Lack of Analgesia by Oral Standardized Cannabis Extract on Acute Inflammatory Pain and Hyperalgesia in Volunteers

Kraft, Birgit; Frickey, Nathalie; Kaufmann, Rainer; Reif, Marcus; Frey, Richard; Gustorff, Burkhard; Kress, Hans G.

doi:10.1097/aln.0b013e31817881e1

Cited by 113 publications

(108 citation statements)

References 46 publications

(51 reference statements)

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“…However, it must be borne in mind that the reduced pain sensitivity in CB1 receptor-deficient mice and the analgesic action of CB1 receptor antagonists is limited to activity-dependent pain sensitization and has not been observed in inflammatory or neuropathic pain models. This is supported by findings from acute human pain models [15,22], as well as from clinical studies in postoperative pain patients. In these settings, cannabinoids not only failed to show an analgesic effect, but instead resulted in increased pain.…”

Section: Disinhibition Following Nociceptor Stimulationsupporting

confidence: 67%

Spinal neuroplasticity in chronic pain

Zeilhofer

2011

E-Neuroforum

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Neuroplastic changes play an important role in the generation and maintenance of chronic pain syndromes. Such changes occur at all levels of the neuraxis, from the peripheral terminals of primary sensory neurons to the cerebral cortex. Changes observed in the spinal dorsal horn in particular provide a mechanistic basis for many of the characteristics of chronic pain syndromes. While facilitated synaptic transmission between nociceptive fibers and spinal projection neurons contributes to enhanced perception of noxious stimuli (hyperalgesia), diminished function of GABA-ergic and glycinergic interneurons not only induces hyperalgesia, but also triggers nociceptive reactions on exposure to innocuous stimuli and spontaneous pain behavior in the absence of any sensory stimulation. Spinal disinhibition thus recapitulates typical symptoms of chronic pathological pain syndromes. Studies performed by various groups over the last 10 years demonstrate that such spinal disinhibition occurs naturally in response to peripheral inflammation and nerve damage. The present article summarizes current status of this research.

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Section: Disinhibition Following Nociceptor Stimulationsupporting

confidence: 67%

Spinal neuroplasticity in chronic pain

Zeilhofer

2011

E-Neuroforum

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“…In view of these attributes, we have argued that assays of pain-depressed behavior may complement conventional assays of pain-stimulated behavior and increase the predictive validity of preclinical candidate analgesic assessment (Negus et al, , 2010a. Given the poor efficacy of THC and other cannabinoid receptor agonists to treat acute pain in humans (Raft et al, 1977;Buggy et al, 2003;Naef et al, 2003;Beaulieu, 2006;Kraft et al, 2008;Klooker et al, 2011) we predicted that THC and CP55940 would not produce antinociception in assays of acute pain-depressed behavior in rats despite the apparent efficacy of these drugs in standard assays of pain-stimulated behavior.…”

Section: Introductionmentioning

confidence: 99%

“…Results with THC and CP55940 have illustrated this discordance insofar as cannabinoid agonists produce robust and reliable antinociception in most assays of acute pain-stimulated behavior but little or no analgesia against acute pain in humans (Rice, 2006;Karst et al, 2010;Kraft, 2012). For example, oral delivery of THC or other cannabinoids lacked analgesic efficacy or exacerbated pain in most well controlled clinical studies of postoperative or acute experimental pain (Raft et al, 1977;Buggy et al, 2003;Naef et al, 2003;Beaulieu, 2006;Kraft et al, 2008;Klooker et al, 2011); for the lone exception, see Campbell et al (2001). Likewise, smoked marijuana at doses up to those producing untoward motor/cognitive/subjective effects produced little or no change in sensitivity to acute thermal, mechanical, or chemical noxious stimuli in clinical laboratory studies, and as with oral cannabinoids, pain ratings were sometimes worsened by smoked cannabis (Greenwald and Stitzer, 2000;Wallace et al, 2007).…”

mentioning

confidence: 99%

Dissociable Effects of the Cannabinoid Receptor Agonists Δ⁹-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

Kwilasz

Negus

2012

J Pharmacol Exp Ther

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Cannabinoid receptor agonists produce reliable antinociception in most preclinical pain assays but have inconsistent analgesic efficacy in humans. This disparity suggests that conventional preclinical assays of nociception are not sufficient for the prediction of cannabinoid effects related to clinical analgesia. To extend the range of preclinical cannabinoid assessment, this study compared the effects of the marijuana constituent and low-efficacy cannabinoid agonist ⌬ 9 -tetrahydrocannabinol (THC) and the high-efficacy synthetic cannabinoid agonist 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol (CP55940) in assays of pain-stimulated and paindepressed behavior. Intraperitoneal injection of dilute lactic acid (1.8% in 1 ml/kg) stimulated a stretching response or depressed intracranial self-stimulation (ICSS) in separate groups of male Sprague-Dawley rats. THC (0.1-10 mg/kg) and CP55940 (0.0032-0.32 mg/kg) dose-dependently blocked acidstimulated stretching but only exacerbated acid-induced depression of ICSS at doses that also decreased control ICSS in the absence of a noxious stimulus. Repeated THC produced tolerance to sedative rate-decreasing effects of THC on control ICSS in the absence of the noxious stimulus but failed to unmask antinociception in the presence of the noxious stimulus. THC and CP55940 also failed to block pain-related depression of feeding in rats, although THC did attenuate satiationrelated depression of feeding. In contrast to the effects of the cannabinoid agonists, the clinically effective analgesic and nonsteroidal anti-inflammatory drug ketoprofen (1 mg/kg) blocked acid-stimulated stretching and acid-induced depression of both ICSS and feeding. The poor efficacy of THC and CP55940 to block acute pain-related depression of behavior in rats agrees with the poor efficacy of cannabinoids to treat acute pain in humans.

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“…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). Although dronabinol did not produce analgesia in these experimental pain models, a single study successfully demonstrated the effectiveness of smoked marijuana in reducing sensitivity to radiant heat stimulation (Greenwald and Stitzer, 2000).…”

Section: Discussionmentioning

confidence: 99%

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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Lack of Analgesia by Oral Standardized Cannabis Extract on Acute Inflammatory Pain and Hyperalgesia in Volunteers

Cited by 113 publications

References 46 publications

Spinal neuroplasticity in chronic pain

Spinal neuroplasticity in chronic pain

Dissociable Effects of the Cannabinoid Receptor Agonists Δ⁹-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

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

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Lack of Analgesia by Oral Standardized Cannabis Extract on Acute Inflammatory Pain and Hyperalgesia in Volunteers

Cited by 113 publications

References 46 publications

Spinal neuroplasticity in chronic pain

Spinal neuroplasticity in chronic pain

Dissociable Effects of the Cannabinoid Receptor Agonists Δ9-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

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

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Dissociable Effects of the Cannabinoid Receptor Agonists Δ⁹-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats