The effects of acute oral naltrexone pretreatment on the abuse potential of intranasal methamphetamine, and the relationship between reward/punishment sensitivity and methamphetamine's effects.

One potential medication for treating methamphetamine use disorder is the opioid antagonist naltrexone (NLTX). Despite encouraging preclinical findings, the results of clinical studies have been mixed. The primary aim of the current trial was to examine the effects of acute NLTX pretreatment on the subjective and reinforcing effects of intranasal methamphetamine. Nonmedical psychostimulant users completed outpatient testing sessions in which they received oral placebo (0 mg) or NLTX (50 mg) before intranasal methamphetamine (30 mg/70 kg). Primary outcome measures were peak positive subjective effects (e.g. drug 'Liking') assessed on a visual analog scale (0-100), and methamphetamine self-administration using an operant self-administration task. Participants also completed a probabilistic categorization task to assess reward and punishment learning sensitivity. Complete data were available from 13 male and 1 transgender (male-to-female) participant (age: 33.4 ± 7.6 years). Intranasal methamphetamine significantly increased subjective ratings of drug 'Liking', 'Good Effect' and 'High' from baseline (P's < 0.01), but did not significantly vary as a function of placebo or NLTX pretreatment. Similarly, methamphetamine self-administration did not vary between the placebo and NLTX pretreatment conditions. This sample did not demonstrate a significant 'bias' in learning from positive and negative outcomes (i.e. reward and punishment sensitivity), and reward/punishment sensitivity was not correlated with the effects of methamphetamine or the effects of NLTX on methamphetamine. The current study argues against the use of NLTX as a stand-alone medication for treating methamphetamine use disorder.

Effects of lorcaserin on oxycodone self-administration and subjective responses in participants with opioid use disorder.

BACKGROUND: Lorcaserin, a high-affinity 5-HT2C receptor agonist approved for treating obesity, decreased self-administration of oxycodone and cue-induced reinstatement of drug-seeking behavior in preclinical studies. The current investigation is the first clinical trial to evaluate the ability of lorcaserin to alter the reinforcing and subjective effects of oxycodone. METHODS: In this 7-week inpatient trial, 12 non-treatment-seeking volunteers (11 males) with moderate-to-severe opioid use disorder were detoxified from opioids. In a randomized cross-over fashion, participants were first stabilized on lorcaserin (10 mg BID) or placebo (0 mg BID). Participants underwent a two-week testing period during which the reinforcing and subjective effects of intranasal oxycodone were examined in verbal choice, cue-exposure, and progressive-ratio choice sessions. The two testing weeks were identical with the exception that during the first week, active oxycodone (10 mg) was available during verbal choice (self-administration) sessions, and during the second week placebo oxycodone was available. Subsequently, participants were stabilized on the other medication condition (placebo or lorcaserin) and underwent the same testing procedures again. RESULTS: Lorcaserin did not alter oxycodone self-administration. However, lorcaserin had a trend to increase "wanting heroin" when oxycodone was available, and to accentuate oxycodone-induced miosis. CONCLUSION: Under the current experimental conditions, lorcaserin at a dose of 10 mg BID did not reliably decrease the abuse liability of oxycodone, even though the study was sufficiently powered (≥80 %) to detect clinically meaningful differences in the main outcome variables between the placebo and active lorcaserin condition. Future research could explore a wider dose range of lorcaserin and oxycodone.

Assessing the contribution of opioid- and dopamine-related genetic polymorphisms to the abuse liability of oxycodone.

BACKGROUND: Attempts to identify opioid users at increased risk of escalating to opioid use disorder have had limited success. Data from a variety of sources suggest that genetic variation may mediate the subjective response to opioid drugs, and therefore contribute to their abuse potential. The goal of the current study was to observe the relationship between select genetic polymorphisms and the subjective effects of oxycodone under controlled clinical laboratory conditions. METHODS: Non-dependent, volunteers with some history of prescription opioid exposure (N = 36) provided a blood sample for analyses of variations in the genes that encode for the µ-, κ- and δ-opioid receptors, and the dopamine metabolizing enzyme, catechol-O-methyltransferase (COMT). Participants then completed a single laboratory test session to evaluate the subjective and analgesic effects of oral oxycodone (0, 10, and 20 mg, cumulative dose = 30 mg). RESULTS: Oxycodone produced typical µ-opioid receptor agonist effects, such as miosis, and decreased pain perception. Oxycodone also produced dose-dependent increases in positive subjective responses such as: drug "Liking" and "Good Effect." Genetic variants in the µ- (rs6848893) and δ-opioid receptor (rs581111) influenced the responses to oxycodone administration. Additionally, self-reported "Stimulated" effects of oxycodone varied significantly as a function of COMT rs4680 genotype. DISCUSSION: The current study shows that the euphoric and stimulating effects of oxycodone can vary as a function of genetic variation. Though the relationship between the stimulating effects of opioids and their abuse liability is not well established, we know that the ability of opioids to provide intense feelings of pleasure is a significant motivator for continued use. If replicated, specific genetic variants may be useful in predicting who is at increased risk of developing maladaptive patterns of use following medical exposure to opioid analgesics.

The PPARγ Agonist Pioglitazone Fails to Alter the Abuse Potential of Heroin, But Does Reduce Heroin Craving and Anxiety.

Possibly through its effects on glia, the peroxisome proliferator-activated gamma receptor (PPARγ) agonist pioglitazone (PIO) has been shown to alter the effects of heroin in preclinical models. Until now, these results have not been assessed in humans. Heroin-dependent participants were randomized to either active (45 mg, n = 14) or placebo (0 mg, n = 16) PIO maintenance for the duration of the three-week study. After stabilization on buprenorphine (8 mg), participants began a two-week testing period. On the first to fourth test days, participants could self-administer drug or money by making verbal choices for either option. On the fifth day, active heroin and money were administered and participants could work to receive heroin or money using a progressive ratio choice procedure. Test days 6-10 were identical to test days 1-5 with the exception that, during one of the test weeks, placebo was available on the first four days, and during the other week heroin was available. PIO failed to alter the reinforcing or positive subjective effects of heroin, but it did reduce heroin craving and overall anxiety. Although we were unable to replicate the robust effects found in preclinical models, these data provide an indication of drug effects that deserves further exploration.

Pioglitazone, a PPARγ agonist, reduces nicotine craving in humans, with marginal effects on abuse potential.

Possibly through their actions upon glia, peroxisome proliferator-activated receptor agonists (PPAR) have been shown to alter the abuse potential of addictive drugs in several preclinical models. The current study extends this research into the human laboratory as the first clinical study into the effects of the PPAR gamma agonist, pioglitazone, on the abuse potential of nicotine. Heavy smokers were recruited for this 3-week study. Upon admission, participants were randomized to either active (45mg, n=14) or placebo (0mg, n=13) PIO maintenance conditions for the duration of the study. After 5-7days of stabilization on a 7mg nicotine patch, participants began laboratory testing. On the 1st-4th test days, participants could self-administer cigarettes or receive money by making verbal choices for either option. On the 5th day, participants were administered 10 puffs of their usual brand of cigarette in the morning and later chose between smoking and money by making finger presses on a computer mouse in a progressive ratio self-administration task. Later on the 5th day participants also underwent a smoking cue exposure session. The 8th-11th test days were identical to the 1st-4th test days with the exception that during one of the test weeks de-nicotinized cigarettes were available, and during the other nicotinized cigarettes were available. Nicotinized cigarettes were always administered on the 5th and 12th days. On some measures PIO increased indicators of abuse potential, though this effect was typically not statistically significant. However, PIO did significantly reduce measures of craving.

Abuse liability of intravenous buprenorphine vs. buprenorphine/naloxone: Importance of absolute naloxone amount.

BACKGROUND: This study sought to determine the relative importance of a range of Bup/Nx doses compared to Bup alone in producing subjective and reinforcing effects. METHODS: Heroin-using volunteers (n=13) were transitioned onto daily oral hydromorphone (40mg). Laboratory sessions assessed the reinforcing and subjective effects of intravenous (IV) doses of Bup (1.51, 2.16, 6.15, and 8.64mg) and Bup/Nx (1.51/0.44, 2.16/0.61, 6.15/1.71, and 8.64/2.44mg). Placebo (Pbo), heroin (25mg) and Nx (0.3mg) were tested as neutral, positive, and negative controls, respectively. RESULTS: IV Bup alone was self-administered substantially less than IV heroin, though the two largest doses of Bup produced positive subjective effects, drug "Liking" (0-100mm), which were comparable to heroin (mean difference: Heroin vs Bup 6.15mg: -3.4mm, Heroin vs Bup 8.64mg: -11.3mm). All indicators of abuse potential seen with IV Bup alone were substantially decreased with the addition of Nx. All Bup/Nx combinations produced ratings of aversive effects, "Bad", which were comparable to, or greater than IV, Nx. On three of the four measures of aversive effects, the largest difference is seen with the 8.64 vs 8.64/2.44 condition. CONCLUSIONS: This study further demonstrates the ability of the Bup/Nx combination to deter IV use. Although none of the Bup/Nx combinations showed indications of abuse potential, formulations with larger absolute Nx, may be less abusable as they precipitate a greater degree of withdrawal.

Effects of Ibudilast on the Subjective, Reinforcing, and Analgesic Effects of Oxycodone in Recently Detoxified Adults with Opioid Dependence.

Ibudilast, a nonselective phosphodiesterase inhibitor, is used clinically in Asia for the treatment of asthma and poststroke dizziness. Recent preclinical studies have suggested that it also inhibits glial cell activation in rodents, and may alter opioid-mediated effects, including analgesia and withdrawal symptoms. The effects of ibudilast on the abuse potential of opioids in humans are largely unknown. The present study was designed to examine the influence of ibudilast on subjective (including drug craving), reinforcing, and analgesic effects of oxycodone in human volunteers diagnosed with opioid dependence (equivalent to moderate-severe opioid use disorder). Non-treatment-seeking opioid-dependent male volunteers (n=11) underwent an in-patient detoxification with morphine, followed by maintenance on placebo (0 mg b.i.d.) and active ibudilast (50 mg b.i.d.). Under each maintenance dose, six experimental sample and choice sessions were completed involving oral oxycodone administration (0, 15, and 30 mg/70 kg, p.o.). Subjective effects of oxycodone and drug craving were measured with visual analog scales (VAS) and a Drug Effects Questionnaire. The cold pressor test was used to produce pain, and a modified progressive-ratio choice procedure was used to measure the reinforcing effects of oxycodone. Under the active ibudilast condition compared with the placebo condition, ratings of drug liking following 15 mg of oxycodone were decreased significantly. The mean drug breakpoint value was also significantly lower in the active vs the placebo ibudilast condition under the 15 mg oxycodone condition, but not significantly lower under the 30 mg oxycodone condition. Heroin craving was significantly reduced under active ibudilast vs placebo, and similar effects were observed for tobacco and cocaine craving. Furthermore, mean subjective ratings of pain were lower in the active ibudilast condition. Our data suggest that ibudilast may be useful for treating opioid use disorders and it may enhance the analgesic effects of oxycodone.

The effects of pioglitazone, a PPARγ receptor agonist, on the abuse liability of oxycodone among nondependent opioid users.

AIMS: Activation of PPARγ by pioglitazone (PIO) has shown some efficacy in attenuating addictive-like responses in laboratory animals. The ability of PIO to alter the effects of opioids in humans has not been characterized in a controlled laboratory setting. The proposed investigation sought to examine the effects of PIO on the subjective, analgesic, physiological and cognitive effects of oxycodone (OXY). METHODS: During this investigation, nondependent prescription opioid abusers (N=17 completers) were maintained for 2-3weeks on ascending daily doses of PIO (0mg, 15mg, 45mg) prior to completing a laboratory session assessing the aforementioned effects of OXY [using a within-session cumulative dosing procedure (0, 10, and 20mg, cumulative dose=30mg)]. RESULTS: OXY produced typical mu opioid agonist effects: miosis, decreased pain perception, and decreased respiratory rate. OXY also produced dose-dependent increases in positive subjective responses. Yet, ratings such as: drug "liking," "high," and "good drug effect," were not significantly altered as a function of PIO maintenance dose. DISCUSSION: These data suggest that PIO may not be useful for reducing the abuse liability of OXY. These data were obtained with a sample of nondependent opioid users and therefore may not be applicable to dependent populations or to other opioids. Although PIO failed to alter the abuse liability of OXY, the interaction between glia and opioid receptors is not well understood so the possibility remains that medications that interact with glia in other ways may show more promise.

Baseline characteristics of patients predicting suitability for rapid naltrexone induction.

BACKGROUND AND OBJECTIVES: Extended-release (XR) injection naltrexone has proved promising in the treatment of opioid dependence. Induction onto naltrexone is often accomplished with a procedure known as rapid naltrexone induction. The purpose of this study was to evaluate pre-treatment patient characteristics as predictors of successful completion of a rapid naltrexone induction procedure prior to XR naltrexone treatment. METHODS: A chart review of 150 consecutive research participants (N = 84 completers and N = 66 non-completers) undergoing a rapid naltrexone induction with the buprenorphone-clonidine procedure were compared on a number of baseline demographic, clinical and psychosocial factors. Logistic regression was used to identify client characteristics that may predict successful initiation of naltrexone after a rapid induction-detoxification. RESULTS: Patients who failed to successfully initiate naltrexone were younger (AOR: 1.040, CI: 1.006, 1.075), and using 10 or more bags of heroin (or equivalent) per day (AOR: 0.881, CI: 0.820, 0.946). Drug use other than opioids was also predictive of failure to initiate naltrexone in simple bivariate analyses, but was no longer significant when controlling for age and opioid use level. CONCLUSIONS: Younger age, and indicators of greater substance dependence severity (more current opioid use, other substance use) predict difficulty completing a rapid naltrexone induction procedure. Such patients might require a longer period of stabilization and/or more gradual detoxification prior to initiating naltrexone. SCIENTIFIC SIGNIFICANCE: Our study findings identify specific characteristics of patients who responded positively to rapid naltrexone induction.

Abuse potential of intranasal buprenorphine versus buprenorphine/naloxone in buprenorphine-maintained heroin users.

In spite of the clinical utility of buprenorphine, parenteral abuse of this medication has been reported in several laboratory investigations and in the real world. Studies have demonstrated lower abuse liability of the buprenorphine/naloxone combination relative to buprenorphine alone. However, clinical research has not yet examined the utility of the combined formulation to deter intranasal use in a buprenorphine-maintained population. Heroin-using volunteers (n = 12) lived in the hospital for 8-9 weeks and were maintained on each of three sublingual buprenorphine doses (2, 8, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intranasal doses of buprenorphine (8, 16 mg), buprenorphine/naloxone (8/2, 8/8, 8/16, 16/4 mg) and controls (placebo, heroin 100 mg, naloxone 4 mg) were assessed. Intranasal buprenorphine alone typically produced increases in positive subjective effects and the 8 mg dose was self-administered above the level of placebo. The addition of naloxone dose dependently reduced positive subjective effects and increased aversive effects. No buprenorphine/naloxone combination dose was self-administered significantly more than placebo. These data suggest that within a buprenorphine-dependent population, intranasal buprenorphine/naloxone has reduced abuse potential in comparison to buprenorphine alone. These data strongly argue in favor of buprenorphine/naloxone rather than buprenorphine alone as the more reasonable option for managing the risk of buprenorphine misuse.

Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use.

The concurrent use of opioids, benzodiazepines (BZDs), and/or alcohol poses a formidable challenge for clinicians who manage chronic pain. While the escalating use of opioid analgesics for the treatment of chronic pain and the concomitant rise in opioid-related abuse and misuse are widely recognized trends, the contribution of combination use of BZDs, alcohol, and/or other sedative agents to opioid-related morbidity and mortality is underappreciated, even when these agents are used appropriately. Patients with chronic pain who use opioid analgesics along with BZDs and/or alcohol are at higher risk for fatal/nonfatal overdose and have more aberrant behaviors. Few practice guidelines for BZD treatment are readily available, especially when they are combined clinically with opioid analgesics and other central nervous system-depressant agents. However, coadministration of these agents produces a defined increase in rates of adverse events, overdose, and death, warranting close monitoring and consideration when treating patients with pain. To improve patient outcomes, ongoing screening for aberrant behavior, monitoring of treatment compliance, documentation of medical necessity, and the adjustment of treatment to clinical changes are essential. In this article, we review the prevalence and pharmacologic consequences of BZDs and/or alcohol use among patients with pain on chronic opioid therapy, as well as the importance of urine drug testing, an indispensable tool for therapeutic drug monitoring, which helps to ensure the continued safety of patients. Regardless of risk or known aberrant drug-related behaviors, patients on chronic opioid therapy should periodically undergo urine drug testing to confirm adherence to the treatment plan.

Effects of acute oral naltrexone on the subjective and physiological effects of oral D-amphetamine and smoked cocaine in cocaine abusers.

Despite the prevalent worldwide abuse of stimulants, such as amphetamines and cocaine, no medications are currently approved for treating this serious public health problem. Both preclinical and clinical studies suggest that the opioid antagonist naltrexone (NTX) is effective in reducing the abuse liability of amphetamine, raising the question of whether similar positive findings would be obtained for cocaine. The purpose of this study was to evaluate the ability of oral NTX to alter the cardiovascular and subjective effects of D-amphetamine (D-AMPH) and cocaine (COC). Non-treatment-seeking COC users (N=12) completed this 3-week inpatient, randomized, crossover study. Participants received 0, 12.5, or 50 mg oral NTX 60 min before active or placebo stimulant administration during 10 separate laboratory sessions. Oral AMPH (0, 10, and 20 mg; or all placebo) was administered in ascending order within a laboratory session using a 60-min interdose interval. Smoked COC (0, 12.5, 25, and 50 mg; or all placebo) was administered in ascending order within a laboratory session using a 14-min interdose interval. Active COC and AMPH produced dose-related increases in cardiovascular function that were of comparable magnitude. In contrast, COC, but not AMPH, produced dose-related increases in several subjective measures of positive drug effect (eg, high, liking, and willingness to pay for the drug). NTX did not alter the cardiovascular effects of AMPH or COC. NTX also did not alter positive subjective ratings after COC administration, but it did significantly reduce ratings of craving for COC and tobacco during COC sessions. These results show that (1) oral AMPH produces minimal abuse-related subjective responses in COC smokers, and (2) NTX reduces craving for COC and tobacco during COC sessions. Future studies should continue to evaluate NTX as a potential anti-craving medication for COC dependence.

Buprenorphine/naloxone as a promising therapeutic option for opioid abusing patients with chronic pain: reduction of pain, opioid withdrawal symptoms, and abuse liability of oral oxycodone.

Few studies have examined abuse of prescription opioids among individuals with chronic pain under buprenorphine/naloxone (Bup/Nx) maintenance. The current 7-week inpatient study assessed oral oxycodone self-administration by patients with chronic pain who had a history of opioid abuse. Participants (n=25) were transitioned from their preadmission prescribed opioid to Bup/Nx. All of the participants were tested under each of the sublingual Bup/Nx maintenance doses (2/0.5, 8/2 or 16/4 mg) in random order. During each maintenance period, participants could self-administer oxycodone orally (0, 10, 20, 40 or 60 mg prescription opioids) or receive money during laboratory sessions. Drug choice (percentage) was the primary dependent variable. Subjective ratings of clinical pain and withdrawal symptoms also were measured. Mann-Whitney tests compared percentage of drug choice for each active oxycodone dose to placebo. Logistic regression analyses identified correlates of oxycodone preference, defined as 60% or greater choice of oxycodone compared to money. Pain was significantly reduced while participants were maintained on Bup/Nx compared to preadmission ratings. No differences in percentage drug choice were observed between the active oxycodone doses and placebo under each Bup/Nx maintenance dose. However, factors associated with oxycodone preference were lower Bup/Nx maintenance dose, more withdrawal symptoms and more pain. These data suggest that Bup/Nx was effective in reducing pain and supplemental oxycodone use. Importantly, adequate management of pain and withdrawal symptoms by Bup/Nx may reduce oxycodone preference in this population.

Polydrug abuse: a review of opioid and benzodiazepine combination use.

This paper reviews studies examining the pharmacological interactions and epidemiology of the combined use of opioids and benzodiazepines (BZDs). A search of English language publications from 1970 to 2012 was conducted using PubMed and PsycINFO(®). Our search found approximately 200 articles appropriate for inclusion in this paper. While numerous reports indicate that the co-abuse of opioids and BZDs is ubiquitous around the world, the reasons for the co-abuse of these medications are not entirely clear. Though the possibility remains that opioid abusers are using BZDs therapeutically to self-medicate anxiety, mania or insomnia, the data reviewed in this paper suggest that BZD use is primarily recreational. For example, co-users report seeking BZD prescriptions for the purpose of enhancing opioid intoxication or "high," and use doses that exceed the therapeutic range. Since there are few clinical studies investigating the pharmacological interaction and abuse liability of their combined use, this hypothesis has not been extensively evaluated in clinical settings. As such, our analysis encourages further systematic investigation of BZD abuse among opioid abusers. The co-abuse of BZDs and opioids is substantial and has negative consequences for general health, overdose lethality, and treatment outcome. Physicians should address this important and underappreciated problem with more cautious prescribing practices, and increased vigilance for abusive patterns of use.