIV infection and addiction, with inpatient care for medically-ill patients on a detoxification unit. At the end of the rotation, residents reported greater comfort with caring for these patients and improved self-rated competence. They also rated the rotation highly. Our experience shows that a rotation combining inpatient and outpatient substance abuse and HIV care was valued by residents and increased their comfort and proficiency with caring for these underserved and stigmatized populations.