Anhedonia in chronic pain and prescription opioid misuse.

BACKGROUND: Both acute and chronic pain can disrupt reward processing. Moreover, prolonged prescription opioid use and depressed mood are common in chronic pain samples. Despite the prevalence of these risk factors for anhedonia, little is known about anhedonia in chronic pain populations. METHODS: We conducted a large-scale, systematic study of anhedonia in chronic pain, focusing on its relationship with opioid use/misuse, pain severity, and depression. Chronic pain patients across four distinct samples (N = 488) completed the Snaith-Hamilton Pleasure Scale (SHAPS), measures of opioid use, pain severity and depression, as well as the Current Opioid Misuse Measure (COMM). We used a meta-analytic approach to determine reference levels of anhedonia in healthy samples spanning a variety of countries and diverse age groups, extracting SHAPS scores from 58 published studies totaling 2664 psychiatrically healthy participants. RESULTS: Compared to healthy samples, chronic pain patients showed higher levels of anhedonia, with ~25% of patients scoring above the standard anhedonia cut-off. This difference was not primarily driven by depression levels, which explained less than 25% of variance in anhedonia scores. Neither opioid use duration, dose, nor pain severity alone was significantly associated with anhedonia. Yet, there was a clear effect of opioid misuse, with opioid misusers (COMM ⩾13) reporting greater anhedonia than non-misusers. Opioid misuse remained a significant predictor of anhedonia even after controlling for pain severity, depression and opioid dose. CONCLUSIONS: Study results suggest that both chronic pain and opioid misuse contribute to anhedonia, which may, in turn, drive further pain and misuse.

Psychotic-like experiences with cannabis use predict cannabis cessation and desire to quit: a cannabis discontinuation hypothesis.

BACKGROUND: Evidence suggests that cannabis-induced psychotic-like experiences may be a marker of psychosis proneness. The effect of such experiences on cannabis use has not systematically been examined. METHODS: We undertook a mixed-methods online survey of 1231 cannabis users (including 926 continued users) using the Cannabis Experiences Questionnaire. We examined the effect of psychotic-like and pleasurable experiences on cessation of cannabis and intention to quit. Socio-demographic variables, cannabis use parameters and substance misuse history were included as covariates. Free-text data explored subjective reasons for changes in use. RESULTS: Cessation of cannabis use was associated with greater psychotic-like experiences [p < 0.001, Exp(B) 1.262, 95% confidence interval (CI) 1.179-1.351], whilst continued cannabis users were more likely to report pleasurable experiences [p < 0.001, Exp(B) 0.717, 95% CI 0.662-0.776]. Intention to quit cannabis in continued users was associated with greater psychotic-like experiences [p < 0.003, Exp(B) 1.131, 95% CI 1.044-1.225], whilst intention to not quit was significantly associated with increased pleasurable experiences [p < 0.015, Exp(B) 0.892, 95% CI 0.814-0.978]. Whereas former users clearly ascribed cessation to negative experiences, continued users who expressed intention to quit less readily ascribed the intention to negative experiences. CONCLUSIONS: Elucidation of psychotic-like experiences may form the basis of a therapeutic intervention for those who wish to quit. Cessation in those with cannabis-induced psychotomimetic experiences may offset the risk for the development of a psychotic disorder, in this higher risk group.

The Role of Pleasure Neurobiology and Dopamine in Mental Health Disorders.

Recent evidence and research has demonstrated that the pleasure response and associated neurotransmitters and brain circuits play a significant role in substance use disorders (SUDs). It was thought that negative behaviors associated with SUDs resulted from negative choices, but it is now known that chemical changes in the brain drive those behaviors. Several mental health disorders (e.g., eating disorders, non-suicidal self-injury, compulsive sex behaviors, internet gaming, gambling) are also thought to involve those same pleasure responses, neurotransmitters, and brain regions. Studies have shown that the use of naltrexone, a dopamine antagonist, can reduce symptoms of these disorders. It is important for nurses to understand the underlying physiology of mental health disorders that are thought to have an addictive or craving component. This understanding can help reduce stigma. Educating patients about likely neurobiological causes for their disorders can also help reduce guilt and shame. Nurses should educate patients about these disorders and evidence-based treatments, including off-label use of naltrexone. [Journal of Psychosocial Nursing and Mental Health Services, 55(9), 17-21.].

Dissociating the role of endocannabinoids in the pleasurable and motivational properties of social play behaviour in rats.

Social play behaviour is a vigorous form of social interaction, abundant during the juvenile and adolescent phases of life in many mammalian species, including humans. Social play is highly rewarding and it is important for social and cognitive development. Being a rewarding activity, social play can be dissociated in its pleasurable and motivational components. We have previously shown that endocannabinoids modulate the expression of social play behaviour in rats. In the present study, we investigated whether endocannabinoids modulate the motivational and pleasurable properties of social play behaviour, using operant and place conditioning paradigms, respectively. Treatment with the anandamide hydrolysis inhibitor URB597 did not affect operant responding or social play-induced conditioned place preference (CPP) when administered at a dose (0.1mg/kg) known to increase the expression of social play behaviour, while it modestly reduced operant responding at a higher dose (0.2mg/kg). The cannabinoid-1 (CB1) receptor antagonist rimonabant reduced operant responding when administered at a dose (1mg/kg) known to decrease the expression of social play behaviour, although this effect may be secondary to concurrent drug-induced stereotypic behaviours (i.e., grooming and scratching). These data demonstrate that enhancing endocannabinoid levels does not differentially affect the motivational and pleasurable aspects of social play behaviour, whereas CB1 receptor blockade reduces the motivational aspects of social play behaviour, possibly due to response competition. Thus, endocannabinoids likely drive the expression of social play behaviour as a whole, without differentially affecting its motivational or pleasurable properties.

Placebo improves pleasure and pain through opposite modulation of sensory processing.

Placebo analgesia is often conceptualized as a reward mechanism. However, by targeting only negative experiences, such as pain, placebo research may tell only half the story. We compared placebo improvement of painful touch (analgesia) with placebo improvement of pleasant touch (hyperhedonia) using functional MRI and a crossover design. Somatosensory processing was decreased during placebo analgesia and increased during placebo hyperhedonia. Both placebo responses were associated with similar patterns of activation increase in circuitry involved in emotion appraisal, including the pregenual anterior cingulate, medial orbitofrontal cortex, amygdala, accumbens, and midbrain structures. Importantly, placebo-induced coupling between the ventromedial prefrontal cortex and periaqueductal gray correlated with somatosensory decreases to painful touch and somatosensory increases to pleasant touch. These findings suggest that placebo analgesia and hyperhedonia are mediated by activation of shared emotion appraisal neurocircuitry, which down- or up-regulates early sensory processing, depending on whether the expectation is reduced pain or increased pleasure.

Over-the-Counter Relief From Pains and Pleasures Alike: Acetaminophen Blunts Evaluation Sensitivity to Both Negative and Positive Stimuli.

Acetaminophen, an effective and popular over-the-counter pain reliever (e.g., the active ingredient in Tylenol), has recently been shown to blunt individuals' reactivity to a range of negative stimuli in addition to physical pain. Because accumulating research has shown that individuals' reactivity to both negative and positive stimuli can be influenced by a single factor (an idea known as differential susceptibility), we conducted two experiments testing whether acetaminophen blunted individuals' evaluations of and emotional reactions to both negative and positive images from the International Affective Picture System. Participants who took acetaminophen evaluated unpleasant stimuli less negatively and pleasant stimuli less positively, compared with participants who took a placebo. Participants in the acetaminophen condition also rated both negative and positive stimuli as less emotionally arousing than did participants in the placebo condition (Studies 1 and 2), whereas nonevaluative ratings (extent of color saturation in each image; Study 2) were not affected by drug condition. These findings suggest that acetaminophen has a general blunting effect on individuals' evaluative and emotional processing, irrespective of negative or positive valence.

Pursuing Pleasures of Productivity: University Students' Use of Prescription Stimulants for Enhancement and the Moral Uncertainty of Making Work Fun.

This article presents ethnographic data on the use of prescription stimulants for enhancement purposes by university students in New York City. The study shows that students find stimulants a helpful tool in preventing procrastination, particularly in relation to feeling disinterested, overloaded, or insecure. Using stimulants, students seek pleasure in the study situation, for example, to get rid of unpleasant states of mind or intensify an already existing excitement. The article illustrates the notion that enhancement strategies do not only concern productivity in the quantitative sense of bettering results, performances, and opportunities. Students also measure their own success in terms of the qualitative experience of working hard. The article further argues that taking an ethnographic approach facilitates the study of norms in the making, as students experience moral uncertainty-not because they improve study skills and results-but because they enhance the study experience, making work fun. The article thereby seeks to nuance simplistic neoliberal ideas of personhood.

Sweet-liking is associated with transformation of heavy drinking into alcohol-related problems in young adults with high novelty seeking.

BACKGROUND: We tested the hypothesis that high novelty seeking (NS) (a trait that promotes experimentation) and sweet-liking (SL) (a phenotype that may reflect processing of hedonic stimuli) act independently and synergistically to increase the risk of having alcohol-related problems in young adults. METHODS: A sample of 163 young adults, ages 18 to 26, was recruited and balanced for gender and evidence for presence of alcohol problems to yield 150 evaluable participants. NS was evaluated using the Tridimensional Personality Questionnaire. Pleasurable response to sweet taste was tested to identify sweet-likers and sweet-dislikers. Alcohol use and problems were assessed by the Alcohol Use Disorders Identification Test and the Rutgers Alcohol Problem Index. RESULTS: NS, but not SL, was positively and significantly associated with alcohol consumption and alcohol problems; however, the effect of NS on alcohol problems was significantly enhanced in the presence of the SL phenotype, thus showing a strong synergistic interaction. The combination of SL and high NS was associated with increased odds of having alcohol problems -20.64 (95% CI: -89.98, 4.74) compared to those with low NS and sweet-disliking. Other combinations did not produce such odds ratios. SL and low NS showed OR = 1.88 (95% CI 0.44, 7.99), and sweet-dislikers and high novelty seekers had OR = 4.07 (95%, CI 1.01, 16.46). CONCLUSIONS: These results support and extend our hypothesis that as clinically distinct phenotypes, high NS and the SL phenotype are associated with risk of alcohol-related problems. High NS is associated with the use of alcohol, and the presence of the SL phenotype appears to bias an individual to alcohol problems once alcohol use is initiated. Understanding the biology and phenomenology of these phenotypes will allow a more complete picture of the processes that lead to alcohol problems.

Effect of drug use and influence of abstinence on sexual functioning in a Spanish male drug-dependent sample: a multisite study.

INTRODUCTION: To date, it has been difficult to address the issue of sexual functioning and drug use, and many approaches to it have basic problems and methodological errors. AIM: The present cross-sectional study compared the sexual functioning scores of a group of drug users with those of a group of nondrug users. It explored the relationship between drug abstinence and sexual functioning. MAIN OUTCOME MEASURES: A sample of 905 males participated in this study (549 met the substance dependence criteria and 356 were controls). All of them were assessed with the Changes in Sexual Functioning Questionnaire-Drugs version. METHOD: The assessment was conducted from September 2009 to January 2011. The clinical sample was evaluated in nine different substance abuse treatment facilities. RESULTS: Results show that, overall, all dimensions (pleasure, desire, arousal, and orgasm) were moderately impaired. Yet, differences regarding preferred substance were observed. Pleasure and orgasm were the two areas most significantly impaired. In these areas, all drugs seemed to negatively affect sexual functioning. However, desire and arousal were not affected by all the substances. In addition, at least after 2 weeks of drug abstinence, no relationship was found between drug abstinence and improvement in sexual functioning. The sample studied had an average of 1 year of drug abstinence and was found to have poorer sexual functioning than the control group. CONCLUSIONS: Therefore, these results seem to contradict those that argue that drug use only impairs sexual functioning temporarily. Moreover, they suggest that sexual functioning does not improve just by stopping drug use.

Adaptation, equivalence, and validation of the changes in sexual functioning questionnaire-drugs in a sample of drug-dependent men.

This study aimed to adapt and validate the changes in sexual functioning questionnaire-short form in a sample of drug-dependent men, achieving equivalence. Participants were 301 drug-dependent and 202 non-drug-dependent men took part in this study. The analysis of invariance revealed strong factor equivalence (RMSEA = .06; χ2/df = 2.66 and ΔCFI = -.01) for the 4-factor model (desire, pleasure, arousal, and orgasm). This model has shown the best fit indices. No items showed differential item functioning (ΔR (2) Nagelkerke < .035). Reliability ranged from α = 0.83 for pleasure to α = 0.61 for orgasm. A comparison between the scores of control and experimental participants showed significant differences (CI = 99%) in all the dimensions. Thus, a worse sexual functioning has been observed in the drug consumer group. The adaptation of the Changes in Sexual Functioning Questionnaire-short form to drug-dependent individuals showed good psychometric properties.

Antidepressant-like action of intracerebral 6-fluoronorepinephrine, a selective full α-adrenoceptor agonist.

The present study examined the ability of 6-fluoronorepinephrine (6FNE), a full selective α-adrenoceptor agonist, to produce antidepressant-like effects in mice. The drug, administered in the 4th ventricle, produced marked anti-immobility effects at mid-dose range in the acute forced swim, tail suspension and repeated open-space forced swim tests with minimal effect on open-field motor activity and also reversed anhedonia following lipopolysaccharide administration. Its antidepressant effects were equal to or greater than that of an established systemic antidepressant, desmethylimipramine, given subacutely. Experiments with α-adrenoceptor antagonists indicated that the drug acts primarily via the α2-receptor in contrast to endogenous catecholamines which appear to control depressive behaviour primarily via the α1-receptor. Antidepressant activity declined at higher doses signifying a possible pro-depressant effect of one of the α-adrenoceptor subtypes. Compared to the selective α2-agonist, dexmedetomidine, 6FNE showed equivalent antidepressant action in the tail suspension test but appeared to have a greater efficacy or speed of action in the repeated open-space forced swim test which produces a more sustained depression. Studies of regional brain Fos expression induced during the antidepressant tests showed that 6FNE tended to inhibit neural activity in two stress-responsive regions (locus coeruleus and paraventricular hypothalamus) but to enhance activity in two areas involved in motivated behaviour (nucleus accumbens shell and lateral septal nucleus) producing a neural pattern consistent with antidepressant action. It is concluded that 6FNE elicits a rapid and effective antidepressant and anti-stress response that may compare favourably with available antidepressants.

Cocaine sensitization models an anhedonia-like condition in rats.

Anhedonia is a core symptom of depression that also characterizes substance abuse-related mood disorders, in particular those secondary to stimulant abuse. This study investigated the long-lasting condition of cocaine sensitization as an inducing condition for anhedonia in rats. Cortical-mesolimbic dopamine plays a central role in assessing the incentive value of a stimulus and an increased dopamine output in these areas after a novel palatable meal seems to correlate with the ability to acquire an instrumental behaviour aimed at earning it again. This dopaminergic response is associated with consistent modifications in the phosphorylation pattern of some cAMP-dependent protein kinase (PKA) substrates and it is mediated by dopamine D1 receptor stimulation. Thus, since behavioural cocaine sensitization is characterized by tonically increased levels of phospho-Thr75 DARPP-32 that is a potent PKA inhibitor, we hypothesized that cocaine-sensitized rats might reveal deficits in palatable food responding. Indeed, non-food-deprived cocaine-sensitized rats showed no interest in palatable food, no dopaminergic response after a palatable meal in terms of increased dopamine output and DARPP-32 phosphorylation changes, and no ability to acquire a palatable food-sustained instrumental behaviour. Repeated administration of an established antidepressant compound, imipramine, corrected these deficits and reinstated the dopaminergic response in the cortico-mesolimbic areas to control values. Thus, the behavioural modifications observed in cocaine-sensitized rats satisfy some requirements for an experimental model of anhedonia since they are induced by repeated cocaine administration (aetiological validity), they mimic an anhedonia-like symptom (construct validity), and are reversed by the administration of imipramine (predictive validity).

Update in the methodology of the chronic stress paradigm: internal control matters.

To date, the reliability of induction of a depressive-like state using chronic stress models is confronted by many methodological limitations. We believe that the modifications to the stress paradigm in mice proposed herein allow some of these limitations to be overcome. Here, we discuss a variant of the standard stress paradigm, which results in anhedonia. This anhedonic state was defined by a decrease in sucrose preference that was not exhibited by all animals. As such, we propose the use of non-anhedonic, stressed mice as an internal control in experimental mouse models of depression. The application of an internal control for the effects of stress, along with optimized behavioural testing, can enable the analysis of biological correlates of stress-induced anhedonia versus the consequences of stress alone in a chronic-stress depression model. This is illustrated, for instance, by distinct physiological and molecular profiles in anhedonic and non-anhedonic groups subjected to stress. These results argue for the use of a subgroup of individuals who are negative for the induction of a depressive phenotype during experimental paradigms of depression as an internal control, for more refined modeling of this disorder in animals.

An open randomized pilot trial on the differential effects of aripiprazole versus risperidone on anhedonia and subjective well-being.

INTRODUCTION: Negative symptoms of schizophrenia often predict an unfavorable clinical outcome. Disturbed dopamine transmission in different brain parts may underlie different aspects of negative symptoms, and the effect of antipsychotics on them may also differ. This pilot study investigated the potentially therapeutic effects of the partial dopamine agonist aripiprazole on different negative symptoms. METHODS: This pilot study randomly assigned patients with schizophrenia (N=40) to either aripiprazole or risperidone. After 6 weeks of treatment, the severity of negative symptoms was determined by the PANSS. Subscales of self-report questionnaires were used to assess differences in initiative, anhedonia, social functioning and subjective well-being. RESULTS: Patients treated with aripiprazole showed a significant improvement on measures for anhedonia and subjective wellbeing. Negative symptoms in general, lack of initiative and social inhibition were also lower in the aripiprazole treated group, but without reaching statistical significance. DISCUSSION: According to this pilot study, aripiprazole appears to specifically improve anhedonia and subjective wellbeing compared to risperidone. This may be caused by a specific effect of aripiprazole on the limbic branch of the dopamine system. Future studies should replicate this finding with a larger sample size.

Long-term opioid blockade and hedonic response: preliminary data from two open-label extension studies with extended-release naltrexone.

The emergence of extended-release naltrexone (XR-NTX) raises the opportunity to explore the role of endorphin blockade on hedonic response during long-term alcohol dependence treatment. A hedonic survey was administered to 74 alcohol dependent patients treated for an average of 3.5 years with nearly continuous month-long intramuscular XR-NTX. The paper-and-pencil, one-time survey asked patients about the degree of pleasure they experienced in the past 90 days with drinking alcohol, sex, exercise and other daily activities. The data revealed lower pleasure ratings for alcohol than for sex, exercise and 10 other common activities. Mean responses to drinking alcohol and gambling were significantly lower than to listening to music, sex, reading, being with friends, eating good food, eating spicy food, and playing video/card games. This effect was independent of XR-NTX dose or duration. Although this exploratory study lacked baseline data, a comparison group or control for the impact of patient discontinuation, the data indicate the feasibility of examining long-term hedonic response in recovery. The differential hedonic ratings suggest that, in patients who persist with long-term continuous therapy, XR-NTX may selectively inhibit the pleasure associated with drinking alcohol, compared to a variety of other activities.

The role of oxytocin in delay of gratification and flexibility in non-social decision making.

Oxytocin is well-known for its impact on social cognition. This specificity for the social domain, however, has been challenged by findings suggesting a domain-general allostatic function for oxytocin by promoting future-oriented and flexible behavior. In this pre-registered study, we tested the hypothesized domain-general function of oxytocin by assessing the impact of intranasal oxytocin (24 IU) on core aspects of human social (inequity aversion) and non-social decision making (delay of gratification and cognitive flexibility) in 49 healthy volunteers (within-subject design). In intertemporal choice, patience was higher under oxytocin than under placebo, although this difference was evident only when restricting the analysis to the first experimental session (between-group comparison) due to carry-over effects. Further, oxytocin increased cognitive flexibility in reversal learning as well as generosity under conditions of advantageous but not disadvantageous inequity. Our findings show that oxytocin affects both social and non-social decision making, supporting theoretical accounts of domain-general functions of oxytocin.

A role for endogenous opiates in incubation behavior in ring neck doves (Streptopelia risoria).

Incubation of eggs is a critical component of parental care in avian species. However, we do not fully understand the neuroendocrine mechanisms underlying this vital behavior. While prolactin is clearly involved, it alone cannot explain the fine-tuning of incubation behavior. The present experiments explored the possibility that incubation is reinforced through a hedonic system in which contact with eggs elicited an opiate-mediated reinforcing state. Blockade of opiate receptors with naloxone reduced time ring neck doves (Streptopelia risoria) spent on the nest, possibly by uncoupling the opiate-receptor mediated hedonic experience of contact with eggs from nest-sitting behavior. Likewise, activation of opiate receptors with morphine also reduced time spent on the nest, possibly by activating an opiate-receptor mediated hedonic experience, hence rendering the eliciting behavior (contact with eggs) unnecessary. Taken together, the results suggest that the opiate system may play a previously unrecognized role in facilitating incubation through reinforcement.