***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Women often exhibit larger hormonal and subjective responses to opioid receptor antagonists than men , but the biological mechanisms mediating this effect remain unclear . Among women , fluctuations in estradiol ( E2 ) and progesterone ( P4 ) across the menstrual cycle ( MC ) affect the endogenous opioid system . Therefore , the goal of the current study was to compare acute naltrexone response between women in the early follicular phase of the MC ( low E2 and P4 ) , women in the luteal phase of the MC ( high E2 and P4 ) , and men . Seventy healthy controls ( n=46 women ) participated in two morning sessions in which they received 50 mg naltrexone or placebo in a r and omized , counterbalanced order . Women were r and omized to complete both sessions in either the early follicular ( n=23 ) or luteal phase of the MC . Serum cortisol , salivary cortisol , prolactin , luteinizing hormone ( LH ) , and subjective response were assessed upon arrival to the laboratory and at regular intervals after pill administration . In luteal and early follicular women but not men , naltrexone ( vs. placebo ) increased serum cortisol and prolactin levels from baseline ; however , the naltrexone-induced increases in these hormones were significantly greater in luteal women than early follicular women . Additionally , only luteal women demonstrated an increase from baseline in salivary cortisol levels and the severity of adverse drug effects in response to naltrexone . In sum , the results indicate that luteal phase women are more sensitive to acute hormonal and subjective effects of naltrexone than early follicular women and men . These findings may have important implication s for the use of naltrexone in women Nalbuphine , an agonist-antagonist kappa-opioid , produces brief analgesia followed by enhanced pain/hyperalgesia in male postsurgical patients . However , it produces profound analgesia without pain enhancement when co-administration with low dose naloxone . To examine the effect of nalbuphine or nalbuphine plus naloxone on activity in brain regions that may explain these differences , we employed pharmacological magnetic resonance imaging ( phMRI ) in a double blind cross-over study with 13 healthy male volunteers . In separate imaging sessions subjects were administered nalbuphine ( 5 mg/70 kg ) preceded by either saline ( Sal-Nalb ) or naloxone 0.4 mg ( Nalox-Nalb ) . Blood oxygen level-dependent ( BOLD ) activation maps followed by contrast and connectivity analyses revealed marked differences . Sal-Nalb produced significantly increased activity in 60 brain regions and decreased activity in 9 ; in contrast , Nalox-Nalb activated only 14 regions and deactivated only 3 . Nalbuphine , like morphine in a previous study , attenuated activity in the inferior orbital cortex , and , like noxious stimulation , increased activity in temporal cortex , insula , pulvinar , cau date , and pons . Co-administration/pretreatment of naloxone selectively blocked activity in pulvinar , pons and posterior insula . Nalbuphine induced functional connectivity between cau date and regions in the frontal , occipital , temporal , insular , middle cingulate cortices , and putamen ; naloxone co-admistration reduced all connectivity to non-significant levels , and , like phMRI measures of morphine , increased activation in other areas ( e.g. , putamen ) . Naloxone pretreatment to nalbuphine produced changes in brain activity possess characteristics of both analgesia and algesia ; naloxone selectively blocks activity in areas associated with algesia . Given these findings , we suggest that nalbuphine interacts with a pain salience system , which can modulate perceived pain intensity BACKGROUND Extended-release naltrexone ( XR-NTX ) , an opioid antagonist , and sublingual buprenorphine-naloxone ( BUP-NX ) , a partial opioid agonist , are pharmacologically and conceptually distinct interventions to prevent opioid relapse . We aim ed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX . METHODS We initiated this 24 week , open-label , r and omised controlled , comparative effectiveness trial at eight US community-based inpatient services and followed up participants as out patients . Participants were 18 years or older , had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder , and had used non-prescribed opioids in the past 30 days . We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with r and om equally weighted block sizes of four and six for r and omisation ( 1:1 ) to receive XR-NTX or BUP-NX . XR-NTX was monthly intramuscular injections ( Vivitrol ; Alkermes ) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film ( Suboxone ; Indivior ) . The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment . Relapse was 4 consecutive weeks of any non- study opioid use by urine toxicology or self-report , or 7 consecutive days of self-reported use . This trial is registered with Clinical Trials.gov , NCT02032433 . FINDINGS Between Jan 30 , 2014 , and May 25 , 2016 , we r and omly assigned 570 participants to receive XR-NTX ( n=283 ) or BUP-NX ( n=287 ) . The last follow-up visit was Jan 31 , 2017 . As expected , XR-NTX had a substantial induction hurdle : fewer participants successfully initiated XR-NTX ( 204 [ 72 % ] of 283 ) than BUP-NX ( 270 [ 94 % ] of 287 ; p<0·0001 ) . Among all participants who were r and omly assigned ( intention-to-treat population , n=570 ) 24 week relapse events were greater for XR-NTX ( 185 [ 65 % ] of 283 ) than for BUP-NX ( 163 [ 57 % ] of 287 ; hazard ratio [ HR ] 1·36 , 95 % CI 1·10 - 1·68 ) , most or all of this difference accounted for by early relapse in nearly all ( 70 [ 89 % ] of 79 ) XR-NTX induction failures . Among participants successfully inducted ( per- protocol population , n=474 ) , 24 week relapse events were similar across study groups ( p=0·44 ) . Opioid-negative urine sample s ( p<0·0001 ) and opioid-abstinent days ( p<0·0001 ) favoured BUP-NX compared with XR-NTX among the intention-to-treat population , but were similar across study groups among the per- protocol population . Self-reported opioid craving was initially less with XR-NTX than with BUP-NX ( p=0·0012 ) , then converged by week 24 ( p=0·20 ) . With the exception of mild-to-moderate XR-NTX injection site reactions , treatment-emergent adverse events including overdose did not differ between treatment groups . Five fatal overdoses occurred ( two in the XR-NTX group and three in the BUP-NX group ) . INTERPRETATION In this population it is more difficult to initiate patients to XR-NTX than BUP-NX , and this negatively affected overall relapse . However , once initiated , both medications were equally safe and effective . Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications . FUNDING NIDA Clinical Trials Network Abstract Opioid painkillers are a promising treatment for  chronic breathlessness  , but are associated with potentially fatal side effects . In the treatment of breathlessness , their mechanisms of action are unclear . A better underst and ing might help to identify safer alternatives . Learned associations between previously neutral stimuli ( e.g. stairs ) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness , contributing to the downward spiral of decline seen in clinical population s. As opioids are known to influence associative learning , we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas , including the amygdala and the hippocampus . Healthy volunteers  viewed visual cues ( neutral stimuli ) immediately before induction of experimental breathlessness with inspiratory resistive loading . Thus , an association was formed between the cue and breathlessness . Subsequently , this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low‐dose remifentanil ( 0.7 ng/ml target‐controlled infusion ) or saline ( r and omised ) . During saline infusion , breathlessness anticipation activated the right anterior insula and the adjacent operculum . Breathlessness was associated with activity in a network including the insula , operculum , dorsolateral prefrontal cortex , anterior cingulate cortex and the primary sensory and motor cortices . Remifentanil  reduced breathlessness unpleasantness but not breathlessness intensity . Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness . During breathlessness , remifentanil decreased activity in the anterior insula , anterior cingulate cortex and sensory motor cortices . Remifentanil‐induced  reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens , components of the endogenous opioid system known to decrease the perception of aversive stimuli . These findings suggest that in addition to effects on brainstem respiratory control , opioids palliate breathlessness through an interplay of altered associative learning mechanisms . These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness . HighlightsThe mechanisms of how low‐dose opioids relieve breathlessness are unknown . We tested whether low‐dose opioids affect conditioned anticipation and perception of breathlessness .  Low‐dose opioids reduced unpleasantness , but not intensity of breathlessness . Reduced breathlessness unpleasantness was associated with activation of the endogenous opioid system . Breathlessness relief was predicted by decreased anticipatory activity in amygdala/hippocampus BACKGROUND Cue-induced craving plays an important role in relapse , and the neural correlates of cue-induced craving have been eluci date d using fMRI . This study examined the utility of real-time fMRI ( rtfMRI ) neurofeedback to strengthen self-regulation of craving-related neural activation and cue-reactivity in cigarette smokers . METHODS Nicotine-dependent smokers were r and omized to rtfMRI neurofeedback or to a no-feedback control group . Participants completed 3 neuroimaging visits . Within each visit , an initial run during which smoking-related cues were used to provoke craving , an individualized craving-related region of interest ( ROI ) in the prefrontal cortex or anterior cingulate cortex was identified . In the rtfMRI group , activity from the ROI was fed back via a visual display during 3 subsequent runs while participants were instructed to reduce craving during cue exposure . The control group had an identical experience with no feedback provided . RESULTS Forty-four nicotine-dependent smokers were recruited to participate in our study ; data from the 33 participants who completed a 1-week follow-up visit were included in the analysis . Subjective craving ratings and cue-induced brain activation were lower in the rtfMRI group than in the control group . LIMITATIONS As participants were not seeking treatment , clinical outcomes are lacking . CONCLUSION Nicotine-dependent smokers receiving rtfMRI feedback from an individualized ROI attenuated smoking cue-elicited neural activation and craving , relative to a control group . Further studies are needed in treatment-seeking smokers to determine if this intervention can translate into a clinical ly meaningful treatment modality The behavioral response to pain is driven by sensory and affective components , each of which is mediated by the CNS . Subjective pain ratings are used as readouts when appraising potential analgesics ; however , pain ratings alone can not enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically . Having a more objective readout of potential analgesic effects may allow improved underst and ing and detection of pharmacological efficacy for pain . The pharmacological/functional magnetic resonance imaging ( phMRI/fMRI ) methodology can be used to objective ly evaluate drug action on the CNS . In this context , we aim ed to evaluate two drugs that had been developed as analgesics : one that is efficacious for pain ( buprenorphine ( BUP ) ) and one that failed as an analgesic in clinical trials aprepitant ( APREP ) . Using phMRI , we observed that activation induced solely by BUP was present in regions with μ-opioid receptors , whereas APREP-induced activation was seen in regions expressing NK1 receptors . However , significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration . By implementing an evoked pain fMRI paradigm , these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain . We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration . This investigation demonstrates how 
    Output:
    
We found convergent evidence that individuals with OUD display widespread heightened neural activation to heroin cues .
This pattern is potentiated by heroin , attenuated by medication-assisted treatments for opioids , predicts treatment response , and is reduced following extended abstinence .