Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial

Svendsen, Kristina Bacher; Jensen, Troels Staehelin; Bach, Flemming W.

doi:10.1136/bmj.38149.566979.ae

Cited by 429 publications

(303 citation statements)

References 45 publications

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“…Similarly, oral administration of 15 mg THC reduced the affective ratings of heat pain stimuli (Lee et al, 2013). The notion that THC influences predominantly the affective components of pain is further corroborated by THC's reported efficacy in chronic pain conditions (Abrams et al, 2007;Berman et al, 2004;Noyes et al, 1975;Nurmikko et al, 2007;Svendsen et al, 2004), especially when a psychological component such as pronounced distress is involved (Fernandez and Turk, 1992;Martin and Lichtman, 1998).…”

Section: Discussionmentioning

confidence: 54%

Brain Mapping-Based Model of Δ9-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix

Walter

Oertel

Felden

et al. 2015

Neuropsychopharmacol

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Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) has progressed with justified caution, which also owes to the incomplete mechanistic understanding of its analgesic effects, in particular its interference with the processing of sensory or affective components of pain. The present placebo-controlled crossover study therefore focused on the effects of 20 mg oral THC on the connectivity between brain areas of the pain matrix following experimental stimulation of trigeminal nocisensors in 15 non-addicted healthy volunteers. A general linear model (GLM) analysis identified reduced activations in the hippocampus and the anterior insula following THC administration. However, assessment of psychophysiological interaction (PPI) revealed that the effects of THC first consisted in a weakening of the interaction between the thalamus and the secondary somatosensory cortex (S2). From there, dynamic causal modeling (DCM) was employed to infer that THC attenuated the connections to the hippocampus and to the anterior insula, suggesting that the reduced activations in these regions are secondary to a reduction of the connectivity from somatosensory regions by THC. These findings may have consequences for the way THC effects are currently interpreted: as cannabinoids are increasingly considered in pain treatment, present results provide relevant information about how THC interferes with the affective component of pain. Specifically, the present experiment suggests that THC does not selectively affect limbic regions, but rather interferes with sensory processing which in turn reduces sensory-limbic connectivity, leading to deactivation of affective regions.

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Section: Discussionmentioning

confidence: 54%

Brain Mapping-Based Model of Δ9-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix

Walter

Oertel

Felden

et al. 2015

Neuropsychopharmacol

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“…In addition, Sativex®, a 1:1 THC: CBD ratio oromucosal spray formulation, is currently marketed in Canada for treatment of neuropathic pain associated with multiple sclerosis. Indeed, separate clinical studies have demonstrated that dronabinol (oral THC) (Svendsen et al, 2004), GW-2000-02 (oromucosal spray containing primarily THC), and GW-1000-02 (Sativex) (Berman et al, 2004) were marginally, yet significantly, effective against pain symptoms associated with multiple sclerosis, although each drug produced greater adverse events than placebo treatment. In that study comparisons were only made to placebo treatment.…”

Section: Preclinical and Clinical Interactions Between Thc And Cbdmentioning

confidence: 99%

Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Δ9-tetrahydrocannabinol

Vann

Gamage

Warner

et al. 2008

Drug and Alcohol Dependence

114

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Cannabis sativa (marijuana plant) contains myriad cannabinoid compounds; yet, investigative attention has focused almost exclusively on Δ 9 -tetrahydrocannabinol (THC), its primary psychoactive substituent. Interest in modulation of THC's effects by these other cannabinoids [e.g., cannabidiol (CBD)] has been stimulated anew by recent approval by Canada of Sativex (a 1:1 dose ratio combination of CBD:THC) for the treatment of multiple sclerosis. The goal of this study was to determine the degree to which THC's abuse-related effects were altered by co-administration of CBD. To this end, CBD and THC were assessed alone and in combination in a two-lever THC discrimination procedure in Long-Evans rats and in a conditioned place preference/aversion (CPP/ A) model in ICR mice. CBD did not alter the discriminative stimulus effects of THC at any CBD:THC dose ratio tested. In contrast, CBD, at CBD:THC dose ratios of 1:1 and 1:10, reversed CPA produced by acute injection with 10 mg/kg THC. When administered alone, CBD did not produce effects in either procedure. These results suggest that CBD, when administered with THC at therapeutically relevant ratios, may ameliorate aversive effects (e.g., dysphoria) often associated with initial use of THC alone. While this effect may be beneficial for therapeutic usage of a CBD:THC combination medication, our discrimination results showing that CBD did not alter THC's discriminative stimulus effects suggest that CBD:THC combination medications may also produce THC-like subjective effects at these dose ratios.

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“…Peak subjective ratings of dronabinol's drug effects occurred 60 min after administration, whereas dronabinol-induced decreases in pain sensitivity and increases in pain tolerance were highest about 4 h after drug administration, suggesting that the magnitude and time course of these subjective drug effects do not necessarily predict analgesia in the CPT. Clinical studies have demonstrated the analgesic effectiveness of cannabinoids including marijuana and dronabinol in neuropathic pain populations (Svendsen et al, 2004;Abrams et al, 2007;Nurmikko et al, 2007;Wilsey et al, 2008;Ellis et al, 2009;Ware et al, 2010). However, the cannabinoids proved to be less effective in attenuating other pain modalities; dronabinol (5 mg) failed to decrease postoperative pain (Buggy et al, 2003) and sensitivity to a thermal stimulus (Roberts et al, 2006), and a higher dronabinol dose (20 mg) failed to reduce acute inflammatory pain, hyperalgesia (Kraft et al, 2008), or increase pain threshold in a pressure test (Naef et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Cannabinoids have long been thought to be effective in reducing pain (Russo, 2008) and findings from doubleblind, placebo-controlled studies have substantiated such hypotheses demonstrating that smoked and vaporized marijuana (Abrams et al, 2007;Ellis et al, 2009;Wilsey et al, 2008Wilsey et al, , 2013, oral D 9 -tetrahydrocannabinol (THC; dronabinol), the primary psychoactive component of marijuana (Mechoulam et al, 1970;Svendsen et al, 2004), and Sativex , an oromucuosal preparation of THC and cannabidiol, decrease subjective ratings of pain in neuropathic pain populations. Because of its recent legalization for medical use in a number of US states (Hoffmann and Weber, 2010), marijuana is now being prescribed therapeutically to manage a wide variety of pain conditions (Reinarman et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…As discussed above, clinical studies have demonstrated the analgesic effects of cannabinoids in pain patients (Svendsen et al, 2004;Abrams et al, 2007;Nurmikko et al, 2007;Wilsey et al, 2008;Ellis et al, 2009;Ware et al, 2010), but none have compared the effects of marijuana to dronabinol. Therefore, this within-subject, randomized, placebo-controlled, double-dummy, double-blind study directly compared the therapeutic analgesic potential of marijuana to dronabinol in response to a laboratory measure of acute pain in healthy, daily marijuana smokers.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of the Analgesic Effects of Dronabinol and Smoked Marijuana in Daily Marijuana Smokers

Cooper

Comer

Haney

2013

Neuropsychopharmacol

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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 D 9 -tetrahydrocannabinol (THC; dronabinol). This randomized, placebocontrolled, double-dummy, double-blind study compared the magnitude and duration of analgesic effects of smoked marijuana and dronabinol under well-controlled conditions using a validated experimental model of pain. Healthy male (N ¼ 15) and female (N ¼ 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 hand in cold water (4 1C), and the time to report pain (pain sensitivity) and withdraw the hand 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.

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Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial

Cited by 429 publications

References 45 publications

Brain Mapping-Based Model of Δ9-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix

Brain Mapping-Based Model of Δ9-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix

Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Δ9-tetrahydrocannabinol

Comparison of the Analgesic Effects of Dronabinol and Smoked Marijuana in Daily Marijuana Smokers

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