***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: & NA ; Under specific experimental conditions , oxycodone seems to exert spinal ( temporal summation ) rather than supraspinal ( conditioned pain modulation ) analgesic effects in humans . & NA ; Opioid analgesia is mediated primarily by modulating ( inhibiting and enhancing ) pain mechanisms at the spinal and supraspinal levels . Advanced psychophysical paradigms of temporal summation ( TS ) and conditioned pain modulation ( CPM ) likely represent pain mechanisms at both levels . Therefore , the study of opioid effects on TS and CPM can shed light on their analgesic mechanisms in humans . The current r and omized , double‐blind study tested the effects of oxycodone on the magnitude of both TS and CPM in 40 healthy subjects .  TS was tested by measuring increments in pain intensity in response to 10 repetitive painful phasic heat stimuli . CPM was assessed by subtracting the response to a painful phasic heat stimulus administrated simultaneously with a conditioning cold pain stimulus from a painful phasic heat stimulus alone . These paradigms were tested before and at 60 , 120 , and 180 minutes after administration of a single oral dose of either oxycodone or an active placebo . Repeated‐ measures analysis of variance revealed significant effects of oxycodone , but not placebo , on the magnitude of TS ( F = 7.196 , P < .001 ) . Pairwise comparisons revealed that relative to baseline , TS was significantly reduced at 60 minutes ( P = .008 ) and at 180 minutes ( P = .017 ) after oxycodone administration . In contrast , no significant effects of either oxycodone ( F = 0.871 , P = .458 ) or placebo ( F = 2.086 , P = .106 ) on the magnitude of CPM were found . These results suggest that under the current experimental conditions , oxycodone exerted spinal , rather than supraspinal , analgesic effects . Furthermore , compared with CPM , TS seems more suitable for study ing the mechanisms of opioid analgesia in humans Background Variation in the serotonin transporter ( 5-HTT ) gene ( SLC6A4 ) has been shown to influence a wide range of affective processes . Low 5-HTT gene-expression has also been suggested to increase the risk of chronic pain . Conditioned pain modulation ( CPM ) - i.e. ‘ pain inhibits pain ’ - is impaired in chronic pain states and , reciprocally , aberrations of CPM may predict the development of chronic pain . Therefore we hypothesized that a common variation in the SLC6A4 is associated with inter-individual variation in CPM . Forty-five healthy subjects recruited on the basis of tri-allelic 5-HTTLPR genotype , with inferred high or low 5-HTT-expression , were included in a double-blind study . A submaximal-effort tourniquet test was used to provide a st and ardized degree of conditioning ischemic pain . Individualized noxious heat and pressure pain thresholds ( PPTs ) were used as subjective test-modalities and the nociceptive flexion reflex ( NFR ) was used to provide an objective neurophysiological window into spinal processing . Results The low , as compared to the high , 5-HTT-expressing group exhibited significantly reduced CPM-mediated pain inhibition for PPTs ( p = 0.02 ) and heat-pain ( p = 0.02 ) . The CPM-mediated inhibition of the NFR , gauged by increases in NFR-threshold , did not differ significantly between groups ( p = 0.75 ) . Inhibition of PPTs and heat-pain were correlated ( Spearman ’s rho = 0.35 , p = 0.02 ) , whereas the NFR-threshold increase was not significantly correlated with degree of inhibition of these subjectively reported modalities . Conclusions Our results demonstrate the involvement of the tri-allelic 5-HTTLPR genotype in explaining clinical ly relevant inter-individual differences in pain perception and regulation . Our results also illustrate that shifts in NFR-thresholds do not necessarily correlate to the modulation of experienced pain . We discuss various possible mechanisms underlying these findings and suggest a role of regulation of 5-HT receptors along the neuraxis as a function of differential 5-HTT-expression & NA;Diffuse noxious inhibitory controls ( DNIC ) were tested for their effect on noxious only , non‐noxious and proprioceptive cells in the dorsal horn of the intact anaesthetized rat . Unlike convergent neurones , as described in the previous paper , there was no effect of DNIC on these neurones , It is concluded that convergent neurones are specifically inhibited by DNIC.The effect of DNIC could not be demonstrated for convergent neurones in the spinal animal . Thus the neuronal substrate for DNIC must involve supraspinal structures . Because of the level of firing in convergent neurones induced by hair and touch receptors , presumably constantly and r and omly activated in the freely moving animal , a noxious message arriving at higher centres may be partly masked by this background noise . On the basis of the known role of convergent neurones in nociception , we propose the following mechanism which may interpret this paradoxical convergence : two pools of convergent neurones are influenced by a painful peripheral stimulation , one segmental pool being activated whilst the remaining population of cells is inhibited ; the “ contrast ” between the messages from these two pools may well produce a significant pain signalling output from the convergent dorsal horn cells . These results and their theoretical implication s are discussed with regard to the concept of the “ analgesic system ” , certain clinical observations and the paradoxical pain relieving effects of counterirritation and some forms of acupuncture Attenuation of responses to repeated sensory events has been thoroughly studied in many modalities ; however , attenuation of pain perception has not yet benefitted from such extensive investigation . Described here are two psychophysical studies that examined the effects of repeated exposure to thermal stimuli , assessing potential attenuation of the perception of pain and its possible spatial specificity . Twenty-two subjects were presented thermal stimuli to the volar surface of the right and left forearms . Twelve subjects in study 1 received the same stimuli and conditions on each of five daily experimental sessions , whereas 10 subjects in study 2 received thermal stimuli , which were restricted to one side for four daily sessions and then applied to the other side on the fifth session . Ratings of warmth intensity , pain intensity , and pain unpleasantness were recorded while the subjects performed a thermal sensory discrimination task . Results of study 1 demonstrate that repeated stimulation with noxious heat can lead to long-term attenuation of pain perception ; results of study 2 extend these findings of attenuation to both pain intensity and unpleasantness and show that this effect is highly specific to the exposed body side for both aspects of the pain experience . We suggest that the functional plasticity underlying this attenuation effect lies in brain areas with a strong contralateral pattern of pain-related activation The subjective experience of one 's environment is constructed by interactions among sensory , cognitive , and affective processes . For centuries , meditation has been thought to influence such processes by enabling a nonevaluative representation of sensory events . To better underst and how meditation influences the sensory experience , we used arterial spin labeling functional magnetic resonance imaging to assess the neural mechanisms by which mindfulness meditation influences pain in healthy human participants . After 4 d of mindfulness meditation training , meditating in the presence of noxious stimulation significantly reduced pain unpleasantness by 57 % and pain intensity ratings by 40 % when compared to rest . A two-factor repeated- measures ANOVA was used to identify interactions between meditation and pain-related brain activation . Meditation reduced pain-related activation of the contralateral primary somatosensory cortex . Multiple regression analysis was used to identify brain regions associated with individual differences in the magnitude of meditation-related pain reductions . Meditation-induced reductions in pain intensity ratings were associated with increased activity in the anterior cingulate cortex and anterior insula , areas involved in the cognitive regulation of nociceptive processing . Reductions in pain unpleasantness ratings were associated with orbitofrontal cortex activation , an area implicated in reframing the context ual evaluation of sensory events . Moreover , reductions in pain unpleasantness also were associated with thalamic deactivation , which may reflect a limbic gating mechanism involved in modifying interactions between afferent input and executive-order brain areas . Together , these data indicate that meditation engages multiple brain mechanisms that alter the construction of the subjectively available pain experience from afferent information & NA ; Inhibitory and facilitatory descending pathways , originating at higher central nervous system sites , modulate activity of dorsal horn nociceptive neurons , and thereby influence pain perception . Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain . The N‐methyl‐d‐aspartate receptor antagonist ketamine has a prolonged analgesic effect in chronic pain patients . This effect is due to desensitization of sensitized N‐methyl‐d‐aspartate receptors . Additionally , ketamine may modulate or enhance endogenous inhibitory control of pain perception . Diffuse noxious inhibitory control ( DNIC ) and offset analgesia ( OA ) are 2 mechanisms involved in descending inhibition . The present study investigates the effect of a ketamine infusion on subsequent DNIC and OA responses to determine whether ketamine has an influence on descending pain control . Ten healthy subjects ( 4 men/6 women ) received a 1‐hour placebo or S(+)‐ketamine ( 40 mg per 70 kg ) infusion on 2 separate occasions in r and om order . Upon the termination of the infusion , DNIC and OA responses were obtained . After placebo treatment , significant descending inhibition of pain responses was present for DNIC and OA . In contrast , after ketamine infusion , no DNIC was observed , but rather a significant facilitatory pain response ( P < 0.01 ) ; the OA response remained unchanged . These findings suggest that the balance between pain inhibition and pain facilitation was shifted by ketamine towards pain facilitation . The absence of an effect of ketamine on OA indicates differences in the mechanisms and neurotransmitter influences between OA and DNIC . Diffuse noxious inhibitory control responses following a 1‐hour low‐dose ketamine treatment displayed facilitation of pain in response to experimental noxious thermal stimulation The endogenous analgesia ( EA ) system is psychophysically evaluated using various paradigms , including conditioned pain modulation ( CPM ) and offset analgesia ( OA ) testing , respectively , the spatial and temporal filtering processes of noxious information . Though both paradigms assess the function of the EA system , it is still unknown whether they reflect the same aspects of EA and consequently whether they provide additive or equivalent data . Twenty-nine healthy volunteers ( 15 males ) underwent 5 trials of different stimulation conditions in r and om order including : ( 1 ) the classic OA three-temperature stimulus train ( ‘ OA ’ ) ; ( 2 ) a three-temperature stimulus train as control for the OA ( ‘ OAcon ’ ) ; ( 3 ) a constant temperature stimulus ( ‘ constant ’ ) ; ( 4 ) the classic parallel CPM ( ‘ CPM ’ ) ; and ( 5 ) a combination of OA and CPM ( ‘ OA + CPM ’ ) . We found that in males , the pain reduction during the OA + CPM condition was greater than during the OA ( P = 0.003 ) and CPM ( P = 0.07 ) conditions . Furthermore , a correlation was found between OA and CPM ( r = 0.62 , P = 0.01 ) at the time of maximum OA effect . The additive effect found suggests that the two paradigms represent at least partially different aspects of EA . The moderate association between the CPM and OA magnitudes indicates , on the other h and , some commonality of their underlying mechanisms BACKGROUND Tapentadol is an analgesic agent for treatment of acute and chronic pain that activates the µ-opioid receptor combined with inhibition of neuronal norepinephrine reuptake . Both mechanisms are implicated in activation of descending inhibitory pain pathways . In this study , we investigated the influence of tapentadol on conditioned pain modulation ( CPM , an experimental measure of endogenous pain inhibition that gates incoming pain signals as a consequence of a preceding tonic painful stimulus ) and offset analgesia ( OA , a test in which a disproportionally large amount of analgesia becomes apparent upon a slight decrease in noxious heat stimulation ) . METHODS Twenty-four patients with diabetic polyneuropathy ( DPN ) were r and omized to receive daily treatment with tapentadol sustained-release ( SR ) [ average daily dose 433 ( 31 ) mg ] or placebo for 4 weeks . CPM and OA were measured before and on the last day of treatment . RESULTS Before treatment , none of the patients had significant CPM or OA responses . At week 4 of treatment , CPM was significantly activated by tapentadol SR and coincided with significant analgesic responses . CPM increased from 9.1 (5.4)% ( baseline ) to 14.3 (7.2)% ( placebo ) and 24.2 (7.7)% ( tapentadol SR , P<0.001 vs  placebo ) ; relief of DPN pain was also greater in patients treated with tapentadol than placebo ( P=0.028 ) . Neither placebo nor tapentadol SR treatment had an effect on the magnitude of the OA responses ( P=0.78 ) . CONCLUSIONS Tapentadol 's analgesic effect in chronic pain patients with DPN is dependent on activation of descending inhibitory pain pathways as observed by CPM responses . CLINICAL TRIAL REGISTRATION The study was registered at trialregister.nl under number NTR2716 OBJECTIVE Temporal summation ( TS ) of pain , conditioned pain modulation ( CPM ) 
    Output:
    
OA can function as a non-opioid mediated assessment tool for endogenous pain inhibition , and activates brain regions such as periaqueductal gray ( PAG ) , dorsolateral prefontral cortex , insula , medulla , pons and cerebellum , indicating strong brain derived pain modulation .
The primary somatosensory cortex is , conversely , less activated during OA .
OA is decreased in neuropathic patients .
Nonetheless , evidence for the influence of individual factors on OA is limited .
OA and CPM seem to rely on different mechanisms .
This systematic review displays OA as a temporal filtering mechanisms that is more brain-derived compared to the spatial assessment method CPM .