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Vivitrol and Depression
Abstract
The introduction of a long-acting depot formulation of naltrexone (Vivitrol), FDA approved for the treatment of alcohol and opioid dependence in 2006 and 2010, respectively, has raised safety concerns including: (1) risk of development or exacerbation of depressive symptoms during treatment; and (2) increased risk of opioid overdose after treatment cessation. The concern that treatment with long-acting naltrexone may lead to depressive symptoms has a plausible theoretical basis given the medication’s blockade of µ-opioid receptors, which, when activated, lead to positive mood states. Risk of depression and suicidality are listed as potential adverse reactions in the manufacturer’s insert and are commonly relayed to patients during informed consent for treatment (http://www.vivitrol.com/About/Safety). However, these concerns may not be substantiated. Given that depression is commonly comorbid with alcohol and opioid dependence, concerns about the exacerbation of depression could prevent many individuals from receiving beneficial treatment as more evidence emerges supporting the efficacy of depot naltrexone. A recent multisite randomized trial found that opioid-dependent subjects receiving long-acting naltrexone were far more likely to remain abstinent over 6 months of treatment (median of 90% abstinent weeks for naltrexone group vs. 35% for placebo group). In this paper, we review the existing literature on the effects of short-acting and long-acting naltrexone on mood as well as effects on preexisting depressive disorders, with the aim of assisting clinicians in selecting appropriate patients for treatment with this medication.
... Vivitrol® is administered via the IM route for the management of alcohol and opioid dependence. The efficacy of naltrexone-loaded microspheres has been demonstrated in several clinical trials, with much longer-lasting abstinence to and greater reduction in alcohol and opioid consumption/craving than placebo [124,125]. The successful development of Vivitrol® provides a promising alternative to oral naltrexone formulations, while the latter was limited by poor patient compliance despite its demonstrated ability to reduce alcohol and opioid reinforcement [87,88]. ...
Long acting injectable formulations have been developed to sustain the action of drugs
in the body over desired periods of time. These delivery platforms have been utilized
for both systemic and local drug delivery applications. This review gives an overview of
long acting injectable systems that are currently in clinical use. These products are
categorised in three different groups: biodegradable polymeric systems, including
microparticles and implants; micro and nanocrystal suspensions and oil-based
formulations. Furthermore, the applications of these drug delivery platforms for the
management of various chronic diseases are summarized. Finally, this review
addresses industrial challenges regarding the development of long acting injectable
formulations.
Purpose: Cigarette use is highly prevalent in psychiatric populations. Studies suggest that smokeless tobacco use is not significantly associated with past-year psychiatric morbidity, with evidence that tobacco use differ among sexes. The relationships between current tobacco use and past-year serious psychological distress, major depressive episode and anxiety disorder were therefore examined. Sex differences in the aforementioned relationship were also examined.
Methods: A total of 133,221 adults from four successive independent samples of the 2005–2008 National Survey on Drug Use and Health were included. Prevalence odds ratios and 95 % confidence intervals were calculated using multivariable logistic regression adjusting for demographic factors, survey year, pregnancy (women only), past-year medical morbidity, past-year psychiatric comorbidity, and past-year substance use disorders.
Results: No associations were demonstrated among smokeless tobacco users. Statistically significant sex differences were found for current tobacco use and serious psychological distress (p < 0.001). Both male and female smokers were significantly more likely to have serious psychological distress and anxiety disorder compared to never users, while only female smokers were more likely to have major depressive episode. The strongest associations were found for anxiety disorder among all adults as well as both sexes.
Conclusions: The null associations for both sexes for smokeless tobacco may support a reduced risk profile. Female cigarette smokers may be more vulnerable to subclinical distress and depression than males. Studies using other nationally representative samples are needed to confirm these data.
The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n=18), we used an μ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids have a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well being in the social environment.Molecular Psychiatry advance online publication, 20 August 2013; doi:10.1038/mp.2013.96.
Context Sustained-release naltrexone implants may improve outcomes of nonagonist treatment of opioid addiction.
Objective To compare outcomes of naltrexone implants, oral naltrexone hydrochloride, and nonmedication treatment.
Design Six-month double-blind, double-dummy, randomized trial.
Setting Addiction treatment programs in St Petersburg, Russia.
Participants Three hundred six opioid-addicted patients recently undergoing detoxification.
Interventions Biweekly counseling and 1 of the following 3 treatments for 24 weeks: (1) 1000-mg naltrexone implant and oral placebo (NI+OP group; 102 patients); (2) placebo implant and 50-mg oral naltrexone hydrochloride (PI+ON group; 102 patients); or (3) placebo implant and oral placebo (PI+OP group; 102 patients).
Main Outcome Measure Percentage of patients retained in treatment without relapse.
Results By month 6, 54 of 102 patients in the NI+OP group (52.9%) remained in treatment without relapse compared with 16 of 102 patients in the PI+ON group (15.7%) (survival analysis, log-rank test, P < .001) and 11 of 102 patients in the PI+OP group (10.8%) (P < .001). The PI+ON vs PI+OP comparison showed a nonsignificant trend favoring the PI+ON group (P = .07). Counting missing test results as positive, the proportion of urine screening tests yielding negative results for opiates was 63.6% (95% CI, 60%-66%) for the NI+OP group; 42.7% (40%-45%) for the PI+ON group; and 34.1% (32%-37%) for the PI+OP group (P < .001, Fisher exact test, compared with the NI+OP group). Twelve wound infections occurred among 244 implantations (4.9%) in the NI+OP group, 2 among 181 (1.1%) in the PI+ON group, and 1 among 148 (0.7%) in the PI+OP group (P = .02). All events were in the first 2 weeks after implantation and resolved with antibiotic therapy. Four local-site reactions (redness and swelling) occurred in the second month after implantation in the NI+OP group (P = .12), and all resolved with antiallergy medication treatment. Other nonlocal-site adverse effects were reported in 8 of 886 visits (0.9%) in the NI+OP group, 4 of 522 visits (0.8%) in the PI+ON group, and 3 of 394 visits (0.8%) in the PI+ON group; all resolved and none were serious. No evidence of increased deaths from overdose after naltrexone treatment ended was found.
Conclusions The implant is more effective than oral naltrexone or placebo. More patients in the NI+OP than in the other groups develop wound infections or local irritation, but none are serious and all resolve with treatment.
Trial Registration clinicaltrials.gov Identifier: NCT00218426
Opioid dependence is a condition with serious clinical ramifications. Treatment has focused on detoxification, agonist therapy with methadone or buprenorphine, or remission maintenance with the opioid antagonist, naltrexone. Treatment with oral naltrexone has been limited by poor treatment adherence and relapse. Studies with long-acting formulations have shown increased treatment adherence. Extended-release injectable naltrexone has been used for the treatment of alcohol dependence, and has recently received an indication for treatment of opioid dependence from the US Food and Drug Administration. Dosing occurs once monthly and existing data with long-acting naltrexone supports efficacy of treatment for opioid dependence; however published data is sparse. Treatment with long-acting naltrexone should be monitored for hepatotoxicity, and patients should be made aware of increased risk of overdose with administration of opioids during and immediately after discontinuation of long-acting naltrexone.
Opioid neurotransmission mediates hedonic value of sweet tastants; their intake may be exaggerated by the consumption of exogenous opioids (e.g., opioid dependence). Sweet Taste Test (STT) is a validated quantitative instrument assessing taste perception and hedonic features of sugar (sucrose) using a randomized and double-blind administration at five different sucrose concentrations ranging from 0.05 to 0.83 M.
The STT and cue-induced craving procedure were administered to opioid-dependent patients (n = 15) before and 1 week after the injection of a long-acting depot naltrexone (XRNT) preparation.
Analyses of covariance, employing sucrose concentration and its perceived taste as covariates, showed that XRNT therapy significantly reduced the self-reported hedonic and motivational characteristics of sucrose. Greater reductions in both these characteristics were associated with more diminution in the cue-induced opioid craving.
Opioid antagonism in opioid-dependent subjects leads to a smaller sweet taste reward, which, in turn, may be proportional to decreased opioid craving. These pilot results support the heuristic value of the STT as a potential marker of the XRNT treatment response and call for further inquiry into potential clinical applications of the test.
Acute mood changes occur with various forms of physical activity. Increased levels of endogenous opioids (endorphins) in response to exercise may mediate activity-induced shifts in mood state. Thirteen female and six male aerobics class participants aged 20-46 years received the opiate receptor antagonist naltrexone and a placebo in randomized, double-blind crossover fashion on two separate occasions at the same 75-min high-intensity aerobics class. Mood states were assessed before and after each class, which were spaced 5 days apart, using the Profile of Mood States questionnaire (POMS), a mood adjective checklist, and a Visual Analogue Scale (VAS) which measured mood in relation to several emotional extremes. Mood changes over the course of each aerobics class were compared in the naltrexone and placebo groups. For men and women, significant differences between conditions were observed in overall mood by both the POMS (P less than 0.005) and VAS (P less than 0.02). There were significant differences between conditions for most subscales of each mood instrument (P less than 0.05); with the placebo, mood states became calmer, more relaxed and pleasant, tending away from depression, anger and confusion. Positive mood shifts did not occur when subjects were preloaded with naltrexone, suggesting that activity-generated mood changes are mediated through endorphinergic mechanisms.
Human affective responses appear to be regulated by limbic and paralimbic circuits. However, much less is known about the neurochemical systems engaged in this regulation. The mu-opioid neurotransmitter system is distributed in, and thought to regulate the function of, brain regions centrally implicated in affective processing.
To examine the involvement of mu-opioid neurotransmission in the regulation of affective states in healthy human volunteers.
Measures of mu-opioid receptor availability in vivo were obtained with positron emission tomography and the mu-opioid receptor selective radiotracer [11C]carfentanil during a neutral state and during a sustained sadness state. Subtraction analyses of the binding potential maps were then performed within subjects, between conditions, on a voxel-by-voxel basis.
Imaging center at a university medical center.
Fourteen healthy female volunteers. Intervention Sustained neutral and sadness states, randomized and counterbalanced in order, elicited by the cued recall of an autobiographical event associated with that emotion.
Changes in mu-opioid receptor availability and negative and positive affect ratings between conditions. Increases or reductions in the in vivo receptor measure reflect deactivation or activation of neurotransmitter release, respectively.
The sustained sadness condition was associated with a statistically significant deactivation in mu-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, amygdala, and inferior temporal cortex. This deactivation was reflected by increases in mu-opioid receptor availability in vivo. The deactivation of mu-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, and amygdala was correlated with the increases in negative affect ratings and the reductions in positive affect ratings during the sustained sadness state.
These data demonstrate dynamic changes in mu-opioid neurotransmission in response to an experimentally induced negative affective state. The direction and localization of these responses confirms the role of the mu-opioid receptor system in the physiological regulation of affective experiences in humans.
Naltrexone is frequently used for the treatment of opioid or alcohol dependence. However, the reports on its potential to worsen affective disorders are contradicting. Here we report on a patient with combined alcohol and opioid dependence whose co-morbid major depression deteriorated reversibly and repeatedly under naltrexone. By exchanging buprenorphine for naltrexone, his depression and craving for alcohol and opioids disappeared. This underlines the close interaction between depression, substance dependence and the opioid system.
Naltrexone treatment has demonstrated some advantages for special populations of heroin addicted individuals, but patients' compliance seems to be very poor, with a low adherence and low retention rate. Kappa-opioid system overdrive seems to contribute to opioid protracted abstinence syndrome, with dysphoria and psychosomatic symptoms during naltrexone treatment. The objective of this observational study was to determine the effectiveness of a functional k antagonist in improving naltrexone treatment outcome. A partial mu agonist/kappa antagonist (buprenorphine) and a mu antagonist (naltrexone) were combined during a 12 weeks protocol, theoretically leaving k antagonism as the major medication effect. Sixty patients were submitted to outpatient rapid detoxification utilizing buprenorphine and opioid antagonists. Starting on the fifth day, 30 patients (group A) received naltrexone alone. Alternatively, 30 patients (group B) received naltrexone (50mg oral dose) plus buprenorphine (4 mg sublingual) for the 12 weeks of the observational study. The endpoints of the study were: retention in treatment, negative urinalyses, changes in psychological symptoms (Symptom Checklist-90 Revised: SCL-90) and craving scores (visual analysis scale (VAS)). Thirty-four subjects (56.67%) completed the 12 weeks study. Twenty-one patients (35.0%) had all urine samples negative for opiates and cocaine. nine subjects (15.0%) had urine samples negative for cocaine and opiates for the last 4 weeks of the study. five subjects (8.3%) continued to use cocaine during the 12 weeks of the study. No significant change in pupillary diameter after buprenorphine administration was evidenced during clinical observations from baseline across the weekly measurements. Retention rates in group A (naltrexone) and group B (naltrexone + buprenorphine) at week 12 were respectively 40% (12 patients) and 73.33% (22 patients), with a significant difference in favour of group B (p= 0.018). Patients treated with naltrexone in combination with buprenorphine (B patients) showed a significantly lower rate of positive urines for morphine (4.45%) and cocaine metabolites (9.09%) than those treated with naltrexone alone (A) (25%, morphine; 33.33% cocaine) (p< 0.05; p< 0.05). Irritability, depression, tiredness, psychosomatic symptoms and craving scores decreased significantly less in Group A patients than in group B patients. The dysfunction of opioid system with kappa receptors hyper-activation provoked by heroin exposure, probably underlying dysphoric and psychosomatic symptoms during naltrexone treatment, seems to be counteracted, at least in part, by buprenorphine. The combination of buprenorphine and naltrexone may significantly improve the outcome of opioid antagonists treatment in terms of retention, negative urinalyses, and reduced dysphoria, mood symptoms and craving.
Dysphoria and depression have been cited as side effects of the opioid antagonist naltrexone. We aimed to assess whether depressive symptoms are a clinically relevant side effect in a population receiving naltrexone as a treatment for opioid dependence.
We carried out a randomized controlled, open-label trial comparing rapid opiate detoxification under anesthesia and naltrexone treatment with continued methadone maintenance at the Alcohol and Drug Service, Royal Brisbane and Women's Hospital, Brisbane, Australia. The study subjects were patients stabilized on methadone maintenance treatment for heroin dependence who wished to transfer to naltrexone treatment. The Beck Depression Inventory, State-Trait Anxiety Inventory and Opiate Treatment Index subscales for heroin use and social functioning were used at baseline and follow-up assessments at 1, 2, 3 and 6 months.
Forty-two participants were allocated to receive naltrexone treatment, whereas 38 continued methadone maintenance as the control condition. Participants who received naltrexone did not exhibit worsening of depressive symptoms. In participants attending all follow-up assessments, there was a trend for those receiving naltrexone to exhibit an improvement in depression over time compared with the control group. Participants who were adherent to naltrexone treatment exhibited fewer depressive symptoms than those who were nonadherent.
These results suggest that depression need not be considered a common adverse effect of naltrexone treatment or a treatment contraindication and that engaging with or adhering to naltrexone treatment may be associated with fewer depressive symptoms.
Chronic opioid antagonist treatment up-regulates opioid receptors and produces functional supersensitivity. Although opioid antagonists vary from neutral to inverse, the role of antagonist efficacy in mediating the chronic effects of opioid antagonists is not known. In this study, the effects of two putative inverse agonists (naltrexone, naloxone) and a putative neutral antagonist (6beta-naltrexol) were examined. Initially, peak effect (40 min, naltrexone and naloxone; 70 min, 6beta-naltrexol) and relative potency to antagonize morphine analgesia were determined (relative potencies = 1, 2, and 16, 6beta-naltrexol, naloxone, and naltrexone, respectively). Next, mice were infused for 7 days with naloxone (0.1-10 mg/kg/day), naltrexone (10 or 15 mg s.c. pellet), or 6beta-naltrexol (0.2-20 mg/kg/day), and spinal micro-opioid receptor density was examined, or morphine analgesia dose-response studies were conducted. All antagonists up-regulated mu-opioid receptors (60-122%) and induced supersensitivity (1.8-2.0-fold increase in morphine potency). There were no differences in antagonist potency to produce up-regulation or supersensitivity. These data suggest that opioid antagonist-induced mu-opioid receptor up-regulation and supersensitivity require occupancy of the receptor and that antagonist efficacy is not critical. Finally, the ED(50) to precipitate withdrawal jumping was examined in morphine-dependent mice. Naltrexone, naloxone, and 6beta-naltrexol produced withdrawal jumping, although potencies relative to 6beta-naltrexol were 211, 96, and 1, respectively. Thus, antagonist potency to precipitate opioid withdrawal was related to inverse agonist efficacy. Overall, the estimated relative potency of the opioid antagonists was a function of the outcome measured, and inverse agonist activity was not required for mu-opioid receptor up-regulation and supersensitivity.
A sample of 25 heroin-addicted patients, diagnosed according to DSM-III-R criteria, were divided into two subgroups and treated with naltrexone alone or with a combination of naltrexone and fluoxetine. After 6 months of treatment, the 13 patients who received naltrexone in association with the antidepressant showed a higher probability of abstinence from heroin compared with the 12 subjects treated with the narcotic antagonist alone. The possible mechanism of the fluoxetine effect is discussed.
(1) A significant increase in integrated plasma luteinizing hormone (LH) levels occurred following oral administration of 50 mg of naltrexone to seven healthy adult males who had no past history of opiate use or abuse. (2) All subjects were able to identify naltrexone from placebo in a double-blind study. (3) All subjects reported that naltrexone produced dysphoric effects including fatigue, sleepiness, light-headedness, nausea, sweating and occasional feelings of unreality. (4) Three subjects reported recurrent spontaneous penile erections following naltrexone administration. (5) No dysphoric side effects or penile erections occurred following placebo administration. (6) These findings indicate that naltrexone affects both mood states and sexual function in adult males who have no history of opiate abuse and suggests that these effects may be mediated by hypothalamic and pituitary mechanisms which also subserve LH secretory activity.
To describe drug use and safety with intramuscular injectable extended-release naltrexone (XR-NTX) in opioid dependence during a 1-year open-label extension phase.
Following 6 months of randomized, double-blind, placebo (PBO)-controlled injections given every 28 days, patients receiving XR-NTX 380 mg continued and PBO patients were switched to open-label XR-NTX, with monthly individual drug counseling, for a further year.
Thirteen clinical sites in Russia.
Adult opioid-dependent outpatients.
Monthly urine samples; reports of craving and functioning; adverse events.
For the open-label extension (n = 114), 67 continued on XR-NTX and 47 switched from PBO during the double-blind phase to XR-NTX during the open-label phase. Overall, 62.3% (95% CI: 52.7%, 71.2%) completed the extension. Discontinuation occurred most commonly because of withdrawal of consent (18.4%) and loss to follow-up (11.4%); two patients discontinued as a result of lack of efficacy and one because of adverse events. Urine testing revealed that 50.9% (41.5%, 60.4%) were abstinent from opioids at all assessments during the 1-year open-label phase. Adverse events reported by 21.1% of patients were judged to be study drug-related. Injection site reactions were infrequent (6.1%) and the majority were mild. Elevations in liver function tests occurred for 16.7% of patients, but none of these elevations was judged to be clinically significant. No patients died, overdosed or discontinued as a result of severe adverse events.
During a 1-year open-label extension phase of injectable XR-NTX for the prevention of relapse in opioid dependence, 62.3% of patients completed the phase and 50.9% were abstinent from opioids. No new safety concerns were evident.
The clinical application of the narcotic antagonist, naltrexone for the treatment of opioid dependence has been minimal. This study evaluated the impact of a multi-component, manualized, psychosocial protocol designed to enhance the clinical value of naltrexone for opioid dependence treatment. Eighty-one detoxified individuals meeting DSM-IV criteria for opioid dependence were inducted onto naltrexone and randomly assigned to either a standard (ST) group, with monthly medical monitoring visits, or an enhanced (EN) group in which participants received counseling and educational interventions three times per week. EN group participants took more study medication, were retained in treatment longer, used less opioids while in treatment and showed greater improvement on a number of psychological/affective dimensions. The improved performance of the EN group was relatively short-lived as there were no significant group differences at 6- or 12-month post-admission follow-up points.
In a study evaluating naltrexone with either an intensive psychosocial protocol or standard community treatment for opioid dependence, 13 of 81 subjects overdosed within a 12-month period of study participation. There were four fatalities, one of which was a suicide. Among the nine nonfatal overdoses, there were four suicide attempts. Characteristics of subjects and naltrexone-taking are described.
Among the more consistent observations in patients with major depression is dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis presenting as elevation of basal cortisol, dexamethasone-mediated negative feedback resistance, increased cerebrospinal fluid levels of corticotropin-releasing factor (CRF), and a blunted adrenocorticotropic hormone (ACTH) response to challenge with exogenous CRF. These features appear to be state, rather than trait markers, and are normalized upon successful treatment. These pathophysiologic adaptations may arise from defects in central drive to the neuroendocrine hypothalamus, disruption of normal adrenocortical hormone receptor function or a modification of HPA axis function at any level. Functional assessment of the HPA axis is thought to provide a window into central nervous system operation that may be of diagnostic value in this and other affective disorders regardless of whether CRF and glucocorticoids are directly involved in the origin of major depression or merely exacerbate the consequences of other primary defects.
Opioid dependence is associated with low rates of treatment-seeking, poor adherence to treatment, frequent relapse, and major societal consequences. We aimed to assess the efficacy, safety, and patient-reported outcomes of an injectable, once monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) for treatment of patients with opioid dependence after detoxification.
We did a double-blind, placebo-controlled, randomised, 24-week trial of patients with opioid dependence disorder. Patients aged 18 years or over who had 30 days or less of inpatient detoxification and 7 days or more off all opioids were enrolled at 13 clinical sites in Russia. We randomly assigned patients (1:1) to either 380 mg XR-NTX or placebo by an interactive voice response system, stratified by site and gender in a centralised, permuted-block method. Participants also received 12 biweekly counselling sessions. Participants, investigators, staff , and the sponsor were masked to treatment allocation. The primary endpoint was the response profile for confirmed abstinence during weeks 5–24, assessed by urine drug tests and self report of non-use. Secondary endpoints were self-reported opioid-free days, opioid craving scores, number of days of retention, and relapse to physiological opioid dependence. Analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00678418.
Between July 3, 2008, and Oct 5, 2009, 250 patients were randomly assigned to XR-NTX (n=126) or placebo (n=124). The median proportion of weeks of confirmed abstinence was 90·0% (95% CI 69·9–92·4) in the XR-NTX group compared with 35·0% (11·4–63·8) in the placebo group (p=0·0002). Patients in the XR-NTX group self-reported a median of 99·2% (range 89·1–99·4) opioid-free days compared with 60·4% (46·2–94·0) for the placebo group (p=0·0004). The mean change in craving was –10·1 (95% CI –12·3 to –7·8) in the XR-NTX group compared with 0·7 (–3·1 to 4·4) in the placebo group (p<0·0001). Median retention was over 168 days in the XR-NTX group compared with 96 days (95% CI 63–165) in the placebo group (p=0·0042). Naloxone challenge confirmed relapse to physiological opioid dependence in 17 patients in the placebo group compared with one in the XR-NTX group (p<0·0001). XR-NTX was well tolerated. Two patients in each group discontinued owing to adverse events. No XR-NTX-treated patients died, overdosed, or discontinued owing to severe adverse events.
XR-NTX represents a new treatment option that is distinct from opioid agonist maintenance treatment. XR-NTX in conjunction with psychosocial treatment might improve acceptance of opioid dependence pharmacotherapy and provide a useful treatment option for many patients.
Alkermes.
To examine the change in total symptoms, and symptom clusters, of depression in newly abstinent opioid-dependent individuals being treated with depot naltrexone (Depotrex; Biotek, Inc., Wellesley, MA).
In a series of opioid-dependent patients (N = 34) treated with naltrexone maintenance and relapse prevention therapy, mood was assessed with a 17-item Hamilton Depression (HAM-D) Scale and subscale scores at baseline, and after naltrexone induction at 2- and 4-week post-baseline. Data were analyzed using generalized estimated equation (GEE) models.
Patients demonstrated high baseline affective burden and significant improvement of depression scores over a 4-week period post-baseline (F(2.66) = 8.88; p = .0004). Somatic and cognitive-affective subscale scores significantly declined as well as the seven individual item scores. By contrast, the "late insomnia" item score significantly increased at 2 weeks post-baseline.
Naltrexone induction and maintenance in newly abstinent opioid-dependent individuals does not appear to be associated with worsening of depression; however, it may be associated with sleep impairment early in treatment.
Background:
Both opioid antagonist administration and cigarette smoking acutely increase hypothalamic-pituitary-adrenal (HPA) axis activity as measured by adrenocorticotropic hormone (ACTH) and cortisol levels. However, male and female smokers may differ in their response to the opioid antagonist naltrexone, which may be partially mediated by sex differences in HPA axis function. Smokers, as a group, have frequently been shown to have HPA axis dysfunction, which may have relevance to the course and maintenance of nicotine dependence. The purpose of this study was to examine possible sex differences in HPA axis function by comparing stress-hormone response to naltrexone within healthy male and female smokers. Additionally, exploratory analyses compared the combined effects of naltrexone and cigarette smoking on hormonal responsivity between the sexes.
Method:
Thirty-eight healthy smokers (22 men) were tested in two separate morning sessions after 12h of smoking abstinence. For women, self-reports of menstrual cycle information were obtained prior to each session (date of last menstruation, cycle length, reproductive phase, etc.). Each participant received 50mg naltrexone or placebo capsule (in random order) and plasma levels of ACTH and cortisol were assessed at regular intervals for several hours. A subgroup of 12 participants underwent a similar, additional session in which they smoked a single cigarette three hours after naltrexone administration.
Results:
Naltrexone significantly increased ACTH and cortisol levels in women, but not men (DrugxSexxTime, p<0.05). A post hoc analysis suggested that women at an estimated 'high estrogen' phase had a greater cortisol response (DrugxEstrogen level, p<0.05) than those at an estimated 'low estrogen' phase. Exploratory analyses showed that smoking a single cigarette potentiated naltrexone-induced increases in ACTH (p<0.05) and cortisol (p<0.01) in all participants.
Conclusion:
The findings support the hypothesis that women are more sensitive to opioid antagonism at the level of the HPA axis. Although further studies are needed to examine mechanisms underlying these responses, both results may have clinical implications for the use of naltrexone as a treatment for nicotine dependence.
Recently, we reported that naltrexone at 150 mg/day significantly decreased cocaine and alcohol use for men but not women with co-occurring cocaine and alcohol dependence. The present study is an exploratory investigation of predictors that explain the different gender responses to naltrexone, with a particular focus on differential predictors of treatment attrition. No significant predictors were associated with treatment discontinuation in men. Women, however, were more likely to discontinue treatment when reporting severe pre-treatment psychiatric problems or nausea while in treatment. Further research on the impact of pre-treatment and in-treatment gender differences with naltrexone is warranted.
The primary objectives of this study were to: (a) examine the neuroendocrine effects of naltrexone vs. placebo by comparing serum cortisol levels; and (b) test the biobehavioral correlates of naltrexone-induced changes in cortisol. Non-treatment seeking heavy drinkers (n=37) completed two intravenous alcohol administrations, one after naltrexone (50 mg) and one after placebo. Cortisol levels were measured at baseline and after alcohol intake (BrAC=0.06 g/dl) on both sessions, as were subjective responses to alcohol. Analyses revealed that naltrexone significantly raised overall cortisol levels compared to placebo. Cortisol levels decreased during alcohol administration and a stronger decrease was observed in the naltrexone condition. Cortisol levels were, in turn, inversely related to some of alcohol's the reinforcing effects (i.e., alcohol 'high,' vigor) and positively associated with some of its unpleasant effects (i.e., sedation and subjective intoxication). These results suggest that naltrexone alters cortisol levels in heavy drinkers and that its effects on subjective responses to alcohol may be related, in part, to naltrexone's ability to activate the HPA-axis.
Naltrexone treatment, used to prevent relapse among former opioid addicts, is reported to have an extraordinary rate of noncompliance. Since activation of opioid receptors produces a sense of well-being, naltrexone's blockade of these receptors might produce dysphoria, which could contribute to noncompliance among addicts under treatment. To test this hypothesis, the authors administered naltrexone to four men who had been free of opioids for 9 to 44 months using a 6-week, placebo-controlled crossover design. One subject dropped out with abstinence-like symptoms, and two others reported mild but significantly greater dysphoria during naltrexone administration. The results suggest that naltrexone may induce mild dysphoria long after addicts stop using opioids.
Naltrexone hydrochloride reportedly produces frequent dysphoria. This has led to speculation regarding the role of endorphins in the etiology of depression. Thirty-six subjects completed an 8-week trial of naltrexone or placebo with frequent mood assessments. No significant differences on POMS scales were noted for either subject group. One subject was discontinued from the study because of a severe dysphoric reaction. Naltrexone does not appear to significantly alter mood over a 2-month time course in nonaddicted, healthy individuals. Subpopulations of patients under physiological or psychological stress may react to naltrexone with dysphoric symptoms.
To examine the influence of endogenous opioids on the hormonal response to isotonic exercise, eight males were studied 2 h after oral administration of placebo or 50 mg naltrexone, a long-lasting opioid antagonist. Venous blood samples were obtained before, during, and after 30 min of bicycle exercise at 70% VO2max. Naltrexone had no effect on resting cardiovascular, endocrine, or serum variables. During exercise epinephrine was higher [mean 433 +/- 100 (SE) pg/ml] at 30 min with naltrexone than during placebo (207 +/- 26 pg/ml, P less than 0.05). Plasma norepinephrine showed the same trend but the difference (2,012 +/- 340 pg/ml with naltrexone and 1,562 +/- 241 pg/ml with placebo) was not significant. Plasma glucose was higher at all times with naltrexone. However, the difference was significant only 10 min into recovery from exercise (104.7 +/- 4.7 vs. 94.5 +/- 2.8 mg/dl). Plasma growth hormone and cortisol increased during recovery and these elevations were significantly (P less than 0.05) augmented by naltrexone. Plasma vasopressin and prolactin increased with exercise as did heart rate, blood pressure, lactic acid, and several serum components; these increases were not affected by naltrexone. Psychological tension or anxiety was lower after exercise compared with before and this improved psychological state was not influenced by the naltrexone treatment. These data suggest that exercise-induced activation of the endogenous opioid system may serve to regulate the secretion of several important hormones (i.e., epinephrine) during and after exercise.
The effects of naltrexone on both mood and cognition were examined in overweight male subjects. Subjects were randomly prescribed, in a double-blind fashion, either placebo or naltrexone for 8 weeks. The results of the study showed that a chronic administration of a high dose of naltrexone (300 mg/day) does not significantly change mood or cognitive functioning among overweight adult men.
The effects of intense exercise on pain perception, mood, and plasma endocrine levels in man were studied under naloxone and saline conditions. Twelve long-distance runners (mean weekly mileage = 41.5) were evaluated on thermal, ischemic, and cold pressor pain tests and on mood visual analogue scales (VAS). Blood was drawn for determination of plasma levels of beta-endorphin-like immunoreactivity (BEir), growth hormone (GH), adrenocorticotrophic hormone (ACTH), and prolactin (PRL). These procedures were undertaken before and after a 6.3 mile run at 85% of maximal aerobic capacity. Subjects participated on two occasions in a double-blind procedure counterbalanced for drug order: on one day they received 2 i.v. injections of naloxone (0.8 mg in 2 ml vehicle each) at 20 min intervals following the run; on the other day, 2 equal volume injections of normal saline (2 ml). Sensory decision theory analysis of the responses to thermal stimulation showed that discriminability, P(A), was significantly reduced post-run under the saline condition, a hypoalgesic effect; response bias, B, was unaffected. Ischemic pain reports were significantly reduced post-run on the saline day, also a hypoalgesic effect. Naloxone reversed the post-run ischemic but not thermal hypoalgesic effects. Joy, euphoria, cooperation, and conscientiousness VAS ratings were elevated post-run; naloxone attenuated the elevation of joy and euphoria ratings only. Plasma levels of BEir, ACTH, GH, and PRL were significantly increased post-run. The results show that long-distance running produces hypoalgesia and mood elevation in man. The effects of naloxone implicate endogenous opioid neural systems as mechanisms of some but not all of the run-induced alterations in mood and pain perception.
Naltrexone was given to ten opiate-free volunteer subjects following the same dosage schedule used for initiating treatment of opiate-dependent persons. During the three-week initiation period, three subjects dropped from the study owing to aversive effects of the drug. The remaining seven subjects reported similar unpleasant but tolerable effects. A separate group of ten volunteer subjects was given single doses of 50 or 100 mg of naltrexone or a naltrexone placebo on three separate occasions using blind controls. These subjects also reported aversive effects. The principal symptoms reported were loss of energy, gastrointestinal disturbances and mental depression. It is possible that these aversive reactions of naltrexone have limited acceptance of the drug as a treatment for opiate-dependent persons.
Naltrexone hydrochloride is the first medication approved in the United States for the treatment of alcohol dependence in almost 50 years. This study was designed to collect safety data in a setting that reflected the expected clinical use of naltrexone.
This was a 12-week, nonrandomized, open-label usage study conducted in 40 alcoholism treatment centers throughout the United States, including free-standing alcoholism treatment programs, university clinics, Veterans Administration hospitals, and office-based primary care practices. Eligible patients were assigned, at the investigators' discretion, to a naltrexone treatment group or to a reference group that did not receive study medication. At study entry, patients must have been abstinent from alcohol for 1 to 6 weeks and enrolled in a psychosocial treatment program for alcoholism. Patients often underrepresented in controlled clinical trials, including women and patients with comorbid medical and psychiatric illness, were eligible. Patients with polysubstance abuse or infection with the human immunodeficiency virus were not excluded.
Of 865 patients enrolled, 570 received naltrexone and 295 were in a reference group. The most common new-onset adverse clinical events in the naltrexone group were nausea (9.8%) and headache (6.6%). Naltrexone was discontinued in 15.0% of patients because of adverse events, most frequently nausea. The results of liver function tests in the naltrexone group were similar to those in the reference group. No death occurred during the study.
This is the largest study to date describing the safety of naltrexone in a heterogeneous population of persons with alcoholism. No new safety concerns were identified.
The authors' goal was to determine whether depression is associated with a greater risk of heavy alcohol consumption in women.
The study was based on a 1-year follow-up of the Baltimore cohort of the National Institute of Mental Health Epidemiologic Catchment Area project. The sample consisted of 1,383 women at risk for heavy alcohol use. History of depression and frequency of lifetime-experienced depressive symptoms were assessed at baseline, and incident cases of heavy drinking were identified 1 year later. After calculating descriptive statistics for the sample, the authors developed a series of logistic regression models to estimate the risk of heavy drinking at follow-up associated with depression status.
The initial estimate of the risk for heavy drinking in women with a history of depressive disorder was 2.60 times greater than the risk in women with no history of depressive disorder. This estimate did not change markedly after adjustment for age, history of antisocial personality disorder, or father's history of heavy drinking (relative risk=2.2). A higher frequency of depressive symptoms was also found to be associated with an elevation in the risk for heavy alcohol use (relative risk=1.09).
These results add to other evidence that depression must be considered in the assessment of vulnerability for heavy alcohol use in women. Further research is needed to clarify the mechanisms of the observed association and to discover whether detection and effective treatment of depression might reduce risk of later alcohol problems.
The absorption of ciprofloxacin has been reported to be impaired by concomitant administration of ferrous sulphate. The effects of sodium ferrous citrate and ferric pyrophosphate, which have been used as extensively as ferrous sulphate, on the absorption of ciprofloxacin were compared with that of ferrous sulphate. The effects of ascorbic acid on the interactions between ciprofloxacin and each iron compound were studied in mice. Mice were treated orally with ciprofloxacin (50 mg kg−1) alone, the iron compound (ferrous sulphate, sodium ferrous citrate or ferric pyrophosphate; 50 mg elemental iron kg−1) alone, ciprofloxacin with each iron compound or ciprofloxacin in combination with each iron compound and ascorbic acid (250 mg kg−1).
The maximum serum concentration of ciprofloxacin was significantly (P < 0.01) reduced from 1.15 ± 0.11 μg mL−1 (ciprofloxacin alone) to 0.17 ± 0.01, 0.27 ± 0.01 or 0.28 ± 0.02 μg mL−1, respectively, when ferrous sulphate, sodium ferrous citrate or ferric pyrophosphate was administered along with ciprofloxacin. The addition of ascorbic acid did not affect the inhibitory effects of each iron compound on the absorption of ciprofloxacin. Ciprofloxacin did not affect the variation of serum iron levels after administration of each iron compound. The addition of ascorbic acid significantly (P < 0.01) enhanced the increase in serum iron concentration after administration of sodium ferrous citrate, showing an increase from 270 ± 6 μg dL−1 to 463 ± 11 μg dL−1 compared with an increase from 248 ± 8 μg dL−1 to 394 ± 18 μg dL−1 after administration of sodium ferrous citrate alone. Ascorbic acid also caused a significant (P < 0.01) increase in serum iron concentration from 261 ± 16 μg dL−1 to 360 ± 12 μg dL−1 after administration of ferric pyrophosphate, although it did not affect the levels after ferrous sulphate administration.
The results suggest that sodium ferrous citrate and ferric pyrophosphate should not be administered with ciprofloxacin (as for ferrous sulphate) and that sodium ferrous citrate is converted to the ferric form more easily than ferrous sulphate. This difference in convertibility might contribute to a clinical difference between sodium ferrous citrate and ferrous sulphate.
Several studies have shown that an opioid receptor antagonist, naltrexone, decreases palatable food consumption. Naltrexone has also been reported to reduce ethanol intake in alcohol-preferring rodents and human alcoholics. The aim of the present study was to assess the effects of naltrexone on taste and smell responses in healthy male volunteers. Naltrexone did not alter intensity and pleasantness of sucrose, quinine, citric acid, sodium chloride, and ethanol taste. Similarly, ratings of olfactory stimuli (orange extract and ethanol) and Coca-Cola flavor were not influenced by the opioid antagonist. Our findings may indicate that: (i) naltrexone exerts marginal, if any, effects on gustatory and olfactory responses in humans; (ii) the drug does not alter orosensory responses to ethanol.
Alcohol dependence and major depression commonly occur together; however, few studies have assessed prospectively the magnitude of the risk that one disorder imparts on the subsequent occurrence of the other. We used data from the first two waves of the Epidemiologic Catchment Area community survey (n=14480) to estimate the odds of either major depression or alcohol dependence being followed by the other disorder after 1 year of follow-up. The odds of developing major depression associated with low, medium, and high levels of alcoholic symptoms at baseline were 1.66, 3.98, and 4.32 for females (P<0.001), and 1.19, 2.49, and 2.12 for males (P=0.026). Conversely, odds ratios indicating the 1-year follow-up risk of incident alcohol dependence within low, medium, and high categories of baseline depressive symptomatology were 2.75, 3.52, and 7.88 for females (P<0.001) and 1.50, 1.41, and 1.05 for males (P=0.091). Individuals with alcohol dependence appeared more likely to meet lifetime diagnostic criteria for both disorders after 1 year than individuals with depression. These results suggest that both alcohol dependence and major depression pose a significant risk for the development of the other disorder at 1 year.
This article examines the use of naltrexone in the treatment of heroin dependence. The relationship between naltrexone and depression as well as risk of overdose is examined.
The existing literature is reviewed along with recent interim data from clinical trials underway in Victoria.
Naltrexone is a recent addition to treatment for heroin dependence in Australia. The relationship between depression and naltrexone has been examined in previous literature. Underlying rates of depression in heroin users are high and treatment may resolve or exacerbate depression. Research to date demonstrates that the addition of naltrexone does not necessarily increase depression in patients. The risk of non-fatal heroin overdose is significantly elevated after naltrexone treatment as a result of reduced tolerance. Data from clinical trials underway in Victoria demonstrate a significantly elevated rate of non-fatal overdose in naltrexone patients compared to those in substitution maintenance treatment. The mortality rate subsequent to naltrexone treatment appears to be equivalent to or greater than that for untreated heroin users. Further research is required.
Clinicians need to carefully monitor depression in patients, and warn patients of the risks of reduced tolerance to opiates following naltrexone treatment. Agonist treatments such as methadone, LAAM and buprenorphine carry much less risk of overdose.
A variety of evidence suggests that endogenous opioid peptides play a role in the short-term control of eating. More recently, opioid receptor antagonists like naltrexone have been approved as a treatment for alcohol dependence. Here we review the evidence for a role of opioid peptides in both normal and abnormal eating and drinking behaviours and in particular try to identify the nature of the role of opioids in these behaviours. Particular attention is paid to the idea that opioid reward processes may be involved both in the short-term control of eating and hedonic aspects of alcohol consumption, and parallels are drawn between the effects of opiate antagonists on food pleasantness and the experience of drinking alcohol. The review also explores the extent to which data from studies using opiate antagonists and agonists provide evidence for a direct role of endogenous opioids in the control of ingestive behaviour, or alternatively whether these data may be better explained through non-specific effects such as the nausea commonly reported following administration of opiate antagonists. The review concludes that the present data suggests a single opioid mechanism is unlikely to explain all aspects of ingestive behaviour, but also concludes that opioid-mediated reward mechanisms play an important control in hedonic aspects of ingestion. The review also highlights the need for further empirical work in order to elucidate further the role of opioid peptides in human ingestive behaviour.
Nalmefene Stimulation of the HPA Axis.
The Hypothalamic-pituitary-adrenal (HPA) axis plays a vital role in the body's response to stress. The traditional gold standard for evaluating the HPA axis, the insulin hypoglycemia test (IHT), has several known limitations, and a second test, the standard ACTH stimulation test, can detect severe deficiencies of cortisol, but often misses mild or early cases. Therefore, a better test for the evaluation of the HPA axis is needed. This study evaluated the opiate antagonist nalmefene as a stimulation test of the HPA axis.
25 healthy subjects were studied, 9 women and 16 men, mean age 30.4 yr. (range 21-55), and mean BMI 24.1 kg/m2 (range 18.6-34.2). Subjects received one of 3 doses of intravenously administered nalmefene: 2 mg (n = 6), 6 mg (n = 12), or 10 mg (n = 7). Serum cortisol and plasma ACTH were measured before and serially over two hours after the administration of nalmefene.
ACTH and cortisol levels rose significantly and similarly after the 10 mg dose and the 6 mg dose. After the 10 mg dose, mean peak ACTH was 82.4 +/- 22.6 pg/ml and mean peak cortisol was 25.2 +/- 1.8 microg/dl. After the 6 mg dose, mean peak ACTH was 70.3 +/- 7.7 pg/ml and mean peak cortisol was 24.7 +/- 1.7 microg/dl. Cortisol levels rose above 18 microg/dl in all subjects receiving 10 mg of nalmefene, and in all but two of the subjects receiving 6 mg of nalmefene. Side effects to nalmefene were of greater duration and intensity in the subjects receiving 10 mg of nalmefene vs. those receiving 6 or 2 mg. These included most notably fatigue, lightheadedness, nausea and vomiting.
Of the nalmefene doses we studied, 6 mg achieved the best combination of stimulation of ACTH and cortisol and fewest side effects. If further studies show a concordance between nalmefene and IHT, nalmefene testing could be used to assess the HPA axis in patients at risk for dysfunction of this axis.
Oral naltrexone can completely antagonize the effects produced by opioid agonists. However, poor compliance with naltrexone has been a major obstacle to the effective treatment of opioid dependence.
To evaluate the safety and efficacy of a sustained-release depot formulation of naltrexone in treating opioid dependence.
Randomized, double-blind, placebo-controlled, 8-week trial conducted at 2 medical centers.
Sixty heroin-dependent adults.
Participants were stratified by sex and years of heroin use (> or = 5 vs < 5) and then were randomized to receive placebo or 192 or 384 mg of depot naltrexone. Doses were administered at the beginning of weeks 1 and 5. All participants received twice-weekly relapse prevention therapy, provided observed urine samples, and completed other assessments at each visit.
Retention in treatment and percentage of opioid-negative urine samples.
Retention in treatment was dose related, with 39%, 60%, and 68% of patients in the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively, remaining in treatment at the end of 2 months. Time to dropout had a significant main effect of dose, with mean time to dropout of 27, 36, and 48 days for the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively. The percentage of urine samples negative for opioids, methadone, cocaine, benzodiazepines, and amphetamine varied significantly as a function of dose. When the data were recalculated without the assumption that missing urine samples were positive, a main effect of group was not found for any drugs tested except cocaine, where the percentage of cocaine-negative urine samples was lower in the placebo group. Adverse events were minimal and generally mild. This formulation of naltrexone was well tolerated and produced a robust, dose-related increase in treatment retention.
These data provide new evidence of the feasibility, efficacy, and tolerability of long-lasting antagonist treatments for opioid dependence.
Although disulfiram and naltrexone have been approved by the Food and Drug Administration for the treatment of alcoholism, no medications have been approved for individuals with alcohol dependence and comorbid psychiatric disorders. In particular, the effect of these medications on alcohol use outcomes and on specific psychiatric symptoms is still unknown in patients with the most common co-occurring disorder, major depression.
Two hundred fifty-four patients with a major Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in an outpatient medication study conducted at 3 Veterans Administration outpatient clinics. Randomization included (1) open randomization to disulfiram or no disulfiram, and (2) double-blind randomization to naltrexone or placebo. This resulted in 4 groups: (1) naltrexone alone, (2) placebo alone, (3) disulfiram and naltrexone, and (4) disulfiram and placebo. Primary outcomes were measures of alcohol use. Secondary outcomes included psychiatric symptoms assessed by the Hamilton Depression Rating Scale, alcohol craving, gamma-glutamyltransferase levels, and adverse events.
One hundred thirty-nine subjects (54.7%) met the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression. There was no relationship between the diagnosis of depression and medication treatment on alcohol use outcomes, psychiatric symptoms, or the reporting of side effects for these medications. There was a significant interaction between diagnosis, medication group, and craving, where subjects with depression on disulfram reported lower craving over time than subjects with depression on naltrexone.
The results suggest that disulfiram and naltrexone are safe pharmacotherapeutic agents for dually diagnosed individuals with depression for the treatment of alcohol use disorders.
Heroin dependence is associated with a hyperactive hypothalamic-pituitary-adrenal (HPA) axis, proposed as a biological correlate of craving. Maintenance treatment with methadone normalizes HPA axis activity. Here, we examined HPA axis activity under maintenance treatment with the increasingly utilized partial opiate agonist buprenorphine.
Responses to a metyrapone challenge were compared in 20 buprenorphine-maintained heroin addicts and 20 healthy volunteers (10 received a single 50 mg naltrexone dose [NTX+] and 10 received no naltrexone [NTX-]). Patients were 16 male subjects and 4 female subjects, aged 30 to 38 years, heroin-dependent and relapse-free under buprenorphine maintenance (BUP) for a minimum of 6 months. Healthy volunteers were 9 male subjects and 11 female subjects, aged 36 to 49 years, with no history of dependence. Serial measures were obtained of plasma adrenocorticotropic hormone (ACTH) and cortisol and Profile of Mood States (POMS) ratings over time. Subjects were genotyped for the OPRM1 118A/G polymorphism.
Buprenorphine maintenance showed a dampened HPA axis response to metyrapone, with OPRM1 118G carriers showing a significantly attenuated response compared with 118A carriers. The response of the NTX+ group was markedly increased. In contrast, negative affect was elevated in the BUP group but did not differ between NTX- and NTX+. Buprenorphine maintenance and NTX- groups did not differ in positive affect, whereas the NTX+ group was lower.
In contrast to exaggerated HPA axis responsiveness reported in untreated heroin dependence, response to metyrapone was subnormal in heroin addicts maintained on buprenorphine. Despite this, increased measures of negative affect were seen in this group. This implies a dissociation of HPA axis responsiveness and affect in heroin dependence.
. Long-term opioid blockade and hedonic response: preliminary data from two open-label extension studies with extended-release naltrexone.
- OBrien