human
***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: The aim of the present study was to investigate the effects of nabilone on capsaicin‐induced pain and hyperalgesia , as well as on biomarkers of cannabinoid central nervous system ( CNS ) effects . A r and omized , double‐blind , placebo‐controlled , crossover study was conducted in 30 healthy male volunteers receiving single doses of nabilone ( 1 , 2 or 3 mg ) .  Pain intensity after intradermal capsaicin injections in the forearm was assessed by continuous visual analogue scale ( 0–100 mm ) . Capsaicin cream was applied to the calf to induce hyperalgesia . Primary hyperalgesia was assessed by measuring heat pain thresholds , whereas secondary hyperalgesia was assessed by measuring the area where light tactile stimulation was felt to be painful . Pain and hyperalgesia were measured at baseline and 2–3.5 h after dosing . The CNS effects were assessed at baseline and up to 24 h after dosing using visual analogue mood scales for feeling ‘ stimulated ’ , ‘ anxious ’ , ‘ se date d ’ and ‘ down ’ . Plasma sample s for pharmacokinetic analysis were obtained up to 24 h after drug administration . Nabilone did not significantly attenuate either ongoing pain or primary or secondary hyperalgesia , whereas dose‐dependent CNS effects were observed from 1.5 to 6 h after dosing , being maximal at 4–6 h. Plasma concentrations of nabilone and its metabolite carbinol were maximal 1–2 h after dosing . Adverse events ( AE ) were common on nabilone treatment . Four subjects withdrew due to pronounced CNS AE ( anxiety , agitation , altered perception , impaired consciousness ) . Although nabilone had marked CNS effects , no analgesic or antihyperalgesic effects were observed Medicinal cannabis has already entered mainstream medicine in some countries . This systematic review ( SR ) aim ed at evaluating the efficacy , acceptability and safety of cannabis-based medicines for chronic pain management . Qualitative systematic review of SRs of r and omized controlled trials with cannabis-based medicines for chronic pain management . The Cochrane data bases of SRs , Data base of Abstract s of Review s of Effects and PubMed were search ed for SR published in the period January 2009 to January 2017 . Assessment of the method ological quality of SR was performed by the AMSTAR checklist . Out of 748 papers identified , 10 SRs met the inclusion criteria . The method ological quality was high in four and moderate in six SRs . There were inconsistent findings of four SRs on the efficacy of cannabis-based medicines in neuropathic pain and of one SR for painful spasms in multiple sclerosis . There were consistent results that there was insufficient evidence of any cannabis-based medicine for pain management in patients with rheumatic diseases ( three SRs ) and in cancer pain ( two SRs ) . Cannabis-based medicines undoubtedly enrich the possibilities of drug treatment of chronic pain conditions . It remains the responsibility of the health care community to continue to pursue rigorous study of cannabis-based medicines to provide evidence that meets the st and ard of 21st century clinical care . SIGNIFICANCE We provide an overview of systematic review s on the efficacy , tolerability and safety of cannabis-based medicines for chronic pain management . There are inconsistent findings of the efficacy of cannabinoids in neuropathic pain and painful spasms in multiple sclerosis . There are inconsistent results on tolerability and safety of cannabis-based medicines for any chronic pain The effect of marijuana and placebo on pain tolerance was compared in cannabis-experienced and naive subjects . A statistically significant increase in tolerance was observed after smoking marijuana . Although there was no statistically significant interaction between the drug effect and having had previous cannabis experience , there was a definite trend towards a greater increase for the experienced ( 16 % ) compared to the naive group(8 % ) Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Evidence for an analgesic interaction between delta-9-tetrahydrocannabinol ( Delta(9)-THC ) and morphine was sought using an experimental pain model applied to normal volunteers . The study incorporated a double blinded , four treatment , four period , four sequence , crossover design . Subjects received Delta(9)-THC 5 mg orally or placebo and 90 min later morphine 0.02 mg/kg intravenously or placebo . Fifteen minutes later subjects rated the pain associated with the application of thermal stimuli to skin using two visual analog scales , one for the sensory and one for the affective aspects of pain . Among sensory responses , neither morphine nor Delta(9)-THC had a significant effect at the doses used , and there was no significant interaction between the two . Among affective responses , although neither morphine nor Delta(9)-THC had a significant effect , there was a positive analgesic interaction between the two ( p = 0.012 ) , indicating that the combination had a synergistic affective analgesic effect . The surprisingly limited reported experimental experience in humans does not support a role for Delta(9)-THC as an analgesic or as an adjunct to cannabinoid analgesia , except for our finding of synergy limited to the affective component of pain . Comparison of our results with those of others suggests that extrapolation from experimental pain models to the clinic is not likely to be a straight-forward process . Future studies of Delta(9)-THC or other cannabinoids in combination with opiates should focus upon clinical rather than experimental pain The aim of the present study was to develop a physiologically compatible inhalation solution of delta-9-tetrahydrocannabinol ( THC ) , and to compare the pharmacokinetic and analgesic properties of pulmonal THC versus pulmonal placebo and intravenous ( iv ) THC , respectively . Eight healthy volunteers were included in this r and omized , double-blind , crossover study . The aqueous THC formulations were prepared by using a solubilization technique . iv THC ( 0.053 mg/kg body weight ) , pulmonal THC ( 0.053 mg/kg ) , or a placebo inhalation solution was administered as single dose . At defined time points , blood sample s were collected , and somatic and psychotropic side effects as well as vital functions monitored . An ice water immersion test was performed to measure analgesia . Using a pressure-driven nebulizer , the pulmonal administration of the THC liquid aerosol result ed in high THC peak plasma levels within minutes . The bioavailability of the pulmonal THC was 28.7 + /- 8.2 % ( mean + /- SEM ) . The side effects observed after pulmonal THC were coughing and slight irritation of the upper respiratory tract , very mild psychotropic symptoms , and headache . The side effects after iv THC were much more prominent . Neither pulmonal nor iv THC significantly reduced experimentally induced pain Recent studies have demonstrated the therapeutic potential of cannabinoids to treat pain , yet none have compared the analgesic effectiveness of smoked marijuana to orally administered Δ9-tetrahydrocannabinol ( THC ; dronabinol ) . This r and omized , placebo-controlled , double-dummy , double-blind study compared the magnitude and duration of analgesic effects of smoked marijuana and dronabinol under well-controlled conditions using a vali date d experimental model of pain . Healthy male ( N=15 ) and female ( N=15 ) daily marijuana smokers participated in this outpatient study comparing the analgesic , subjective , and physiological effects of marijuana ( 0.00 , 1.98 , or 3.56 % THC ) to dronabinol ( 0 , 10 , or 20 mg ) . Pain response was assessed using the cold-pressor test ( CPT ) : participants immersed their left h and in cold water ( 4 ° C ) , and the time to report pain ( pain sensitivity ) and withdraw the h and from the water ( pain tolerance ) were recorded . Subjective pain and drug effect ratings were also measured as well as cardiovascular effects . Compared with placebo , marijuana and dronabinol decreased pain sensitivity ( 3.56 % ; 20 mg ) , increased pain tolerance ( 1.98 % ; 20 mg ) , and decreased subjective ratings of pain intensity ( 1.98 , 3.56 % ; 20 mg ) . The magnitude of peak change in pain sensitivity and tolerance did not differ between marijuana and dronabinol , although dronabinol produced analgesia that was of a longer duration . Marijuana ( 1.98 , 3.56 % ) and dronabinol ( 20 mg ) also increased abuse-related subjective ratings relative to placebo ; these ratings were greater with marijuana . These data indicate that under controlled conditions , marijuana and dronabinol decreased pain , with dronabinol producing longer-lasting decreases in pain sensitivity and lower ratings of abuse-related subjective effects than marijuana Background : Although the pre clinical literature suggests that cannabinoids produce antinociception and antihyperalgesic effects , efficacy in the human pain state remains unclear . Using a human experimental pain model , the authors hypothesized that inhaled cannabis would reduce the pain and hyperalgesia induced by intradermal capsaicin . Methods : In a r and omized , double-blinded , placebo-controlled , crossover trial in 15 healthy volunteers , the authors evaluated concentration – response effects of low- , medium- , and high-dose smoked cannabis ( respectively 2 % , 4 % , and 8 % 9-&dgr;-tetrahydrocannabinol by weight ) on pain and cutaneous hyperalgesia induced by intradermal capsaicin . Capsaicin was injected into opposite forearms 5 and 45 min after drug exposure , and pain , hyperalgesia , tetrahydrocannabinol plasma levels , and side effects were assessed . Results : Five minutes after cannabis exposure , there was no effect on capsaicin-induced pain at any dose . By 45 min after cannabis exposure , however , there was a significant decrease in capsaicin-induced pain with the medium dose and a significant increase in capsaicin-induced pain with the high dose . There was no effect seen with the low dose , nor was there an effect on the area of hyperalgesia at any dose . Significant negative correlations between pain perception and plasma & dgr;-9-tetrahydrocannabinol levels were found after adjusting for the overall dose effects . There was no significant difference in performance on the neuropsychological tests . Conclusions : This study suggests that there is a window of modest analgesia for smoked cannabis , with lower doses decreasing pain and higher doses increasing pain This article review s recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms , as well as r and omized clinical trials employing cannabinoids in pain treatment .  Tetrahydrocannabinol ( THC , Marinol ® ) and nabilone ( Cesamet ® ) are currently approved in the United States and other countries , but not for pain indications . Other synthetic cannabinoids , such as ajulemic acid , are in development . Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation . Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC ( partial CB1 receptor agonist ) and cannabidiol ( CBD , a non-euphoriant , anti-inflammatory analgesic with CB1 receptor antagonist and endocannabinoid modulating effects ) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis , and in 2007 for intractable cancer pain . Numerous r and omized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain , rheumatoid arthritis and cancer pain . An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006 . Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles . Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise Background The grading of recommendation , assessment , development and evaluation ( GRADE ) approach is widely implemented in health technology assessment and guideline development organisations throughout the world . GRADE provides a transparent approach to reaching judgements about the quality of evidence on the effects of a health care intervention , but is complex and therefore challenging to apply in a consistent manner . Methods We developed a checklist to guide the research er to extract the data required to make a GRADE assessment . We applied the checklist to 29 meta-analyses of r and omised controlled trials on the effectiveness of health care interventions . Two review ers used the checklist for each paper and used these data to rate the quality of evidence for a particular outcome . Results For most ( 70 % ) checklist items , there was good agreement between review ers . The main problems were for items relating to indirectness where considerable judgement is required . Conclusions There was consistent agreement between review ers on most items in the checklist . The use of this checklist may be an aid to improving the consistency and reproducibility of GRADE assessment s , particularly for inexperienced users or in rapid review s without the re sources to conduct assessment s by two research ers independently The purpose of this study was to determine whether marijuana produced dose-dependent antinociception in humans and , if so , whether endogenous opiates modulate this effect . A total of five male regular marijuana users participated in three test sessions during which 
    Output:
    
agent
Conclusions and Relevance Cannabinoid drugs may prevent the onset of pain by producing small increases in pain thresholds but may not reduce the intensity of experimental pain already being experienced ; instead , cannabinoids may make experimental pain feel less unpleasant and more tolerable , suggesting an influence on affective processes .
Cannabis-induced improvements in pain-related negative affect may underlie the widely held belief that cannabis relieves pain
***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: The aim of the present study was to investigate the effects of nabilone on capsaicin‐induced pain and hyperalgesia , as well as on biomarkers of cannabinoid central nervous system ( CNS ) effects . A r and omized , double‐blind , placebo‐controlled , crossover study was conducted in 30 healthy male volunteers receiving single doses of nabilone ( 1 , 2 or 3 mg ) .  Pain intensity after intradermal capsaicin injections in the forearm was assessed by continuous visual analogue scale ( 0–100 mm ) . Capsaicin cream was applied to the calf to induce hyperalgesia . Primary hyperalgesia was assessed by measuring heat pain thresholds , whereas secondary hyperalgesia was assessed by measuring the area where light tactile stimulation was felt to be painful . Pain and hyperalgesia were measured at baseline and 2–3.5 h after dosing . The CNS effects were assessed at baseline and up to 24 h after dosing using visual analogue mood scales for feeling ‘ stimulated ’ , ‘ anxious ’ , ‘ se date d ’ and ‘ down ’ . Plasma sample s for pharmacokinetic analysis were obtained up to 24 h after drug administration . Nabilone did not significantly attenuate either ongoing pain or primary or secondary hyperalgesia , whereas dose‐dependent CNS effects were observed from 1.5 to 6 h after dosing , being maximal at 4–6 h. Plasma concentrations of nabilone and its metabolite carbinol were maximal 1–2 h after dosing . Adverse events ( AE ) were common on nabilone treatment . Four subjects withdrew due to pronounced CNS AE ( anxiety , agitation , altered perception , impaired consciousness ) . Although nabilone had marked CNS effects , no analgesic or antihyperalgesic effects were observed Medicinal cannabis has already entered mainstream medicine in some countries . This systematic review ( SR ) aim ed at evaluating the efficacy , acceptability and safety of cannabis-based medicines for chronic pain management . Qualitative systematic review of SRs of r and omized controlled trials with cannabis-based medicines for chronic pain management . The Cochrane data bases of SRs , Data base of Abstract s of Review s of Effects and PubMed were search ed for SR published in the period January 2009 to January 2017 . Assessment of the method ological quality of SR was performed by the AMSTAR checklist . Out of 748 papers identified , 10 SRs met the inclusion criteria . The method ological quality was high in four and moderate in six SRs . There were inconsistent findings of four SRs on the efficacy of cannabis-based medicines in neuropathic pain and of one SR for painful spasms in multiple sclerosis . There were consistent results that there was insufficient evidence of any cannabis-based medicine for pain management in patients with rheumatic diseases ( three SRs ) and in cancer pain ( two SRs ) . Cannabis-based medicines undoubtedly enrich the possibilities of drug treatment of chronic pain conditions . It remains the responsibility of the health care community to continue to pursue rigorous study of cannabis-based medicines to provide evidence that meets the st and ard of 21st century clinical care . SIGNIFICANCE We provide an overview of systematic review s on the efficacy , tolerability and safety of cannabis-based medicines for chronic pain management . There are inconsistent findings of the efficacy of cannabinoids in neuropathic pain and painful spasms in multiple sclerosis . There are inconsistent results on tolerability and safety of cannabis-based medicines for any chronic pain The effect of marijuana and placebo on pain tolerance was compared in cannabis-experienced and naive subjects . A statistically significant increase in tolerance was observed after smoking marijuana . Although there was no statistically significant interaction between the drug effect and having had previous cannabis experience , there was a definite trend towards a greater increase for the experienced ( 16 % ) compared to the naive group(8 % ) Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Evidence for an analgesic interaction between delta-9-tetrahydrocannabinol ( Delta(9)-THC ) and morphine was sought using an experimental pain model applied to normal volunteers . The study incorporated a double blinded , four treatment , four period , four sequence , crossover design . Subjects received Delta(9)-THC 5 mg orally or placebo and 90 min later morphine 0.02 mg/kg intravenously or placebo . Fifteen minutes later subjects rated the pain associated with the application of thermal stimuli to skin using two visual analog scales , one for the sensory and one for the affective aspects of pain . Among sensory responses , neither morphine nor Delta(9)-THC had a significant effect at the doses used , and there was no significant interaction between the two . Among affective responses , although neither morphine nor Delta(9)-THC had a significant effect , there was a positive analgesic interaction between the two ( p = 0.012 ) , indicating that the combination had a synergistic affective analgesic effect . The surprisingly limited reported experimental experience in humans does not support a role for Delta(9)-THC as an analgesic or as an adjunct to cannabinoid analgesia , except for our finding of synergy limited to the affective component of pain . Comparison of our results with those of others suggests that extrapolation from experimental pain models to the clinic is not likely to be a straight-forward process . Future studies of Delta(9)-THC or other cannabinoids in combination with opiates should focus upon clinical rather than experimental pain The aim of the present study was to develop a physiologically compatible inhalation solution of delta-9-tetrahydrocannabinol ( THC ) , and to compare the pharmacokinetic and analgesic properties of pulmonal THC versus pulmonal placebo and intravenous ( iv ) THC , respectively . Eight healthy volunteers were included in this r and omized , double-blind , crossover study . The aqueous THC formulations were prepared by using a solubilization technique . iv THC ( 0.053 mg/kg body weight ) , pulmonal THC ( 0.053 mg/kg ) , or a placebo inhalation solution was administered as single dose . At defined time points , blood sample s were collected , and somatic and psychotropic side effects as well as vital functions monitored . An ice water immersion test was performed to measure analgesia . Using a pressure-driven nebulizer , the pulmonal administration of the THC liquid aerosol result ed in high THC peak plasma levels within minutes . The bioavailability of the pulmonal THC was 28.7 + /- 8.2 % ( mean + /- SEM ) . The side effects observed after pulmonal THC were coughing and slight irritation of the upper respiratory tract , very mild psychotropic symptoms , and headache . The side effects after iv THC were much more prominent . Neither pulmonal nor iv THC significantly reduced experimentally induced pain Recent studies have demonstrated the therapeutic potential of cannabinoids to treat pain , yet none have compared the analgesic effectiveness of smoked marijuana to orally administered Δ9-tetrahydrocannabinol ( THC ; dronabinol ) . This r and omized , placebo-controlled , double-dummy , double-blind study compared the magnitude and duration of analgesic effects of smoked marijuana and dronabinol under well-controlled conditions using a vali date d experimental model of pain . Healthy male ( N=15 ) and female ( N=15 ) daily marijuana smokers participated in this outpatient study comparing the analgesic , subjective , and physiological effects of marijuana ( 0.00 , 1.98 , or 3.56 % THC ) to dronabinol ( 0 , 10 , or 20 mg ) . Pain response was assessed using the cold-pressor test ( CPT ) : participants immersed their left h and in cold water ( 4 ° C ) , and the time to report pain ( pain sensitivity ) and withdraw the h and from the water ( pain tolerance ) were recorded . Subjective pain and drug effect ratings were also measured as well as cardiovascular effects . Compared with placebo , marijuana and dronabinol decreased pain sensitivity ( 3.56 % ; 20 mg ) , increased pain tolerance ( 1.98 % ; 20 mg ) , and decreased subjective ratings of pain intensity ( 1.98 , 3.56 % ; 20 mg ) . The magnitude of peak change in pain sensitivity and tolerance did not differ between marijuana and dronabinol , although dronabinol produced analgesia that was of a longer duration . Marijuana ( 1.98 , 3.56 % ) and dronabinol ( 20 mg ) also increased abuse-related subjective ratings relative to placebo ; these ratings were greater with marijuana . These data indicate that under controlled conditions , marijuana and dronabinol decreased pain , with dronabinol producing longer-lasting decreases in pain sensitivity and lower ratings of abuse-related subjective effects than marijuana Background : Although the pre clinical literature suggests that cannabinoids produce antinociception and antihyperalgesic effects , efficacy in the human pain state remains unclear . Using a human experimental pain model , the authors hypothesized that inhaled cannabis would reduce the pain and hyperalgesia induced by intradermal capsaicin . Methods : In a r and omized , double-blinded , placebo-controlled , crossover trial in 15 healthy volunteers , the authors evaluated concentration – response effects of low- , medium- , and high-dose smoked cannabis ( respectively 2 % , 4 % , and 8 % 9-&dgr;-tetrahydrocannabinol by weight ) on pain and cutaneous hyperalgesia induced by intradermal capsaicin . Capsaicin was injected into opposite forearms 5 and 45 min after drug exposure , and pain , hyperalgesia , tetrahydrocannabinol plasma levels , and side effects were assessed . Results : Five minutes after cannabis exposure , there was no effect on capsaicin-induced pain at any dose . By 45 min after cannabis exposure , however , there was a significant decrease in capsaicin-induced pain with the medium dose and a significant increase in capsaicin-induced pain with the high dose . There was no effect seen with the low dose , nor was there an effect on the area of hyperalgesia at any dose . Significant negative correlations between pain perception and plasma & dgr;-9-tetrahydrocannabinol levels were found after adjusting for the overall dose effects . There was no significant difference in performance on the neuropsychological tests . Conclusions : This study suggests that there is a window of modest analgesia for smoked cannabis , with lower doses decreasing pain and higher doses increasing pain This article review s recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms , as well as r and omized clinical trials employing cannabinoids in pain treatment .  Tetrahydrocannabinol ( THC , Marinol ® ) and nabilone ( Cesamet ® ) are currently approved in the United States and other countries , but not for pain indications . Other synthetic cannabinoids , such as ajulemic acid , are in development . Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation . Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC ( partial CB1 receptor agonist ) and cannabidiol ( CBD , a non-euphoriant , anti-inflammatory analgesic with CB1 receptor antagonist and endocannabinoid modulating effects ) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis , and in 2007 for intractable cancer pain . Numerous r and omized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain , rheumatoid arthritis and cancer pain . An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006 . Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles . Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise Background The grading of recommendation , assessment , development and evaluation ( GRADE ) approach is widely implemented in health technology assessment and guideline development organisations throughout the world . GRADE provides a transparent approach to reaching judgements about the quality of evidence on the effects of a health care intervention , but is complex and therefore challenging to apply in a consistent manner . Methods We developed a checklist to guide the research er to extract the data required to make a GRADE assessment . We applied the checklist to 29 meta-analyses of r and omised controlled trials on the effectiveness of health care interventions . Two review ers used the checklist for each paper and used these data to rate the quality of evidence for a particular outcome . Results For most ( 70 % ) checklist items , there was good agreement between review ers . The main problems were for items relating to indirectness where considerable judgement is required . Conclusions There was consistent agreement between review ers on most items in the checklist . The use of this checklist may be an aid to improving the consistency and reproducibility of GRADE assessment s , particularly for inexperienced users or in rapid review s without the re sources to conduct assessment s by two research ers independently The purpose of this study was to determine whether marijuana produced dose-dependent antinociception in humans and , if so , whether endogenous opiates modulate this effect . A total of five male regular marijuana users participated in three test sessions during which 
    Output:
    