Megan J. Shram

Acute nicotine enhances c-fos mRNA expression differentially in reward-related substrates of adolescent and adult rat brain

A number of studies have demonstrated that adolescent rodents are more sensitive to the rewarding effects of nicotine compared to adults. To help determine the potential brain circuitry involved, we investigated the effect of acute nicotine administration (0.4 or 0.8mg/kg, s.c.) on the expression of c-fos mRNA in the brains of adolescent (P35) and adult (P67-70) male Wistar rats using in situ hybridization. Nicotine administration increased c-fos mRNA expression in several brain regions, including the central amygdala, locus coeruleus, nucleus accumbens core, paraventricular nucleus of the hypothalamus and lateral septum of adolescent and adult rats. Nicotine increased c-fos mRNA expression more robustly in the bed nucleus of the stria terminalis, nucleus accumbens shell and ventral tegmental area in adolescent rats. The current results suggest that nicotine may have greater activational effects in brain regions associated with reward in adolescent rats and may help to explain the differences between adolescents and adults in behavioral responses to nicotine.

Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse‐deterrent controlled‐release tablets in recreational opioid users

The objective of this study was to evaluate abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered, crushed reformulated OxyContin® (oxycodone HCl controlled‐release) tablets (ORF), relative to crushed original OxyContin® (OC), oxycodone powder (Oxy API), and OC placebo. This randomized, double‐blind, positive‐ and placebo‐controlled crossover study enrolled healthy, adult, nonphysically dependent recreational opioid users with recent history of intranasal drug abuse (N = 27). Active treatments contained oxycodone (30 mg). Pharmacokinetics, pharmacodynamics (e.g., Overall Drug Liking [ODL], Take Drug Again [TDA], and High Visual Analog Scales [VAS]; Subjective Drug Value [SDV]; pupillometry; intranasal irritation), and safety (e.g., adverse events, vital signs, laboratory tests) were assessed to 24 hours postdose. Crushed ORF administration yielded reduced oxycodone Cmax and increased Tmax versus crushed OC and Oxy API. Peak effects for pharmacodynamic measures were delayed with ORF (1–2 hours) versus OC and Oxy API (0.5–1 hour). ODL, TDA, High VAS, and SDV Emax values were significantly lower (P ≤ .05) and some intranasal irritation ratings were greater for ORF versus OC and Oxy API. No significant or unexpected safety findings were observed. Compared with OC and Oxy API, intranasally administered ORF was associated with lower and delayed peak plasma concentrations, decreased drug‐liking, and decreased intranasal tolerability. This suggests that ORF has a decreased potential for intranasal oxycodone abuse. There were no significant or unexpected safety findings. As is true for all abuse potential studies, epidemiological or other appropriate post‐marketing studies are required to assess the impact of the reduction in intranasal oxycodone abuse potential observed in the present study on real‐world patterns of ORF misuse, abuse, and diversion.

Adolescent male Wistar rats are more responsive than adult rats to the conditioned rewarding effects of intravenously administered nicotine in the place conditioning procedure

The initiation of smoking typically begins during adolescence, suggesting that nicotine may have different motivational effects during this developmental stage compared to adulthood. Studies using the conditioned place preference (CPP) procedure have demonstrated that adolescent rats are more sensitive to the conditioned rewarding effects of subcutaneously administered nicotine compared to adult rats, whereas intravenous self-administration studies have not demonstrated consistent age differences in the reinforcing effects of nicotine. This study was designed to evaluate if intravenously administered nicotine has age-dependent conditioned rewarding effects. Using an unbiased CPP procedure, adolescent and adult male Wistar rats were conditioned with one of two intravenous doses of nicotine that are sufficient to maintain self-administration (0.03 or 0.06 mg/kg) or vehicle (saline) over a period of 8 conditioning trials (4 nicotine and 4 vehicle). Adolescent rats conditioned with 0.03 mg/kg nicotine demonstrated a significant CPP, whereas adult rats did not at either dose tested. After 8 extinction trials, reinstatement of the CPP was observed following a nicotine priming injection (0.15 mg/kg, s.c.) in adolescents that had previously been conditioned with 0.03 mg/kg nicotine; vehicle-treated rats did not show a significant preference for either compartment. The present data are consistent with previous CPP studies using subcutaneously administered nicotine and suggest that passively administered intravenous nicotine is more rewarding in adolescent compared to adult rats.

Evaluation of the abuse potential of extended release hydromorphone versus immediate release hydromorphone.

Immediate release (IR) hydromorphone has experienced significant misuse and abuse. An extended release (ER) hydromorphone formulation has been developed to provide sustained pain relief and may reduce the likelihood for abuse by delaying absorption. In this double-blind, placebo-controlled, randomized, 2-part crossover study, the abuse potential of single oral doses of hydromorphone ER (intact: 16-, 32-, and 64-mg; milled: 8-mg) was compared with 8-mg hydromorphone IR and placebo. After drug administration, subjects with a history of recreational opioid use completed a series of assessments, including subjective effects visual analog scales (eg, drug liking) and Addiction Research Center Inventory With Cole Modification, at several timepoints up to 48 hours postdose. Independent of formulation, maximum at-the-moment drug liking was higher for hydromorphone versus placebo. Maximum drug liking occurred earlier and was higher for 8-mg IR versus 16-mg ER but similar to 32- and 64-mg ER. Most positive effects were lower after 16-mg ER compared with other doses, including 8-mg IR. Bad drug effects were higher for hydromorphone ER, particularly the 64-mg dose. Milled 8-mg ER produced similar subjective effects to 8-mg IR. Comparison of scores after administration of 8-mg IR on 2 separate occasions showed that most assessments exhibited good test-retest reliability, although some scores declined marginally between test and retest. Delayed onset of good drug effects and prominent bad drug effects of hydromorphone ER suggest that, when administered intact, this formulation may have lower abuse potential than hydromorphone IR.

Sex differences in yohimbine‐induced increases in the reinforcing efficacy of nicotine in adolescent rats

Stress is an important factor in the initiation and maintenance of smoking in adolescents. Women are more vulnerable to the development of addiction to smoking and have more difficulty quitting than men. Women also showe enhanced responses to stress. Despite these differences, no work has been done examining the effects of stress on the reinforcing efficacy of self‐administered nicotine in adolescent rats, or if there are sex differences. Male and female adolescent Long Evans rats were trained to self‐administer one of three different intravenous doses of nicotine (7.5, 15, 30 μg/kg/infusion) first on fixed ratio, and then on a progressive ratio (PR) schedule beginning on postnatal day 33. The effect of the pharmacological stressor yohimbine (0.3, 0.6 mg/kg, i.p.) on the reinforcing efficacy of nicotine was then determined using the PR schedule. Yohimbine stimulated nicotine intake and increased PR breakpoints and numbers of infusions received in both male and female adolescent rats. The infusion dose of nicotine was positively associated with yohimbine‐induced increases in responding. Female rats showed significantly increased breakpoints at yohimbine doses and nicotine infusion doses at which males did not. The effects of the pharmacological stressor, yohimbine on the reinforcing efficacy of nicotine are therefore linked to sex and nicotine infusion dose. Female rats are more sensitive to stress‐induced potentiation of nicotine self‐administration.

Differences in the In Vitro and In Vivo Pharmacokinetic Profiles of Once-Daily Modified-Release Methylphenidate Formulations in Canada: Examination of Current Bioequivalence Criteria

BACKGROUND Current Canadian bioequivalence criteria rely on rate and extent of drug exposure, that is, C(max) and AUC. In the case of complex modified-release formulations, these criteria may not address pharmacokinetic differences with potential therapeutic and tolerability implications. OBJECTIVE This study was performed to characterize in vitro dissolution and in vivo pharmacokinetic profiles of three modified-release formulations of methylphenidate (MPH) marketed in Canada, two of which meet the criteria for assuming bioequivalence as defined by Health Canada: MPH extended-release (ER-C) and osmotic controlled-release oral-delivery-system (OROS-MPH). METHODS In vitro dissolution tests were performed using 54-mg OROS-MPH, 54-mg MPH ER-C, and 20-mg MPH sustained-release (SR) tablets. In vivo pharmacokinetics of single oral doses of 54 mg OROS-MPH, 54 mg MPH ER-C, and 60 mg MPH-SR were evaluated in an open-label, randomized, crossover study in healthy subjects. Plasma samples were collected up to 24 hours after administration of the drug. RESULTS In vitro dose-corrected release profiles of MPH ER-C and MPH-SR tablets were similar (<10% difference), whereas OROS-MPH exhibited a profile distinct from that of the other formulations. Twenty-four subjects completed the pharmacokinetic study and were included in the analyses. Analysis of C(max) and AUC of MPH showed that OROS-MPH and MPH ER-C met the criteria for assumed bioequivalence according to Health Canada guidelines. However, partial AUCs exhibited significant differences between the two formulations, which were supported by ratios of MPH concentrations over time. Comparison of MPH ER-C with MPH-SR (dose corrected) also satisfied bioequivalence criteria. CONCLUSIONS The pharmacokinetic data suggest that in vitro and in vivo profiles of OROS-MPH and MPH ER-C are distinct. However, using traditional criteria for bioequivalence, MPH ER-C would be assumed bioequivalent to both OROS-MPH and MPH-SR. Inclusion of partial AUCs as additional criteria could aid in ensuring therapeutic equivalence. ClinicalTrials.gov identifier: NCT01118702.

Use of Remifentanil in a Novel Clinical Paradigm to Characterize Onset and Duration of Opioid Blockade by Samidorphan, a Potent μ-Receptor Antagonist.

Abstract A novel clinical study design was used to evaluate the blockade of a selective short-acting &mgr;-opioid agonist (remifentanil) in 24 opioid-experienced subjects. Samidorphan (3-carboxamido-4-hydroxynaltrexone) is a novel opioid modulator with &mgr;-antagonist properties. Objective (pupil diameter) and subjective (visual analog scale) responses to repeated remifentanil and saline infusion challenges were assessed after single oral administration of placebo (day 1) and samidorphan (day 2). Complete blockade persisted with samidorphan for 24 hours for pupil miosis and 48 hours for the drug liking visual analog scale. Samidorphan effects persisted beyond measurable samidorphan exposure (t½ = 7 hours). Samidorphan was associated with complete blockade of remifentanil, and the duration supports daily administration. This study used a novel approach with multiple administrations of remifentanil to successfully demonstrate a durable effect with samidorphan and a rapid and potent blockade of physiological and subjective &mgr;-opioid effects.

Assessing the Subjective and Physiological Effects of Intranasally Administered Crushed Extended-Release Morphine Formulations with and without a Sequestered Naltrexone Core in Recreational Opioid Users

OBJECTIVE To evaluate the pharmacodynamic (PD) effects of morphine sulfate and naltrexone hydrochloride extended-release (MSN) capsules compared with controlled-release morphine sulfate (MS) and placebo when crushed and administered intranasally. METHODS The present study was a randomized, double-blinded, placebo-controlled, single-dose (30 mg), three-way crossover study in healthy, nondependent recreational opioid users. PD measures included assessment of subjective drug effects using visual analogue scales (VAS) ranging from 0 to 100 and assessments of pupil diameter. Blood samples were collected for pharmacokinetic analyses. RESULTS Both MS and MSN showed significantly higher PD values compared with placebo. MSN showed significantly lower scores for drug liking and high VAS scores on both mean peak effect (Emax) (69.6 and 55.2, respectively) and in area under the effect curve over 2 h (86.3 and 66.7, respectively) following dosing compared with MS (Emax 87.6 and 86.6, respectively; area under the curve over 2 h 120.6 and 132.9, respectively; P<0.001). MSN showed significantly lower Emax for all other positive subjective effects (good drug effects, overall drug liking, and take drug again VAS scores) compared with MS (P<0.001). Peak minimum pupil diameter was significantly larger for MSN than MS (P=0.002). Mean peak plasma concentration (Cmax) and median time to Cmax for morphine following administration of MSN and MS were similar (27.3 ng⁄mL and 0.57 h versus 27.7 ng⁄mL and 0.6 h, respectively). Naltrexone mean Cmax was 1497 pg⁄mL after MSN and median time to Cmax was 0.55 h. CONCLUSIONS When crushed and administered intranasally, MSN was associated with significantly lower ratings of drug liking and other positive subjective effects compared with MS.

Pharmacotherapy of Alcohol Dependence: Improving Translation from the Bench to the Clinic

Publisher Summary Alcohol abuse and dependence are the third highest risk to health in developing countries and cause 3.2% of deaths worldwide. There are certain characteristics of alcohol dependence that are of clinical importance, but are seen to a lesser extent with nicotine dependence, though some of these are also features of dependence on opiates or psycho stimulant drugs. A large proportion of alcoholics suffer from other serious psychiatric disorders, many are malnourished, suffering in particular from thiamine deficiency, and have unhealthy diets; 50 to 80% of alcoholics have cognitive deficits and these deficits not only affect the quality of life of alcoholics and the amount of health care they need, but also have a detrimental effect on their ability to benefit from current treatment programs. The effects of long-term alcohol consumption on memory also need to be considered in the context of animal models. Multidrug use is a problem with all types of dependence, including alcohol, but animal models of alcohol dependence have tended to avoid that particular complication. The main animal models in current use for testing drugs for the treatment of alcohol dependence, voluntary drinking and operant self-administration have demonstrated effects of the treatments in current use, but have also shown positive results with compounds that have not proved of value in humans. This chapter discusses some current treatment of alcohol dependence, approaches to the treatment of alcohol dependence, behavioral models of alcohol dependence, and correspondence of efficacy of established and novel treatments for alcohol dependence in animals and humans.

The US FDA Draft Guidance for Developing Abuse-Deterrent Opioid Analgesics: 2014 and Beyond

Prescription medication abuse, particularly of opioids, remains a serious public health problem. Many socioeconomic and healthcare system factors have contributed to the resulting epidemic of prescription opioid abuse. As the scope of this epidemic became evident, efforts to make abuse-deterrent formulations (ADFs) began, and many ADFs are under development. In January 2013, the US Food and Drug Administration (FDA) issued a Draft Guidance outlining the categories of studies needed for evaluating the abuse-deterrent properties of ADF opioids (e.g., pre-market in vitro, pharmacokinetic and abuse potential studies, and post-marketing studies) and the four potential label claims that might be made about the products. Studies to be conducted are those required for approval, those that might be included as data in the label (implicit claims), and those that would be required to merit a specific explicit claim—Tier 1, 2, 3, or 4. In the context of the Guidance, new ADFs need to consider the unique features of their technology, market size, comparator products, actual routes and methods of abuse, the targeted health consequences of abuse, pricing and reimbursement, the impact of other interventions to decrease abuse, and the challenges in doing post-market studies. ADFs will not stop prescription opioid drug abuse; however, easily tampered formulations should not contribute to the problem. All extended-release (ER) opioids and other abusable drugs should have abuse-deterrent properties. Immediate-release (IR) opioids should also be formulated with abuse-deterrent properties, because abuse of IR opioids is a more common and serious problem than that of ER opioids. Maximum dosage strengths of ER opioids should also be limited. Finally, the current situation, where non-abuse-deterrent ER opioids exist concurrently on the market is extremely problematic from a public health policy perspective.