***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: Background Offset analgesia is a disproportionate decrease of pain perception following a slight decrease of noxious thermal stimulus and attenuated in patients with neuropathic pain . We examined offset analgesia in patients with heterogeneous chronic pain disorders and used functional magnetic resonance imaging to explore modification of cerebral analgesic responses in comparison with healthy controls . Results We recruited seventeen patients with chronic pain and seventeen age- , sex-matched healthy controls . We gave a noxious thermal stimulation paradigm including offset analgesia and control stimuli on the left volar forearm , while we obtained a real-time continuous pain rating and a whole-brain functional magnetic resonance imaging . Baseline , first plateau ( 5 s ) , increment ( 5 s ) , and second plateau ( 20 s ) temperatures of offset analgesia stimulus were set at 32 ° C , 46 ° C , 47 ° C , and 46 ° C , respectively . Control stimulus included 30-s 46 ° C stimulus or only the first 10 s of offset analgesia stimulus . We evaluated magnitude of offset analgesia , analyzed cerebral activation by thermal stimulation , and further compared offset analgesia-related activation between the groups . Magnitude of offset analgesia was larger in controls than in patients ( median : 28.9 % ( interquartile range : 11.0–56.0 % ) vs. 19.0 % ( 4.2–48.7 % ) , p = 0.047 ) . During the second plateau , controls showed a larger blood oxygenation level-dependent activation than patients at the putamen , anterior cingulate , dorsolateral prefrontal cortices , nucleus accumbens , brainstem , and medial prefrontal cortex ( p < 0.05 ) , which are known to mediate either of descending pain modulation or reward responses . Offset analgesia-related activity at the anterior cingulate cortex was negatively correlated with neuropathic component of pain in patients with chronic pain ( p = 0.004 ) . Conclusions Attenuation of offset analgesia was associated with suppressed activation of the descending pain modulatory and reward systems in patients with chronic pain , at least in the studied cohort . The present findings might implicate both behavioral and cerebral plastic alterations contributing to chronification of pain . Clinical trial registry : The Japanese clinical trials registry ( UMIN-CTR , No. UMIN000011253 ; http://www.umin.ac.jp/ctr/ OBJECTIVE . The α2-agonist clonidine is an analgesic agent , whose yet uncertain action may involve either increase in pain modulation efficiency , change in autonomic function , and /or decrease in anxiety level . The present study aim ed to examine the effect of oral clonidine on pain perception in healthy subjects in order to reveal its mode of action . DESIGN . R and omized , double-blind , placebo-controlled study . SUBJECTS . Forty healthy subjects . METHODS . Subjects received either 0.15 mg oral clonidine or placebo . We measured pain parameters of heat pain thresholds , tonic heat stimulus , mechanical temporal summation , offset analgesia ( OA ) and conditioned pain modulation ( CPM ) ; autonomic parameters of deep breathing ratio and heart rate variability indices obtained before , during , and after tonic heat stimulus ; and psychological parameters of anxiety and pain catastrophizing . RESULTS . Clonidine decreased systolic blood pressure ( P = 0.022 ) and heart rate ( P = 0.004 ) and increased rMSSD ( P = 0.020 ) , though no effect was observed on pain perception , pain modulation , and psychological parameters . Autonomic changes were correlated with pain modulation capacity ; for OA , the separate slope model was significant ( P = 0.008 ) ; in the clonidine group , more efficient OA was associated with lower heart rate ( r = 0.633 , P = 0.005 ) , unlike in the placebo group . CONCLUSIONS . The change in autonomic function that was related to the increase in pain modulation capacity , and the lack of change in anxiety , suggest a combined modulatory-autonomic mode of analgesic action for clonidine & 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 Background There is evidence for augmented processing of pain and impaired endogenous pain inhibition in Fibromyalgia syndrome ( FM ) . In order to fully underst and the mechanisms involved in FM pathology , there is a need for closer investigation of endogenous pain modulation . In the present study , we compared the functional connectivity of the descending pain inhibitory network in age-matched FM patients and healthy controls (HC).We performed functional magnetic resonance imaging ( fMRI ) in 42 subjects ; 14 healthy and 28 age-matched FM patients ( 2 patients per HC ) , during r and omly presented , subjectively calibrated pressure pain stimuli . A seed-based functional connectivity analysis of brain activity was performed . The seed coordinates were based on the findings from our previous study , comparing the fMRI signal during calibrated pressure pain in FM and HC : the rostral anterior cingulate cortex ( rACC ) and thalamus . Results FM patients required significantly less pressure ( kPa ) to reach calibrated pain at 50 mm on a 0–100 visual analogue scale ( p < .001 , two-tailed ) . During fMRI scanning , the rACC displayed significantly higher connectivity to the amygdala , hippocampus , and brainstem in healthy controls , compared to FM patients . There were no regions where FM patients showed higher rACC connectivity . Thalamus showed significantly higher connectivity to the orbitofrontal cortex in healthy controls but no regions showed higher thalamic connectivity in FM patients . Conclusion Patients with FM displayed less connectivity within the brain ’s pain inhibitory network during calibrated pressure pain , compared to healthy controls . The present study provides brain-imaging evidence on how brain regions involved in homeostatic control of pain are less connected in FM patients . It is possible that the dysfunction of the descending pain modulatory network plays an important role in maintenance of FM pain and our results may translate into clinical implication s by using the functional connectivity of the pain modulatory network as an objective measure of pain dysregulation 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 : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity Summary The magnitude of offset analgesia is not altered by naloxone administration , by remifentanil analgesia , or during opioid‐induced hypersensitivity . Offset analgesia is therefore subserved by nonopio 
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Discussion : Results indicate that pain-free participants show a larger OA response when rating pain continuously compared with individuals with chronic pain