title: Lack of effect of central nervous system‐active doses of nabilone on capsaicin‐induced pain and hyperalgesia Efficacy, tolerability and safety of cannabis‐based medicines for chronic pain management – An overview of systematic reviews Marijuana-produced changes in pain tolerance. Experienced and non-experienced subjects. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Development and pharmacokinetic characterization of pulmonal and intravenous delta-9-tetrahydrocannabinol (THC) in humans. Comparison of the Analgesic Effects of Dronabinol and Smoked Marijuana in Daily Marijuana Smokers Dose-dependent Effects of Smoked Cannabis on Capsaicin-induced Pain and Hyperalgesia in Healthy Volunteers Cannabinoids in the management of difficult to treat pain A checklist designed to aid consistency and reproducibility of GRADE assessments: development and pilot validation Antinociceptive, subjective and behavioral effects of smoked marijuana in humans. The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions Developing optimal search strategies for detecting clinically sound treatment studies in EMBASE. PEDro. A database of randomized trials and systematic reviews in physiotherapy. Marihuana and pain Analgesic and antihyperalgesic effects of nabilone on experimental heat pain.
abstract: 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 they smoked cigarettes containing 0 % ( placebo ) and 3 . 55 % Delta(9)-tetrahydrocannabinol ( Delta(9)-THC ) ( active ) . Each of four controlled smoking bouts per session , spaced at 40-min intervals , consisted of nine puffs from active and placebo cigarettes ( three cigarettes , three puffs per cigarette , one puff per min ) . During successive bouts , participants smoked 0 , 3 , 6 and 9 ( 0 , 3 , 9 and 18 cumulative ) puffs from active marijuana cigarettes , with the remainder of puffs from placebo cigarettes . Test sessions were identical , except for naltrexone 0 , 50 or 200 mg p.o . ( r and omized , double-blind ) administration 1 h before the first smoking bout on the different days . Before smoking , between smoking bouts and postsmoking , participants completed an assessment battery that included antinociceptive ( finger withdrawal from radiant heat stimulation ) , biological , subjective , observer-rated signs and performance measures . Marijuana produced significant dose-dependent antinociception ( increased finger withdrawal latency ) and biobehavioral effects . Naltrexone did not significantly influence marijuana dose-effect curves , suggesting no role of endogenous opiates in marijuana-induced antinociception under these conditions From folk medicine and anecdotal reports it is known that Cannabis may reduce pain .  In animal studies it has been shown that delta‐9‐tetrahydrocannabinol ( THC ) has antinociceptive effects or potentiates the antinociceptive effect of morphine . The aim of this study was to measure the analgesic effect of THC , morphine , and a THC‐morphine combination ( THC‐morphine ) in humans using experimental pain models .  THC ( 20 mg ) , morphine ( 30 mg ) , THC‐morphine ( 20 mg THC+30 mg morphine ) , or placebo were given orally and as single doses . Twelve healthy volunteers were included in the r and omized , placebo‐controlled , double‐blinded , crossover study . The experimental pain tests ( order r and omized ) were heat , cold , pressure , single and repeated transcutaneous electrical stimulation . Additionally , reaction time , side‐effects ( visual analog scales ) , and vital functions were monitored . For the pharmacokinetic profiling , blood sample s were collected . THC did not significantly reduce pain . In the cold and heat tests it even produced hyperalgesia , which was completely neutralized by THC‐morphine . A slight additive analgesic effect could be observed for THC‐morphine in the electrical stimulation test . No analgesic effect result ed in the pressure and heat test , neither with THC nor THC‐morphine . Psychotropic and somatic side‐effects ( sleepiness , euphoria , anxiety , confusion , nausea , dizziness , etc . ) were common , but usually mild OBJECTIVE The ability to accurately identify articles about therapy in large bibliographic data bases such as EMBASE is important for research ers and clinicians . Our study aim ed to develop optimal search strategies for detecting sound treatment studies in EMBASE in the year 2000 . METHODS H and search es of journals were compared with retrievals from EMBASE for c and i date search strategies . Six trained research assistants review ed fifty-five journals indexed in EMBASE and rated articles using purpose and quality indicators . C and i date search strategies were developed for identifying treatment articles and then tested , and the retrievals were compared with the h and - search data . The operating characteristics of the strategies were calculated . RESULTS Three thous and eight hundred fifty articles were original studies on treatment , of which 1,256 ( 32.6 % ) were method ologically sound . Combining search terms revealed a top performing strategy ( r and om:.tw . OR clinical trial:.mp . OR exp health care quality ) with sensitivity of 98.9 % and specificity of 72.0 % . Maximizing specificity , a top performing strategy ( double-blind:.mp . OR placebo:.tw . OR blind : .tw . ) achieved a value over 96.0 % , but with compromised sensitivity at 51.7 % . A 3-term strategy achieved the best optimization of sensitivity and specificity ( r and om:.tw . OR placebo:.mp . OR double-blind:.tw . ) , with both these values over 92.0 % . CONCLUSION Search strategies can achieve high performance for retrieving sound treatment studies in EMBASE This paper describes PEDro , the Physiotherapy Evidence Data base . PEDro is a web-based data base of r and omized controlled trials and systematic review s in physiotherapy . It can be accessed free of charge at http://ptwww.cchs.usyd.edu.au/pedro . The data base contains bibliographic details and abstract s of most English- language r and omized trials and systematic review s in physiotherapy , and of many trials and review s in other language s. Trials on the data base are rated on the basis of their method ological quality so that users of the data base can quickly identify trials of high quality . Trials and systematic review s are extensively indexed to facilitate search ing . PEDro provides an important information re source to support evidence -based clinical practice Twenty-six men participated in a study of pain and sensation thresholds and pain tolerance .  Cutaneous electrical stimulation was applied to the subjects ’ fingers and thresholds were determined before and after smoking marihuana . It was found that marihuana affected thresholds by increasing sensitivity to both painful and nonpainful stimulation and reducing tolerance for pain OBJECTIVE In this study , we explored the analgesic and antihyperalgesic properties of a synthetic cannabinoid ( nabilone ) on experimental heat pain in men and women , as well as its effects on descending pain inhibitory systems . RESEARCH DESIGN AND METHODS A double-blind , placebo controlled , crossover study of nabilone single doses of 0.5 and 1 mg was conducted . Excitatory systems were elicited using a temporal summation test ( tonic heat pain evoked by a Peltier thermode ) administered before and after activation of descending inhibitory control ( triggered using a counter-irritation procedure ) . These tests were given before and after drug treatment . Primary outcome measures included average heat pain , temporal summation of heat pain , and drug-induced changes in the strength of descending analgesia . Possible adverse reactions were monitored throughout treatment . Seven men ( mean age = 22.5 years , SD = + /- 1.5 ) and 10 women ( mean age = 23.2 years , SD = + /- 2.8 ) completed this study . RESULTS Nabilone ( 1 mg and 0.5 mg ) did not reduce the global pain intensity experienced during tonic heat pain ( all values of p > 0.18 ) . It also failed to potentiate the strength of descending inhibitory responses ( all values of p > 43 ) . Nevertheless , at the highest dose ( 1 mg ) , and only for women , nabilone significantly ( p = 0.003 ) dampened the temporal summation experienced during the last portion of the tonic heat pulse test ( i.e. , the period of time during which temporal summation is greatest ) . This antihyperalgesic effect was not observed for men ( at either 0.5 mg or 1 mg dose ) , suggesting that the antihyperalgesic properties of cannabinoids are greater for women than for men . Adverse reactions encountered were generally mild and did not provoke the cessation of testing . CONCLUSIONS Nabilone failed to produce analgesic effects and it did not interact with descending pain inhibitory systems . However , we found that a single 1 mg dose of nabilone reduced temporal summation for women but not men . Although a titration regime and a larger sample of subjects might have provided more robust effects , these preliminary results suggest that nabilone appears effective at relieving hyperalgesic responses in women . Possible neurobiological mechanisms and clinical implication s are further discussed
target: 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
background: Importance Cannabinoid drugs are widely used as analgesics , but experimental pain studies have produced mixed findings .
  The analgesic properties of cannabinoids remain unclear .
  Objective To conduct a systematic review and meta- analysis of the association between cannabinoid drug administration and experimental pain outcomes in studies of healthy adults .