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Cited by 309Cannabis and Cannabinoid ResearchPain Mechanisms and TreatmentsPain Management and Treatment

Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside

Open access
Rahn, Elizabeth J., Hohmann, Andrea G.·2009·Neurotherapeutics
DOI 10.1016/j.nurt.2009.08.002PMC PMC2755639
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Abstract

SummaryNeuropathic pain is a debilitating form of chronic pain resulting from nerve injury, disease states, or toxic insults. Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics. Cannabinoids, drugs that share the same target as Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive ingredient in cannabis, have the potential to address this unmet need. Here, we review studies evaluating cannabinoids for neuropathic pain management in the clinical and preclinical literature. Neuropathic pain associated with nerve injury, diabetes, chemotherapeutic treatment, human immunodeficiency virus, multiple sclerosis, and herpes zoster infection is considered. In animals, cannabinoids attenuate neuropathic nociception produced by traumatic nerve injury, disease, and toxic insults. Effects of mixed cannabinoid CB1/CB2 agonists, CB2 selective agonists, and modulators of the endocannabinoid system (i.e., inhibitors of transport or degradation) are compared. Effects of genetic disruption of cannabinoid receptors or enzymes controlling endocannabinoid degradation on neuropathic nociception are described. Specific forms of allodynia and hyperalgesia modulated by cannabinoids are also considered. In humans, effects of smoked marijuana, synthetic Δ9-THC analogs (e.g., Marinol, Cesamet) and medicinal cannabis preparations containing both Δ9-THC and cannabidiol (e.g., Sativex, Cannador) in neuropathic pain states are reviewed. Clinical studies largely affirm that neuropathic pain patients derive benefits from cannabinoid treatment. Subjective (i.e., rating scales) and objective (i.e., stimulus-evoked) measures of pain and quality of life are considered. Finally, limitations of cannabinoid pharmacotherapies are discussed together with directions for future research.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes preclinical and clinical evidence that cannabinoids and endocannabinoid modulators suppress neuropathic pain via CB1 and CB2 mechanisms. Clinical studies largely support efficacy in neuropathic pain, but side effects, small trials, and long-term safety questions remain.

Key findings

  • In animals, cannabinoids attenuate neuropathic nociception in at least nine surgically induced traumatic nerve/nervous system injury models and in disease/toxic models (diabetes, chemotherapy, HIV, demyelination, post-herpetic neuralgia); mixed CB1/CB2 agonists, CB2-selective agonists, and FAAH/MGL/transport inhibitors are effective, often via CB1 and/or CB2, with nonneuronal microglial CB2 mechanisms implicated.
  • Clinical studies largely affirm benefit: in HIV-associated sensory neuropathy, 52% (13/25) receiving cannabis cigarettes had >30% pain reduction; smoked cannabis was superior to placebo on DDS/VAS without negative impact on CD4/CD8/T-cell counts or viral load.
  • In MS-related neuropathic pain, dronabinol, Cannador, and Sativex improved pain/spasticity/sleep; one 1-year follow-up reported 74% of placebo vs 45% cannabinoid patients discontinued for lack of benefit; Sativex open-label: 95% entered, 54% completed 1 year, 44% completed 2 years, 25% withdrew due adverse events, 95% had ≥1 adverse event.
  • Adverse-event review: 96.6% of medical cannabinoid adverse events were not serious and no serious adverse events were exclusively cannabinoid-related; 99% of serious adverse events from randomized trials came from only two trials. Negative clinical studies were small (≤8 subjects) and used oral dronabinol.

Methods

  • Narrative review of preclinical and clinical literature on cannabinoids for neuropathic pain, covering nerve injury, diabetes, chemotherapy, HIV, MS, and herpes zoster.
  • Compares mixed CB1/CB2 agonists, CB2-selective agonists, endocannabinoid transport/degradation inhibitors, and genetic knockout models; clinical review includes smoked marijuana, synthetic Δ9-THC analogs (Marinol, Cesamet), and cannabis preparations with Δ9-THC and cannabidiol (Sativex, Cannador).
  • No systematic search strategy, meta-analysis, or formal risk-of-bias assessment is described.

Limitations

  • Stated: psychoactive effects of centrally acting CB1 agonists and side effects (dizziness, balance impairment, intoxication, dry mouth, dysgeusia, sedation, hunger) challenge therapy; high-quality long-term safety trials are needed.
  • Stated: two negative clinical studies were small (≤8 subjects), used oral dronabinol titrated to 25 mg/day (mean 16.6 ± 6.5 mg and 15 ± 6 mg), and had prominent side effects/high dropout; patients had mixed refractory neuropathic pain.
  • Evident from text: as a narrative review, it does not systematically quantify evidence; preclinical pharmacological specificity was not consistently assessed, and many clinical studies were small, mixed-population, or open-label extensions.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.nurt.2009.08.002

Cites

186 of 186 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 273 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    None of the reviewed studies evaluated cold allodynia in streptozotocin-induced diabetic neuropathy.

    “None of the studies we reviewed evaluated the presence of cold allodynia.”
    Quote in the paperNot a substantial claim
  • Findingnone given

    WIN55,212-2 is the only compound that has been evaluated in the spinal cord injury model.

    “WIN55,212-2 is the only compound that has been evaluated in the SCI model.”
    Quote in the paperNot a substantial claim
  • Findingnone given

    Mediation by cannabinoid receptors has not been assessed for agonists tested in the streptozotocin-induced diabetic neuropathy model.

    “However, mediation by cannabinoid receptors has not been assessed for agonists tested in this model.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Met-F-AEA, WIN55,212-2, and AM1241 administered chronically suppressed mechanical hyperalgesia associated with streptozotocin-induced diabetic neuropathy.

    “Met-F-AEA, a CB1-specific agonist based upon the structure of anandamide, the mixed cannabinoid agonist WIN55,212-2 and the CB2-specific agonist AM1241, administered chronically, suppressed mechanical hyperalgesia associated with STZ-induced diabetic neuropathy.”
    Quote in the paperSubstantial claim
  • Findingnone given

    Side-effects were reported in all studies in a proportion of patients receiving cannabinoid-based medications.

    “Side-effects were reported in all studies in a proportion of patients receiving cannabinoid-based medications.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 23
  • May combine two claims. 135

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Findingnone given

    Cannabinoid agonists have been evaluated in animal models of disease-related neuropathic pain, but pharmacological specificity has not been consistently assessed.

    “Cannabinoid agonists have been evaluated in animal models of disease-related neuropathic pain, although pharmacological specificity has not been consistently assessed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the reviewed studies, streptozotocin-induced diabetic neuropathy resulted in increased sensitivity to noxious and non-noxious mechanical stimulation and failed to induce thermal hyperalgesia.

    “Diabetic neuropathy induced by a single injection of streptozotocin (STZ) resulted in increased sensitivity to noxious and non-noxious levels of mechanical stimulation, and failed to induce thermal hyperalgesia in the studies reviewed here (Table 6).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    To the authors' knowledge, no study to date has evaluated cannabinoid-mediated suppression of multiple sclerosis-induced neuropathic nociception.

    “Animal models of multiple sclerosis (MS) have been described, although to our knowledge, no study to date has evaluated cannabinoid-mediated suppression of MS-induced neuropathic nociception.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    Three of the reviewed articles used smoking as the route of administration, whereas the other thirteen employed oral preparations in the form of pills or oral-mucosal sprays.

    “Three of the articles reviewed here used smoking as the route of administration, whereas the other thirteen employed oral preparations in the form of pills or oral-mucosal sprays.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingreasoning

    Possible changes in CB1 receptor immunoreactivity were not evaluated in the human tissue and therefore cannot be excluded.

    “However, possible changes in CB1 receptor immunoreactivity, were not evaluated in the human tissue, and therefore cannot be excluded.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both negative studies employed eight or fewer subjects and evaluated dronabinol titrated to a dose of 25 mg/day where tolerated.

    “Both of these studies employed eight or fewer subjects and evaluated dronabinol titrated to a dose of 25 mg/day (where tolerated).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PEA may indirectly alter levels of endocannabinoids by competing with anandamide and other fatty-acid amides for degradation by FAAH or by suppressing FAAH expression at the transcriptional level.

    “PEA may indirectly alter levels of endocannabinoids by competing with anandamide and other fatty-acid amides for degradation by FAAH or by suppressing FAAH expression at the transcriptional level.27, 28”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Re, 2007, Palmitoylethanolamide, endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain: potential use in companion animals, Vet J source

      Not checked in the free run.

    • cites [28] Bisogno, 2002, Fatty acid amide hydrolase, an enzyme with many bioactive substrates, Curr Pharm Des source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB1 receptors are localized to the central nervous system and periphery and are found in sites associated with pain processing, including the periaqueductal gray, rostral ventromedial medulla, thalamus, dorsal root ganglia, amygdala, and cortex.

    “CB1 receptors are localized to the central nervous system (CNS) and the periphery. CB1 receptors are found in sites associated with pain processing, including the periaqueductal gray (PAG),8 rostral ventromedial medulla (RVM),8 thalamus,9 dorsal root ganglia (DRG),10 amygdala,8 and cortex8.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Herkenham, 1991, Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study, J Neurosci source

      Not checked in the free run.

    • cites [9] Matsuda, 1993, Localization of cannabinoid receptor mRNA in rat brain, J Comp Neurol source

      Not checked in the free run.

    • cites [10] Hohmann, 1999, Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study, Neuroscience source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PEA does not bind cannabinoid receptors and has been described as an endogenous ligand for PPAR-α.

    “PEA does not bind cannabinoid receptors and has recently been described as an endogenous ligand for peroxisome proliferator receptor-α (PPAR-α).26”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Lo Verme, 2005, The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide, Mol Pharmacol source

      Not checked in the free run.

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    Premisecitation

    Activation of the CB1 receptor results in hypothermia, sedation, catalepsy, and altered mental status.

    “Activation of the CB1 receptor also results in hypothermia, sedation, catalepsy, and altered mental status.11”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Malan, 2001, CB2 cannabinoid receptor-mediated peripheral antinociception, Pain source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Both CB1 and CB2 receptors are G-protein-coupled receptors that are negatively coupled to adenylate cyclase.

    “Both CB12 and CB23 receptors are G-coupled protein receptors that are negatively coupled to adenylate cyclase.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Matsuda, 1990, Structure of a cannabinoid receptor and functional expression of the cloned cDNA, Nature source

      Not checked in the free run.

    • cites [3] Munro, 1993, Molecular characterization of a peripheral receptor for cannabinoids, Nature source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The CB2 receptor was originally believed to be restricted to the periphery, primarily to immune cells, although it may be present neuronally in some species.

    “The CB2 receptor was originally believed to be restricted to the periphery, primarily to immune cells (e.g. mast cells),12 although they may be present neuronally in some species.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Facci, 1995, Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide, Proc Natl Acad Sci U S A source

      Not checked in the free run.

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    Premisecitation

    CB2 receptor activation stimulates MAPK activity but does not modulate calcium or potassium conductances.

    “CB2 receptor activation stimulates MAPK activity but does not modulate calcium or potassium conductances.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Guindon, 2008, Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain, Br J Pharmacol source

      Not checked in the free run.

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    Premisecitation

    FAAH-/- mice are hypoalgesic in models of acute and inflammatory pain, and these effects are blocked by a CB1 antagonist.

    “FAAH-/- mice are hypoalgesic in models of acute and inflammatory pain; these effects are blocked by a CB1 antagonist.29, 30”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Cravatt, 2001, Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [30] Lichtman, 2004, Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia, Pain source

      Not checked in the free run.

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    Premisecitation

    WIN55,212-2 dose-dependently inhibits windup and CCI-induced increases in spontaneous firing of spinal wide dynamic range neurons through a CB1-dependent mechanism.

    “A neurophysiological basis for these findings is derived from the observation that WIN55,212-2 (i.v.) dose-dependently inhibits windup46 as well as CCI-induced increases in spontaneous firing47 of spinal wide dynamic range (WDR) neurons through a CB1-dependent mechanism.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [46] Strangman, 1999, Cannabinoid WIN 55,212-2 inhibits the activity-dependent facilitation of spinal nociceptive responses, J Neurophysiol source

      Not checked in the free run.

    • cites [47] Liu, 2006, Effects of a cannabinoid agonist on spinal nociceptive neurons in a rodent model of neuropathic pain, J Neurophysiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Monoacylglycerol lipase is a key enzyme implicated in the hydrolysis of 2-arachidonoylglycerol.

    “Monoacylglycerol lipase (MGL) is a key enzyme implicated in the hydrolysis of 2-AG.33, 34”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Hohmann, 2005, An endocannabinoid mechanism for stress-induced analgesia, Nature source

      Not checked in the free run.

    • cites [34] Dinh, 2002, Brain monoglyceride lipase participating in endocannabinoid inactivation, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SR141716 administered acutely is pro-hyperalgesic and pro-allodynic in the CCI model.

    “SR141716, administered acutely, is pro-hyperalgesic and pro-allodynic in this model. 42”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Herzberg, 1997, The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain, Neurosci Lett source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Several mixed cannabinoid CB1/CB2 agonists suppress all forms of neuropathic nociception observed in the CCI model, primarily through CB1-mediated mechanisms.

    “Several mixed cannabinoid CB1/CB2 agonists have been shown to suppress all forms of neuropathic nociception observed in the CCI model, primarily through CB1-mediated mechanisms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CB1 receptors are upregulated in the spinal cord following CCI, and these effects are believed to be modulated by tyrosine kinase and glucocorticoid receptors.

    “CB1 receptors are upregulated in the spinal cord following CCI; these effects are believed to be modulated by tyrosine kinase38 and glucocorticoid39 receptors.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Lim, 2003, Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats, Pain source

      Not checked in the free run.

    • cites [39] Wang, 2007, Central glucocorticoid receptors regulate the upregulation of spinal cannabinoid-1 receptors after peripheral nerve injury in rats, Pain source

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  • May combine two claims.

    Interpretationreasoning

    The behavioral phenotype induced by antagonist treatment may depend upon the level of endocannabinoid tone present in the system, the injection paradigm (chronic vs. acute), and the presence of regulatory changes in cannabinoid receptors or endocannabinoids.

    “Thus, it is important to emphasize that the behavioral phenotype induced by antagonist treatment may depend upon level of endocannabinoid tone present in the system, the injection paradigm (chronic vs. acute), and presence of regulatory changes in cannabinoid receptors or endocannabinoids.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Both AEA and 2-AG can be metabolized by COX-2, a phenomenon that may contribute to the antinociceptive properties of NSAIDs that act through inhibition of COX-2.

    “Both AEA and 2-AG can be metabolized by cyclooxygenase-2 (COX-2), a phenomenon that may contribute to the antinociceptive properties of non-steroidal anti-inflammatory drugs (NSAIDS) that act through inhibition of COX-2.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Guindon, 2008, Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain, Br J Pharmacol source

      Not checked in the free run.

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    Premisecitation

    WIN55,212-2 normalizes prostaglandin E2 levels and nitric oxide activity, two mediators of neuropathic pain that are increased following CCI.

    “WIN55,212-2 also normalizes prostaglandin E2 (PGE2) levels and nitric oxide (NO) activity, two mediators of neuropathic pain that are increased following CCI.48”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Costa, 2004, Repeated treatment with the synthetic cannabinoid WIN 55,212-2 reduces both hyperalgesia and production of pronociceptive mediators in a rat model of neuropathic pain, Br J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB2 receptor mRNA is upregulated in the lumbar spinal cord following CCI, and this upregulation is restricted to non-neuronal cells such as glia.

    “Thus, it is noteworthy that CB2 receptor mRNA is upregulated in the lumbar spinal cord following CCI. This upregulation is restricted to non-neuronal cells (e.g. glia).49”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Zhang, 2003, Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models, Eur J Neurosci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AEA can also activate the PPARγ receptor.

    “AEA can also activate the peroxisome proliferator receptor-γ (PPARγ) receptor.32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Bouaboula, 2005, Anandamide induced PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation, Eur J Pharmacol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Anandamide acts as an endovanilloid at TRPV1 and shows affinity for TRPV1 that is 5-20 fold lower than its affinity for CB1.

    “Anandamide also acts as an endovanalloid at the transient receptor potential cation channel (TRPV1) receptor.31 AEA shows affinity for TRPV1 that is 5-20 fold lower than its affinity for CB1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Ross, 2001, Structure-activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens, Br J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AM404 normalizes CCI-induced changes in nitric oxide activity, COX-2, cytokine levels, and NF-κB levels.

    “AM404 also normalizes CCI-induced changes in NO activity,52, 53 COX-253 activity, cytokine levels (e.g. TNF-α and IL10),52 and NF-κB52 levels.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Costa, 2006, AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain, Br J Pharmacol source

      Not checked in the free run.

    • cites [53] La Rana, 2006, Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide], J Pharmacol Exp Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Basal hypoalgesia is absent in FAAH-/- mice subjected to nerve injury, where genotype differences in evoked neuropathic pain behaviors are not apparent.

    “This basal hypoalgesia is absent in FAAH-/- mice subjected to nerve injury, where genotype differences in evoked neuropathic pain behaviors are not apparent.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Lichtman, 2004, Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia, Pain source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Anti-hyperalgesic effects observed with cannabidiol-containing synthetic analogues are likely independent of cannabinoid receptors and may be mediated through TRPV1.

    “However, anti-hyperalgesic effects observed with these compounds are likely to be independent of cannabinoid receptors, and may be mediated through TRPV1.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] Costa, 2007, The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain, Eur J Pharmacol source

      Not checked in the free run.

    • cites [41] Comelli, 2008, Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved, Phytother Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic constriction injury produces mechanical allodynia as well as thermal allodynia and hyperalgesia in the ipsilateral paw as early as two days post-surgery.

    “CCI produces mechanical allodynia as well as thermal allodynia and hyperalgesia in the ipsilateral paw as early as two days post-surgery.37”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Bennett, 1988, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    AM404, an endocannabinoid transport inhibitor, increases accumulation and bioavailability of anandamide through a mechanism that remains incompletely understood.

    “AM404, an endocannabinoid transport inhibitor, increases accumulation and, hence, bioavailability, of anandamide (and potentially other endocannabinoids) through a mechanism that remains incompletely understood.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Multiple CB2-selective agonists suppress CCI-induced mechanical allodynia, although pharmacological specificity has not been consistently assessed.

    “Multiple CB2-selective agonists have been demonstrated to suppress CCI-induced mechanical allodynia, although pharmacological specificity has not been consistently assessed (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mixed CB1/CB2 agonists such as CP55,940 or WIN55,212-2 typically act as CB1-selective agonists following systemic administration, although CB2-mediated effects may be unmasked following administration of CB2-selective agents or local administration of the same compounds.

    “Mixed CB1/CB2 agonists, such as CP55,940 or WIN55,212-2, typically act as CB1-selective agonists following systemic administration,45 although CB2-mediated effects may be unmasked following administration of CB2-selective agents or following local administration of the same compounds.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Sain, 2009, Antinociceptive effects of the non-selective cannabinoid receptor agonist CP 55,940 are absent in CB1(−/−) and not CB2(−/−) mice in models of acute and persistent pain, Neuropharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SR141716 administered chronically suppresses thermal and mechanical hyperalgesia in both rats and CB1+/+ mice, while failing to produce an effect in CB1-/- mice.

    “However, SR141716 (p.o.), administered chronically, suppresses thermal and mechanical hyperalgesia in both rats and CB1+/+ mice, while failing to produce an effect in CB1-/- mice. 43”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Costa, 2005, Effect of the cannabinoid CB1 receptor antagonist, SR141716, on nociceptive response and nerve demyelination in rodents with chronic constriction injury of the sciatic nerve, Pain source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    CB2 agonists may show therapeutic potential for suppressing neuropathic pain without producing tolerance when administered either alone or as adjuncts to existing treatments.

    “Thus, CB2 agonists may show therapeutic potential for suppressing neuropathic pain without producing tolerance when administered either alone or as adjuncts to exisiting treatments.51”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Yao, 2009, J Pharmacol Exp Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pro-hyperalgesic effects of SR141716 and SR144528 have been reported in the Seltzer model, indicating a potential alteration in endocannabinoid tone following nerve injury.

    “Pro-hyperalgesic effects of SR141716 and SR144528 have been reported in the Seltzer model,65 indicating a potential alteration in endocannabinoid tone following nerve injury.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Helyes, 2003, Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat, Life Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AM404 administered systemically suppressed mechanical allodynia in a CB1-dependent manner without producing motor effects.

    “The transport inhibitor AM404, administered systemically, suppressed mechanical allodynia in a CB1-dependent manner, without producing motor effects.73”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Mitchell, 2007, Actions of the endocannabinoid transport inhibitor AM404 in neuropathic and inflammatory pain models, Clin Exp Pharmacol Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ajulemic acid (CT-3) produced activity in the tetrad but anti-hyperalgesic effects occurred at doses lower than those producing side-effects.

    “Ajulemic acid (CT-3), which was developed as a peripherally restricted cannabinoid analogue, also produced activity in the tetrad but anti-hyperalgesic effects occurred at doses lower than those producing side-effects.69”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Dyson, 2005, Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat, Pain source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Activation of CB1 and CB2 receptors as well as pharmacological manipulation of endocannabinoid accumulation or breakdown suppresses neuropathic nociception in rodents.

    “Thus, activation of CB1 and CB2 receptors as well as pharmacological manipulation of endocannabinoid accumulation or breakdown suppresses neuropathic nociception in rodents.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Anti-hyperalgesic effects of AEA and PEA were blocked by a CB1 and CB2 antagonist, respectively.

    “Anti-hyperalgesic effects of AEA and PEA were blocked by a CB1 and CB2 antagonist, respectively.65”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Helyes, 2003, Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat, Life Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCI increases levels of endogenous AEA, but not 2-AG, in the dorsal raphe.

    “CCI also increases levels of endogenous AEA, but not 2-AG, in the dorsal raphe – an observation which may help explain the anti-hyperalgesic efficacy of an anandamide transport inhibitor in this model.57”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Palazzo, 2006, Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system, Eur J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OL135 and URB597 are antinociceptive in FAAH+/+ mice but fail to produce an effect in FAAH-/- mice.

    “Additionally both OL135 and URB597 are antinociceptive in FAAH+/+ mice, but fail to produce an effect in FAAH-/- mice.59”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Kinsey, 2009, Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain, J Pharmacol Exp Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The MGL inhibitor JZL184 attenuates CCI-induced mechanical and cold allodynia through indirect activation of the CB1 receptor and is efficacious in both FAAH+/+ and FAAH-/- mice.

    “The novel MGL inhibitor, JZL184, attenuates CCI-induced mechanical and cold allodynia through indirect activation of the CB1 receptor; JZL184 was efficacious in attenuating neuropathic nociception in both FAAH+/+ and FAAH-/- mice.59”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Kinsey, 2009, Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain, J Pharmacol Exp Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB2-/- mice develop thermal hyperalgesia and mechanical allodynia in the contralateral paw following surgery, whereas CB2+/+ mice do not.

    “CB2-/- mice reportedly develop thermal hyperalgesia and mechanical allodynia in the contralateral paw following surgery, whereas CB2+/+ do not.63”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Racz, 2008, Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several studies report efficacy of mixed cannabinoid CB1/CB2 agonists in the Seltzer model, although CNS side-effects were observed in the same dose range that resulted in full reversal of neuropathic nociception.

    “Several studies report efficacy of mixed cannabinoid CB1/CB2 agonists in this model, although CNS side-effects were nonetheless observed in the same dose range that resulted in full reversal of neuropathic nociception.68”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Fox, 2001, The role of central and peripheral Cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain, Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCI increases serotonin levels in the dorsal raphe, and this effect is suppressed by both WIN55,212-2 and AM404 in a CB1-dependent manner.

    “CCI increases serotonin (5-HT) levels in the dorsal raphe and this effect was suppressed by both WIN55,212-2 and AM404 in a CB1-dependent manner.57”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Palazzo, 2006, Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system, Eur J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB2 mRNA was upregulated in the ipsilateral versus the contralateral spinal cord and dorsal root ganglion following SNL, and the presence of CB2 mRNA was confirmed in spinal cord microglial cells in culture.

    “CB2 mRNA was also shown to be upregulated in the ipsilateral (versus the contralateral) spinal cord and DRG following SNL and the presence of CB2 mRNA was confirmed in spinal cord microglial cells in culture.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Beltramo, 2006, CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms, Eur J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    URB597 administered locally in the paw, but not systemically, suppressed both thermal hyperalgesia and mechanical allodynia through a CB1 mechanism.

    “The FAAH inhibitor URB597, administered locally in the paw,67 but not systemically62 suppressed both thermal hyperalgesia and mechanical allodynia through a CB1 mechanism.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [62] Jayamanne, 2006, Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models, Br J Pharmacol source

      Not checked in the free run.

    • cites [67] Desroches, 2008, Modulation of the anti-nociceptive effects of 2-arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model, Br J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gabapentin successfully attenuated mechanical allodynia in the SNL model, whereas amitriptyline, fluoxetine, and indomethacin failed to show similar effects.

    “Gabapentin successfully attenuated mechanical allodynia in this model, however, several other commonly prescribed neuropathic pain medications including amitriptyline, fluoxetine and indomethacin failed to show similar effects.80”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] LaBuda, 2005, Pharmacological evaluation of the selective spinal nerve ligation model of neuropathic pain in the rat, J Neurosci Methods source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increases in both AEA and 2-AG have been reported in the ipsilateral injured L5, but not the uninjured L4 dorsal root ganglion after SNL.

    “Increases in both AEA and 2-AG have also been reported in the ipsilateral injured L5, but not the uninjured L4 DRG.83”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Mitrirattanakul, 2006, Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain, Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L29-induced suppression of thermal hyperalgesia was mediated by both the CB1 receptor and PPAR-α, whereas suppression of mechanical allodynia was mediated by CB1/CB2 and PPAR-α receptors.

    “The L29-induced suppression of thermal hyperalgesia was mediated by both the CB1 receptor and PPAR-α, whereas suppression of mechanical allodynia was mediated by CB1/CB2 and PPAR-α receptors.64”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Wallace, 2007, The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy, Br J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Spinal, but not systemic, administration of HU-210 reduces Aδ fiber-evoked responses on spinal wide dynamic range neurons in both sham and SNL rats, whereas HU-210 showed no effect on C-fiber responses of SNL rats.

    “Spinal, but not systemic, administration of HU-210 has been reported to reduce Aδ fiber-evoked responses on spinal WDR neurons in both shams and SNL rats, whereas HU-210 showed no effect on C-fiber responses of SNL rats.82”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Chapman, 2001, Functional changes in the inhibitory effect of spinal cannabinoid (CB) receptor activation in nerve injured rats, Neuropharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L-29 suppressed thermal hyperalgesia and mechanical allodynia in the Seltzer model.

    “The fatty-acid analogue of PEA, L-29, also suppressed thermal hyperalgesia and mechanical allodynia in the Seltzer model.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Wallace, 2007, The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy, Br J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB2 mRNA was upregulated in the lumbar spinal cord following SNL, coincident with the expression of activated microglia.

    “CB2 mRNA was upregulated in the lumbar spinal cord following SNL,49 coincident with the expression of activated microglia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Zhang, 2003, Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models, Eur J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic administration of WIN55,212-2 attenuates the development of mechanical allodynia and suppresses glial activation in the spinal cord following SNL with no overt motor side-effects.

    “Chronic administration of WIN55,212-2 also attenuates the development of mechanical allodynia and suppresses glial activation in the spinal cord following SNL with no overt motor side-effects.81”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Leichsenring, 2009, Analgesic and antiinflammatory effects of cannabinoid receptor agonists in a rat model of neuropathic pain, Naunyn Schmiedebergs Arch Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intrathecal N-arachidonoyl glycine attenuated mechanical allodynia in the Seltzer model, but its anti-hyperalgesic actions are independent of spinal cannabinoid receptors.

    “Intrathecal N-arachidonoyl glycine (NaGly), the arachodonic acid conjugate, also attenuated mechanical allodynia in this model, however, the anti-hyperalgesic actions of this compound are independent of spinal cannabinoid receptors.75”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Vuong, 2008, Actions of N-arachidonyl-glycine in a rat neuropathic pain model, Neuropharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mixed cannabinoid agonists, cannabinoid CB2-selective agonists, and FAAH inhibitors all attenuated neuropathic nociception induced by spinal nerve ligation.

    “Thus, it is noteworthy that mixed cannabinoid agonists, cannabinoid CB2-selective agonists and FAAH inhibitors all attenuated neuropathic nociception induced by SNL (Table 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    URB602 administered locally in the paw suppressed neuropathic nociception in the Seltzer model through activation of both CB1 and CB2 receptors.

    “The MGL inhibitor URB602 (which cannot be used systemically as a selective MGL inhibitor), administered locally in the paw, also suppressed neuropathic nociception in this model through activation of both CB1 and CB2 receptors.67”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Desroches, 2008, Modulation of the anti-nociceptive effects of 2-arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model, Br J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Locally injected paracetamol suppressed mechanical allodynia and thermal hyperalgesia present following partial sciatic nerve ligation, and these effects are blocked by local administration of either a CB1 or a CB2 antagonist.

    “Locally injected (i.paw) paracetamol suppressed mechanical allodynia and thermal hyperalgesia present following partial sciatic nerve ligation and these effects are blocked by local administration of either a CB1 or a CB2 antagonist.76”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Dani, 2007, The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors, Eur J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Spinal administration of URB597 was equally efficacious at attenuating mechanically-evoked responses and increasing levels of endogenous cannabinoids in SNL and sham rats, and these effects were CB1-mediated.

    “In the same study, spinal administration of URB597 was equally efficacious at attenuating mechanically-evoked responses and increasing levels of endogenous cannabinoids in SNL and sham rats and these effects were CB1-mediated.92”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Jhaveri, 2006, Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic constriction injury of the infraorbital nerve results in thermal hyperalgesia and mechanical allodynia ipsilateral to the site of injury.

    “Chronic constriction injury of the infraorbital nerve (CCI-ION) results in thermal hyperalgesia and mechanical allodynia (as measured by head withdrawals) ipsilateral to the site of injury.93”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Vos, 1991, Behavioral changes following ligation of the infraorbital nerve in rats: an animal model of trigeminal neuropathic pain

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Intrathecal JWH015 reduced SNT-induced increases in activated microglia in a CB2-dependent manner, supporting a role for nonneuronal CB2 receptors in anti-hyperalgesic effects of CB2 agonists.

    “Intrathecal JWH015 reduced SNT-induced increases in activated microglia in a CB2-dependent manner, further supporting a role for nonneuronal CB2 receptors in anti-hyperalesic effects of CB2 agonists. 96”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Romero-Sandoval, 2008, Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury, Anesthesiology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CP55,940 reversed mechanical allodynia in the L5 spinal nerve transection model 1 h following a second intrathecal injection, although this dosing paradigm was also associated with motor effects.

    “CP55,940 reversed mechanical allodynia in this model 1 h following a second intrathecal injection, although this dosing paradigm was also associated with motor effects.96”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Romero-Sandoval, 2008, Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury, Anesthesiology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    WIN55,212-2 and HU-210 increased mechanical withdrawal responses and thermal withdrawal latencies on the ipsilateral side of the head in the CCI-ION model.

    “WIN55,212-2 and HU-210 increased mechanical withdrawal responses and thermal withdrawal latencies on the ipsilateral side of the head in this model.94”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Liang, 2007, The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain, Neuropharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High antihyperalgesic doses of WIN55,212-2 decreased rotarod latencies and body temperature, whereas HU210 at the low dose used had no effect on these dependent measures.

    “High antihyperalgesic doses of WIN55,212-2 decreased rotarod latencies and body temperature, whereas HU210, at the singular low dose used (10 μg/kg), had no effect on these dependent measures.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Liang, 2007, The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain, Neuropharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GW405833 administered chronically suppressed the development of mechanical allodynia concomitant with suppression of glial activation at the level of the spinal cord.

    “The CB2-specific agonist GW405833, administered chronically, suppressed the development of mechanical allodynia concomitant with suppression of glial activation at the level of the spinal cord.81”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Leichsenring, 2009, Analgesic and antiinflammatory effects of cannabinoid receptor agonists in a rat model of neuropathic pain, Naunyn Schmiedebergs Arch Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pre-treatment with the CB1 antagonist SR141716 enhanced the effects of A-836339 when applied to the L5 dorsal root ganglion, indicating that blockade of CB1 receptors enhanced the antinociceptive effects of a CB2 agonist.

    “Interestingly, pre-treatment with the CB1 antagonist, SR141716, enhanced the effects of A-836339 when applied to the L5 DRG,88 indicating that blockade of CB1 receptors enhanced the antinociceptive effects of a CB2 agonist, as reported previously.89”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [88] McGaraughty, 2009, A CB(2) receptor agonist, A-836339, modulates wide dynamic range neuronal activity in neuropathic rats: contributions of spinal and peripheral CB(2) receptors, Neuroscience source

      Not checked in the free run.

    • cites [89] Rahn, 2008, Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats, J Pharmacol Exp Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low doses of locally injected URB597 reduced mechanically-evoked responses of wide dynamic range neurons and increased endocannabinoid levels in ipsilateral paw tissue of sham operated rats.

    “Low doses of locally injected URB597 (i.pl.) reduced mechanically-evoked responses of WDR neurons and increased endocannabinoid levels in ipsilateral paw tissue of sham operated rats.92”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Jhaveri, 2006, Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intrathecal JWH015 dose-dependently suppressed behavioral hypersensitivity following a second injection, indicating a cumulative anti-allodynic effect of this drug.

    “Intrathecal JWH015 dose-dependently suppressed behavioral hypersensitivity following a second injection, indicating a cumulative anti-allodynic effect of this drug.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Romero-Sandoval, 2008, Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury, Anesthesiology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB1 receptor upregulation was observed in both the ipsilateral and contralateral superficial layer of the trigeminal caudal nucleus, and this effect was greater on the ipsilateral side.

    “CB1 receptor upregulation was observed in both the ipsilateral and contralateral superficial layer of the trigeminal caudal nucleus, and this effect was greater on the ipsilateral side.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Liang, 2007, The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain, Neuropharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Standard analgesics (morphine, gabapentin, amitryptiline) are efficacious in treating neuropathic nociception resulting from a crush injury of the sciatic nerve, but showed limited efficacy following SNI.

    “Standard analgesics (e.g. morphine, gabapentin, amitryptiline) are efficacious in treating neuropathic nociception resulting from a crush injury of the sciatic nerve, but showed limited efficacy following SNI.101”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Decosterd, 2004, Differential analgesic sensitivity of two distinct neuropathic pain models, Anesth Analg source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lean males subjected to hyperinsulinemia show a 2-fold increase in FAAH mRNA expression whereas obese males subjected to the same conditions failed to show similar alterations.

    “Lean males subjected to hyperinsulinemia show a 2-fold increase in FAAH mRNA expression whereas obese males subjected to the same conditions failed to show similar alterations in gene expression.111”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Murdolo, 2007, Insulin differentially modulates the peripheral endocannabinoid system in human subcutaneous abdominal adipose tissue from lean and obese individuals, J Endocrinol Invest source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The spared nerve injury model reliably produces thermal hyperalgesia and mechanical allodynia in studies that tested for both measures.

    “The spared nerve injury (SNI) model reliably produces thermal hyperalgesia and mechanical allodynia in studies that tested for both measures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Acute systemic WIN55,212-2 suppressed spinal cord injury-induced mechanical allodynia in a CB1-dependent manner, although other parameters of neuropathic pain were not assessed.

    “Acute WIN55,212-2, administered systemically, suppressed SCI-induced mechanical allodynia in a CB1-dependent manner, although other parameters of neuropathic pain were not assessed.103”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Hama, 2007, Antinociceptive effect of cannabinoid agonist WIN 55,212-2 in rats with a spinal cord injury, Exp Neurol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the SNI model, chronic BAY 59-3074 dose escalation produces rapid tolerance to side-effects such as hypothermia but no loss in analgesic efficacy.

    “A dose-escalation study with BAY 59-3074 in the SNI model indicated that tolerance rapidly develops to side-effects observed following chronic administration (e.g. hypothermia), whereas no loss in analgesic efficacy was observed.78”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] De Vry, 2004, 3-[2-cyano-3-(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1-butanesulfo nate (BAY 59-3074): a novel cannabinoid Cb1/Cb2 receptor partial agonist with antihyperalgesic and antiallodynic effects, J Pharmacol Exp Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Spinal cord injury produces mechanical hyperalgesia and allodynia.

    “Spinal cord injury (SCI)102 produces mechanical hyperalgesia and allodynia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Bruce, 2002, Chronic pain after clip-compression injury of the rat spinal cord, Exp Neurol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Δ9-THC exhibited enhanced antinociceptive efficacy in diabetic rats whereas morphine showed reduced antinociceptive efficacy.

    “Interestingly, Δ9-THC exhibited enhanced antinociceptive efficacy in diabetic rats whereas morphine showed reduced antinociceptive efficacy.115”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] Williams, 2008, Decreased basal endogenous opioid levels in diabetic rodents: effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception, Eur J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HU-210 did not alter the hyperglycemia index but normalized cerebral oxidative stress in diabetic mice.

    “HU-210 did not alter the hyperglycemia index; however, it did normalize cerebral oxidative stress present in diabetic mice.114”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Dagon, 2007, The synthetic cannabinoid HU-210 attenuates neural damage in diabetic mice and hyperglycemic pheochromocytoma PC12 cells, Neurobiol Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic WIN55,212-2 reduced mechanical allodynia in the spinal cord injury model with no decrease in effectiveness over time, unlike morphine.

    “Unlike morphine, chronic administration of WIN55,212-2 reduced mechanical allodynia in the SCI model with no decrease in effectiveness over time.104”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Hama, 2009, Sustained antinociceptive effect of cannabinoid receptor agonist WIN 55,212-2 over time in rat model of neuropathic spinal cord injury pain, J Rehabil Res Dev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute WIN55,212-2 suppressed thermal hyperalgesia and mechanical allodynia in both SNS-CB1- mice and their wild-type controls; differences in antinociceptive effects were observed between genotypes, and these effects were greater with mechanical than thermal sensitivity.

    “Acute WIN55,212-2 suppressed thermal hyperalgesia and mechanical allodynia in both mice lacking CB1 receptors in primary nociceptors (SNS-CB1-) and their wild-type controls; however differences in the antinociceptive effects of WIN55,212-2 were observed between genotypes, and these effects were greater with mechanical than thermal sensitivity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Agarwal, 2007, Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors, Nat Neurosci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Increased levels of endocannabinoids have been found in obese patients suffering from Type II diabetes.

    “Increased levels of endocannabinoids have been found in obese patients suffering from Type II diabetes109”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Matias, 2006, Changes in endocannabinoid and palmitoylethanolamide levels in eye tissues of patients with diabetic retinopathy and age-related macular degeneration, Prostaglandins Leukot Essent Fatty Acids source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Streptozotocin-diabetic mice showed a progressive decline in the radial arm maze and reduced neurological scores, both of which were recovered following treatment with HU-210.

    “STZ-diabetic mice showed a progressive decline in the radial arm maze and reduced neurological scores, both of which were recovered following treatment with HU-210.114”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Dagon, 2007, The synthetic cannabinoid HU-210 attenuates neural damage in diabetic mice and hyperglycemic pheochromocytoma PC12 cells, Neurobiol Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SNS-CB1- mice showed exaggerated sensitivity to noxious levels of mechanical stimulation and a cold plate relative to their wild-type counterparts, whereas differential sensitivity was not observed between genotypes with non-noxious levels of mechanical stimulation and noxious levels of thermal stimulation.

    “SNS-CB1- mice showed exaggerated sensitivity to noxious levels of mechanical stimulation and a cold plate relative to their wild-type counterparts, whereas differential sensitivity was not observed between genotypes with non-noxious levels of mechanical stimulation and noxious levels of thermal stimulation.7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Agarwal, 2007, Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors, Nat Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tibial nerve injury produces mechanical allodynia and thermal hyperalgesia.

    “Mechanical allodynia and thermal hyperalgesia were present in the initial study describing this technique105 as well as the study we reviewed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Hofmann, 2003, Pharmacological sensitivity and gene expression analysis of the tibial nerve injury model of neuropathic pain, Eur J Pharmacol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Rimonabant ameliorates insulin resistance and decreases weight gain in patients suffering from metabolic syndromes.

    “The CB1 antagonist rimonabant (Acomplia®) ameliorates insulin resistance and decreases weight gain in patients suffering from metabolic syndromes.112”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Scheen, 2009, The endocannabinoid system: a promising target for the management of type 2 diabetes, Curr Protein Pept Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systemic BAY 59-3074 attenuated both mechanical allodynia and thermal hyperalgesia in the tibial nerve injury model, although pharmacological specificity was not assessed.

    “Systemic BAY 59-3074 was shown to attenuate both forms of neuropathic nociception, although pharmacological specificity was not assessed.78”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] De Vry, 2004, 3-[2-cyano-3-(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1-butanesulfo nate (BAY 59-3074): a novel cannabinoid Cb1/Cb2 receptor partial agonist with antihyperalgesic and antiallodynic effects, J Pharmacol Exp Ther source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In animal models, rimonabant improves resistance to insulin through pathways that are both dependent and independent of adiponectin.

    “In animal models, rimonabant improves resistance to insulin through pathways that are both dependent and independent of adiponectin, a hormone important for the regulation of glucose and catabolism of fatty acids.113”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Watanabe, 2009, Rimonabant ameliorates insulin resistance via both adiponectin-dependent and adiponectin-independent pathways, J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rats receiving zalcitabine displayed modest gliosis whereas combined treatment with HIV-gp120 and zalcitabine increased microglial activation.

    “Rats receiving ddc displayed modest levels of gliosis whereas combined treatment with both HIV-gp120 and ddc increased levels of microglial activation.123”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Wallace, 2007, Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain, Brain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    No hypersensitivity to thermal stimuli or motor deficits was observed following zalcitabine treatment.

    “No hypersensitivity to thermal stimuli or motor deficits was observed following ddc treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Wallace, 2007, Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain, Brain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Using the Flatters and Bennett paclitaxel dosing paradigm, mechanical allodynia but not thermal hyperalgesia was observed.

    “Using the paclitaxel dosing paradigm described by Flatters and Bennett,120 mechanical allodynia, but not thermal hyperalgesia, was observed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Flatters, 2004, Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy, Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    WIN55,212-2 prevented the development of mechanical allodynia induced by cisplatin, but failed to produce an anti-emetic benefit.

    “WIN55,212-2 prevented the development of mechanical allodynia induced by cisplatin, but failed to produce an anti-emetic benefit in this study.116”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Vera, 2007, WIN 55,212-2 prevents mechanical allodynia but not alterations in feeding behaviour induced by chronic cisplatin in the rat, Life Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Perineural HIV-gp120 together with zalcitabine treatment resulted in mechanical allodynia greater than either treatment alone, with no changes in paw withdrawal latencies to thermal stimuli or motor deficits.

    “Perineural HIV-gp120 together with ddc treatment resulted in mechanical allodynia that was greater than either treatment alone; no changes in paw withdrawal latencies to thermal stimuli or motor deficits reported.123”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Wallace, 2007, Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain, Brain source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both mixed CB1/CB2 agonists and selective CB2 agonists suppress paclitaxel-evoked mechanical allodynia.

    “Thus, both mixed CB1/CB2 agonists and selective CB2 agonists suppress paclitaxel-evoked mechanical allodynia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Rats treated with zalcitabine developed mechanical allodynia that persisted up to 43 days post-injection and peaked between days 14 and 32.

    “Rats treated with the antiretroviral agent zalcitabine (ddc) developed mechanical allodynia that persisted up to 43 days post-injection and peaked between days 14 and 32.123”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Wallace, 2007, Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain, Brain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    WIN55,212-2 attenuated mechanical allodynia and thermal hyperalgesia in the lysolecithin model and remained efficacious for up to one hour post injection.

    “WIN55,212-2 attenuated mechanical allodynia and thermal hyperalgesia in this model and remained efficacious for up to one hour post injection.125”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Wallace, 2003, Focal lysolecithin-induced demyelination of peripheral afferents results in neuropathic pain behavior that is attenuated by cannabinoids, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In one study, paclitaxel produced mechanical allodynia starting on day 5 that continued throughout the timecourse, although thermal hyperalgesia was only present from days 18-21.

    “In one study, paclitaxel118 produced mechanical allodynia starting on day 5 that continued throughout the timecourse, although thermal hyperalgesia was only present from days 18-21.119”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [118] Polomano, 2001, A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel, Pain source

      Not checked in the free run.

    • cites [119] Pascual, 2005, A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats, Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    WIN55,212-2 suppressed neuropathic nociception in the paclitaxel model but had no effect on body temperature or immobility.

    “WIN55,212-2 suppressed neuropathic nociception in this model but had no effect on body temperature or immobility.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Pascual, 2005, A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats, Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Female mice showed an increased rate of development and greater allodynia than male counterparts, mimicking the greater prevalence of neuropathic pain symptoms reported by female multiple sclerosis patients.

    “Interestingly, female mice showed an increased rate of development and greater allodynia than their male counterparts, a finding which mimics the greater prevalence of neuropathic pain symptoms reported by female MS patients.127”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [126] Lynch, 2008, Analysis of nociception, sex and peripheral nerve innervation in the TMEV animal model of multiple sclerosis, Pain source

      Not checked in the free run.

    • cites [127] Buchanan, 2003, Gender analyses of nursing home residents with multiple sclerosis, J Gend Specif Med

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vincristine produced mechanical allodynia, but not thermal hyperalgesia, in a 10 day injection paradigm.

    “Vincristine produced mechanical allodynia, but not thermal hyperalgesia, in a 10 day injection paradigm121.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Weng, 2003, Changes in sensory processing in the spinal dorsal horn accompany vincristine-induced hyperalgesia and allodynia, Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the lysolecithin-induced demyelination model, heightened sensitivity to non-noxious and noxious mechanical stimulation emerged 5 days post-exposure and peaked between 9-15 days, with recovery to baseline by day 23.

    “Heightened sensitivity to both non-noxious and noxious mechanical stimulation is observed in lysolecithin-treated rats; this hypersensitivity emerged 5 days post-exposure and peaked between 9-15 days post-exposure.125 Recovery to baseline levels was observed by day 23 post-lysolecithin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Wallace, 2003, Focal lysolecithin-induced demyelination of peripheral afferents results in neuropathic pain behavior that is attenuated by cannabinoids, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MDA7 suppressed paclitaxel-induced mechanical allodynia, although mediation by CB2 receptors was not assessed.

    “Naguib and colleagues85 demonstrated that a novel CB2-specific agonist, MDA7, suppressed paclitaxel-induced mechanical allodynia, although mediation by CB2 receptors was not assessed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Naguib, 2008, MDA7: a novel selective agonist for CB2 receptors that prevents allodynia in rat neuropathic pain models, Br J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dronabinol reduced spontaneous pain intensity as measured with a numerical rating scale over a treatment period of 3 weeks and improved overall pain ratings on the category-rating scale over a treatment period of 15 weeks.

    “Dronabinol reduced spontaneous pain intensity as measured with a numerical rating scale (NRS) over a treatment period of 3 weeks134 and improved overall pain ratings on the category-rating scale over a treatment period of 15 weeks143.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [134] Svendsen, 2004, Does the cannabinoid dronabinol reduce central pain in multiple sclerosis?, BMJ source

      Not checked in the free run.

    • cites [143] Zajicek, 2003, Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial, Lancet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An anonymous cross-sectional questionnaire study revealed that as many as one-third of patients suffering from HIV have used cannabis to treat symptoms.

    “An anonymous cross-sectional questionnaire study revealed that as many as one-third of patients suffering from HIV have used cannabis to treat symptoms.138”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Woolridge, 2005, Cannabis use in HIV for pain and other medical symptoms, J Pain Symptom Manage source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dronabinol improved median radiating pain intensity and pressure threshold, sleep quality, spasms, and spasticity in multiple sclerosis patients.

    “Additionally, this drug improved median radiating pain intensity and pressure threshold,134 sleep quality, spasms, and spasticity143 in MS patients.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [134] Svendsen, 2004, Does the cannabinoid dronabinol reduce central pain in multiple sclerosis?, BMJ source

      Not checked in the free run.

    • cites [143] Zajicek, 2003, Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial, Lancet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Autoimmune encephalomyelitis has been postulated to underlie the development of neuropathic pain in multiple sclerosis.

    “autoimmune encephalomyelitis has been postulated to underlie the development of neuropathic pain in MS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Olechowski, 2009, Neuropathic pain behaviours in a chronic-relapsing model of experimental autoimmune encephalomyelitis (EAE), Pain source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Dronabinol is used to counteract AIDS-related wasting and promote appetite in patients suffering from AIDS-related anorexia.

    “Dronabinol (Marinol®) is used to counteract AIDS-related wasting and promote appetite in patients suffering from AIDS-related anorexia.139”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Beal, 1995, Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS, J Pain Symptom Manage source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cannabidiol's antinociceptive effects have been attributed to inhibition of anandamide degradation, antioxidant properties, or binding to an unknown cannabinoid receptor.

    “CBD's antinociceptive effects have additionally been attributed to inhibition of anandamide degradation, the compound's antioxidant properties, or binding to an unknown cannabinoid receptor.144”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Mechoulam, 2007, Cannabidiol—recent advances, Chem Biodivers source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A mouse model of multiple sclerosis (TMEV infection) is characterized by upregulation of CB2 receptor mRNA and increases in levels of 2-AG and PEA.

    “Interestingly, a mouse model of MS (TMEV infection) is also characterized by an upregulation of CB2 receptor mRNA and increases in levels of 2-AG and PEA.129”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Loria, 2008, Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide, Eur J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This study found no changes in heart rate, blood pressure, plasma HIV RNA, or blood CD4+ lymphocyte counts following cannabis treatment, suggesting that cannabis did not negatively impact the already compromised immune system in these patients.

    “This study found no changes in heart rate, blood pressure, plasma HIV RNA (viral load; VL), or blood CD4+ lymphocyte counts following cannabis treatment, suggesting that cannabis did not negatively impact the already compromised immune system in these patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Ellis, 2009, Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial, Neuropsychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Approximately 50% of rats exposed to varicella-zoster virus developed mechanical allodynia in the ipsilateral paw by 14 days post-infection; no thermal hyperalgesia or cold allodynia was observed.

    “Approximately 50% of rats exposed to the varicella-zoster virus (VZV) developed mechanical allodynia in the ipsilateral paw by 14 days post-infection; no thermal hyperalgesia or cold allodynia was observed.64”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Wallace, 2007, The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy, Br J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ellis and colleagues reported similar results in a crossover study employing multiple concentrations of Δ9-THC in cannabis cigarettes; cannabis was superior to placebo in either phase as measured with the descriptor differential scale or visual analogue scale.

    “In 2009, Ellis and colleagues137 reported similar results in a crossover study employing multiple concentrations of Δ9-THC in cannabis cigarettes administered to patients. Cannabis was superior to placebo in either phase of the crossover as measured with the descriptor differential scale (DDS) or VAS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Ellis, 2009, Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial, Neuropsychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Among symptoms improved following cannabis were appetite (97% reported improvement), pain (improved in 94% of patients with pain), nausea (93% reported improvement), and anxiety (93% reported improvement).

    “Among the symptoms improved following cannabis were appetite (97% reported improvement), pain (improved in 94% of the patients with pain), nausea (93% reported improvement) and anxiety (93% reported improvement).138”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Woolridge, 2005, Cannabis use in HIV for pain and other medical symptoms, J Pain Symptom Manage source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The benefits of Δ9-THC and nabilone for the treatment of chemotherapy-induced nausea and vomiting have been validated.

    “The benefits of Δ9-THC and nabilone for the treatment of chemotherapy-induced nausea and vomiting have also been validated.140, 141”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [140] Vincent, 1983, Review of cannabinoids and their antiemetic effectiveness, Drugs source

      Not checked in the free run.

    • cites [141] Tramer, 2001, Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review, BMJ source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cannabidiol may act as a high potency antagonist of cannabinoid agonists and an inverse agonist at CB2 receptors.

    “It may act as a high potency antagonist of cannabinoid agonists and an inverse agonist at CB2 receptors.144”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Mechoulam, 2007, Cannabidiol—recent advances, Chem Biodivers source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systemic WIN55,212-2 administered from days 18-21 post infection fully reversed mechanical allodynia to baseline levels in the post herpetic neuralgia model, although pharmacological specificity was not assessed.

    “Systemic WIN55,212-2, administered from days 18-21 post infection, fully reversed mechanical allodynia to baseline levels in this model of post herpetic neuralgia, although pharmacological specificity was not assessed.131”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Hasnie, 2007, Further characterization of a rat model of varicella zoster virus-associated pain: Relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugs, Neuroscience source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PEA analogue L-29 suppressed mechanical allodynia in the varicella-zoster virus model with an earlier onset relative to gabapentin.

    “The PEA analogue L-29 suppressed mechanical allodynia in this model with an earlier onset relative to gabapentin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Wallace, 2007, The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy, Br J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients did not increase the titration of their dose, indicating that no tolerance developed to Sativex.

    “Additionally, patients did not increase the titration of their dose indicating that no tolerance developed to Sativex®.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Rog, 2007, Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial, Clin Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cannador administered over a treatment period of 15 weeks improved overall pain ratings as well as sleep quality, spasms, and spasticity on category-rating scales in patients suffering from multiple sclerosis-related neuropathic pain.

    “Cannador®, administered over a treatment period of 15 weeks, improved overall pain ratings as well as sleep quality, spasms, and spasticity on category-rating scales in patients suffering from MS-related neuropathic pain.143”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] Zajicek, 2003, Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Δ9-THC and Sativex, but not placebo or cannabidiol, reduced the visual analogue scale rating of the two worst pain symptoms during the crossover phase.

    “Δ9-THC and Sativex®, but not placebo or CBD, reduced the VAS rating of the two worst pain symptoms during the crossover phase.156”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Notcutt, 2004, Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies, Anaesthesia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both Δ9-THC and Sativex reduced the primary outcome measure (Box-Scale 11 ordinal rating scale) in patients suffering from brachial plexus avulsion, indicating a reduction in pain symptoms versus placebo.

    “Both Δ9-THC and Sativex® reduced the primary outcome measure (Box-Scale 11 ordinal rating scale) in patients suffering from brachial plexus avulsion, indicating a reduction in pain symptoms versus placebo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] Berman, 2004, Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial, Pain source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Cannabinoid-based pharmacotherapies consistently show efficacy for suppressing pain due to multiple sclerosis, a disease state associated with an upregulation of CB2 receptors in microglia.

    “Thus, cannabinoid-based pharmacotherapies consistently show efficacy for suppressing pain due to multiple sclerosis, a disease state associated with an upregulation of CB2 receptors in microglia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    CT-3 has limited CNS availability, which translates into fewer CB1-mediated side-effects.

    “CT-3 has limited CNS availability,69 which translates into fewer CB1-mediated side-effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Dyson, 2005, Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat, Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Twenty-five percent withdrew due to adverse events and 95% experienced one or more adverse events during the course of Sativex treatment.

    “Twenty-five percent withdrew due to adverse events and 95% experienced one or more adverse events during the course of treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Rog, 2007, Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial, Clin Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased CB2 immunoreactivity has been reported in spinal cords derived from multiple sclerosis patients, with greater numbers of microglia/macrophage cells expressing CB2 immunoreactivity relative to controls.

    “Increased CB2 immunoreactivity has been reported in spinal cords derived from multiple sclerosis patients.149 Here, greater numbers of microglia/macrophage cells expressing CB2 immunoreactivity were observed relative to controls.149”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Yiangou, 2006, COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord, BMC Neurol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In this study, Sativex reduced mechanical dynamic and punctate allodynia and improved sleep disturbances.

    “In this study, Sativex® reduced mechanical dynamic and punctate allodynia, and improved sleep disturbances.133”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Nurmikko, 2007, Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial, Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Δ9-THC and Sativex additionally improved muscle spasms and spasticity severity.

    “Δ9-THC and Sativex® additionally improved muscle spasms and spasticity severity.159”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [159] Wade, 2003, A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms, Clin Rehabil source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Most doses of Sativex were administered between 6 PM and 12 AM, demonstrating that pain symptoms may be at their worst during normal sleeping hours for multiple sclerosis patients.

    “Most doses of Sativex® were administered between 6 PM and 12 AM demonstrating that pain symptoms may be at their worst during normal sleeping hours for MS patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Rog, 2007, Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial, Clin Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The NRS-11 completed at the end of the trial or upon withdrawal was not different from the earlier randomized study, indicating that Sativex was still suppressing pain.

    “The NRS-11, completed at the end of the trial or upon withdrawal, was not different from the earlier randomized study indicating that Sativex® was still suppressing pain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Rog, 2007, Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial, Clin Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ajulemic acid suppressed mixed forms of neuropathic pain as assessed with the visual analogue scale in the morning (3 hours after drug administration), but not in the afternoon (8 hours following drug administration).

    “A 21 patient study reported that ajulemic acid (CT-3) suppressed mixed forms of neuropathic pain, as assessed with the VAS, in the morning (3 hours after drug administration), but not in the afternoon (8 hours following drug administration).152”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Karst, 2003, Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CT-3 binds with high affinity to both CB1 and CB2 receptors and also binds with low affinity to PPARγ receptors.

    “CT-3 binds with high affinity to both CB1 and CB2 receptors and also binds with low affinity to PPARγ receptors.154”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Liu, 2003, Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid, Mol Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Smoking cannabis cigarettes improved spontaneous pain relief and pain unpleasantness visual analogue scale ratings in patients suffering from mixed forms of neuropathic pain, but failed to alter stimulus-evoked pain.

    “Smoking cannabis cigarettes also improved spontaneous pain relief and pain unpleasantness VAS ratings in patients suffering from mixed forms of neuropathic pain, but failed to alter stimulus-evoked pain.155”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Wilsey, 2008, A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain, J Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fifty-four percent of patients completed one year and 44% completed two years of the Sativex open-label study.

    “Fifty-four percent of the patients completed one year and 44% of patients completed two years of the study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Rog, 2007, Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial, Clin Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Seventy-one percent of the patients tested chose to continue to the open label study of Sativex with 63% withdrawing by the end of the study for various reasons.

    “Seventy-one percent of the patients tested chose to continue to the open label study of Sativex® with 63% withdrawing by the end of the study for various reasons.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Nurmikko, 2007, Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial, Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients reported improvements in sleep problems and disturbances while experiencing an increase in sleep adequacy in the open-label phase of the study.

    “Patients additionally reported improvements in sleep problems and disturbances while experiencing an increase in sleep adequacy in the open-label phase of the study.168”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Narang, 2008, Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy, J Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One study reported side-effects that were more prominent in older patients and did not correlate with analgesia.

    “One study reported side-effects that were more prominent in older patients and did not correlate with analgesia.164”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Attal, 2004, Are oral cannabinoids safe and effective in refractory neuropathic pain?, Eur J Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent systematic review of adverse effects of medical cannabinoids concluded that most adverse events (96.6%) were not serious and no serious adverse events were related exclusively to cannabinoid administration.

    “A recent systematic review of adverse effects of medical cannabinoids concluded that most adverse events (96.6%) were not serious and no serious adverse events were related exclusively to cannabinoid administration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170] Wang, 2008, Adverse effects of medical cannabinoids: a systematic review, CMAJ source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The present review suggests that cannabinoids show promise for treatment of neuropathic pain in humans either alone or as an add-on to other therapeutic agents.

    “The present review suggests that cannabinoids show promise for treatment of neuropathic pain in humans either alone or as an add-on to other therapeutic agents.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The mean dose was 16.6 ± 6.5 mg oral dronabinol in one study and 15 ± 6 mg in the other study.

    “The mean dose was 16.6 ± 6.5 mg oral dronabinol in one study164 and 15 ± 6 mg in the other study.165”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [164] Attal, 2004, Are oral cannabinoids safe and effective in refractory neuropathic pain?, Eur J Pain source

      Not checked in the free run.

    • cites [165] Clermont-Gnamien, 2002, The therapeutic use of D9-tetrahydrocannabinol (dronabinol) in refractory neuropathic pain, Presse Med

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The authors noted that a small number of subjects responded well to nabilone and side-effects were generally mild and in the expected range.

    “However, the authors noted that a small number of subjects responded well to nabilone and side-effects were generally mild and in the expected range.166”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Frank, 2008, Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study, Bmj source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Patients in this study exhibited a mean baseline visual analogue scale rating of 69.6 mm on a 0-100 mm scale; mean ratings were 59.93 ± 24.42 mm for nabilone and 58.58 ± 24.08 mm for dihydrocodeine.

    “Patients in this study exhibited a mean baseline VAS rating of 69.6 mm on a 0-100 mm VAS scale; mean VAS ratings were 59.93 ± 24.42 mm and 58.58 ± 24.08 mm for patients taking nabilone and dihydrocodeine, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Frank, 2008, Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study, Bmj source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most forms of neuropathic pain had similar prevalence rates and responsiveness to the different pharmacotherapies evaluated.

    “In this study, most forms of neuropathic pain had similar prevalence rates and responsiveness to the different pharmacotherapies evaluated.169”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Toth, 2008, A prospective identification of neuropathic pain in specific chronic polyneuropathy syndromes and response to pharmacological therapy, Pain source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These studies have elucidated neuronal and nonneuronal sites of action for cannabinoids in suppressing pathological pain states and documented regulatory changes in cannabinoid receptors and endocannabinoid accumulation in response to peripheral or central nervous system injury.

    “These studies have elucidated neuronal as well as nonneuronal (i.e. activated microglia) sites of action for cannabinoids in suppressing pathological pain states and documented regulatory changes in cannabinoid receptors and endocannabinoid accumulation in response to peripheral or central nervous system injury.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Side-effects were equally associated with the different cannabinoid pharmacotherapies; the average rate of nonserious adverse events was higher in patients receiving Sativex or oral Δ9-THC than controls.

    “Side-effects were equally associated with the different cannabinoid pharmacotherapies; the average rate of nonserious adverse events was higher in patients receiving Sativex® or oral Δ9-THC than controls. 170”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] Wang, 2008, Adverse effects of medical cannabinoids: a systematic review, CMAJ source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Nonserious adverse events pose the major limitation to patient compliance with pharmacotherapy and are not unique to cannabinoids.

    “However, nonserious adverse events (e.g. dizziness), which pose the major limitation to patient compliance with pharmacotherapy, are not unique to cannabinoids.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Combination therapies including a cannabinoid show efficacy for treatment-resistant neuropathic pain and may be employed to limit doses of analgesics or adjuvants associated with adverse side-effects.

    “Combination therapies including a cannabinoid show efficacy for treatment-resistant neuropathic pain and may be employed to limit doses of analgesics or adjuvants associated with adverse side-effects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    During the last two decades, a large number of research papers have demonstrated the efficacy of cannabinoids and modulators of the endocannabinoid system in suppressing neuropathic pain in animal models.

    “During the last two decades, a large number of research papers have demonstrated the efficacy of cannabinoids and modulators of the endocannabinoid system in suppressing neuropathic pain in animal models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A later study reported that 18% of patients with spinal cord injuries reported pain relief following treatment with oral dronabinol (mean 31 mg per day), whereas 23% experienced enhancement of pain, resulting in subsequent withdrawal by several patients.

    “A later study reported that 18% of the patients with spinal cord injuries reported pain relief following treatment with oral dronabinol (mean 31 mg per day), whereas 23% experienced enhancement of pain, resulting in subsequent withdrawal by several patients.163”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Hagenbach, 2007, The treatment of spasticity with Delta9-tetrahydrocannabinol in persons with spinal cord injury, Spinal Cord source

      Not checked in the free run.

146 of 146

  • The paper relies on this without support.

    Neuropathic pain is a debilitating form of chronic pain caused by damage to the nervous system, resulting from peripheral nerve injury, toxic insults, or disease states.

    “Neuropathic pain is a debilitating form of chronic pain resulting from nerve injury, disease states, or toxic insults.”

  • The paper relies on this without support.

    Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics.

    “Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics.”

  • The paper relies on this without support.

    Neuropathic pain responds poorly to available therapies and remains a significant clinical problem.

    “Neuropathic pain remains a significant clinical problem because it responds poorly to available therapies.”

  • The paper relies on this without support.

    Adverse side-effect profiles may limit therapeutic dosing and contribute to inadequate pain relief.

    “Moreover, adverse side-effect profiles may limit therapeutic dosing and contribute to inadequate pain relief.”

  • The paper relies on this without support.

    Activation of CB1 receptors suppresses neuronal excitability and transmitter release by suppressing calcium conductance and inhibiting inward rectifying potassium conductance.

    “Activation of CB1 receptors suppresses calcium conductance and inhibits inward rectifying potassium conductance, thereby suppressing neuronal excitability and transmitter release.”

  • The paper relies on this without support.

    Microglia secrete pro-inflammatory factors and induce the release of mediators associated with synaptogenesis and plasticity, leading to changes in neuronal excitability.

    “Microglia secrete pro-inflammatory factors and induce the release of several mediators (e.g. nitric oxide (NO), neurotrophins, free radicals) that are associated with synaptogenesis and plasticity, leading to changes in neuronal excitability.”

  • The paper relies on this without support.

    Spontaneous firing of wide dynamic range neurons contributes to behavioral hypersensitivity and neuronal sensitization in neuropathic pain states.

    “Spontaneous firing of WDR neurons is believed to contribute to behavioral hypersensitivity and neuronal sensitization in neuropathic pain states.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Using complementary genetic and pharmacological approaches, distinct components of the endocannabinoid system (receptors and endocannabinoid-regulating enzymes) have emerged as promising targets to treat neuropathic pain.

    “Using complementary genetic and pharmacological approaches, distinct components of the endocannabinoid system (ie, receptors and endocannabinoid-regulating enzymes) have emerged as promising targets to treat neuropathic pain (Table 5; for additional information, Guindon and Hohmann, 2009;Rahn and Hohmann, 2009).”

    From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Rahn and Hohmann, 2009

  • The endocannabinoid system plays a key role in pain mechanisms.

    “The endocannabinoid system plays a key role in pain mechanisms [42], and, previously, cannabinoids were long used by women to alleviate dysmenorrhea [45].”

    From Endocannabinoid involvement in endometriosis. (2010) · cites this paper as [42]

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Related

Authors
Rahn, E. J., & Hohmann, A. G.
Affiliations
University of Georgia (US)
Corresponding author
Hohmann, Andrea G.
ORCID
Hohmann, Andrea G.
Venue
Neurotherapeutics
Publisher
Elsevier BV
Published
2009-10
Volume
6
Issue
4
Pages
713-737
ISSN
1878-7479 (ISSN-L)
DOI
10.1016/j.nurt.2009.08.002
PMC
PMC2755639
OpenAlex
W2020010905
Semantic Scholar
7daf2b1153c0a36249f6f7c9b8f70b259a9da126
Cited by
305
References
187
Citations by year
2026: 9 · 2025: 7 · 2024: 14 · 2023: 17 · 2022: 18 · 2021: 25 · 2020: 22 · 2019: 17 · 2018: 19 · 2017: 22 · 2016: 26 · 2015: 20 · 2014: 24 · 2013: 15 · 2012: 20
FWCI
1.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurotherapeutics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Psi Chi
  • National Institute on Drug Abuse (DA022478, R21DA022478, R01DA021644, DA021644)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
Keywords
cannabinoids, neuropathic pain, delta-9-tetrahydrocannabinol, endocannabinoid system, CB1 receptor, CB2 receptor, CB2 receptor agonist, endocannabinoid degradation, nerve injury, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, HIV neuropathy, multiple sclerosis, herpes zoster, allodynia, hyperalgesia, cannabis smoking, Marinol, Sativex, analgesia
MeSH terms
Animals, Cannabinoids, Chronic Disease, Disease Models, Animal, Humans, Neuralgia, Peripheral Nervous System Diseases, Receptors, Cannabinoid, Cannabinoid Receptor Modulators

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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