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

In the paper

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

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [28] Bisogno, 2002, Fatty acid amide hydrolase, an enzyme with many bioactive substrates, Curr Pharm Des source

In the paper

“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.”

What the sources say

• Not checked yetcites [8] Herkenham, 1991, Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study, J Neurosci source
• Not checked yetcites [9] Matsuda, 1993, Localization of cannabinoid receptor mRNA in rat brain, J Comp Neurol source
• Not checked yetcites [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

In the paper

“PEA does not bind cannabinoid receptors and has recently been described as an endogenous ligand for peroxisome proliferator receptor-α (PPAR-α).26”

What the sources say

• Not checked yetcites [26] Lo Verme, 2005, The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide, Mol Pharmacol source

In the paper

“Activation of the CB1 receptor also results in hypothermia, sedation, catalepsy, and altered mental status.11”

What the sources say

• Not checked yetcites [11] Malan, 2001, CB2 cannabinoid receptor-mediated peripheral antinociception, Pain source

In the paper

“Both CB12 and CB23 receptors are G-coupled protein receptors that are negatively coupled to adenylate cyclase.”

What the sources say

• Not checked yetcites [2] Matsuda, 1990, Structure of a cannabinoid receptor and functional expression of the cloned cDNA, Nature source
• Not checked yetcites [3] Munro, 1993, Molecular characterization of a peripheral receptor for cannabinoids, Nature source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“CB2 receptor activation stimulates MAPK activity but does not modulate calcium or potassium conductances.4”

What the sources say

• Not checked yetcites [4] Guindon, 2008, Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain, Br J Pharmacol source

In the paper

“FAAH-/- mice are hypoalgesic in models of acute and inflammatory pain; these effects are blocked by a CB1 antagonist.29, 30”

What the sources say

• Not checked yetcites [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 yetcites [30] Lichtman, 2004, Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia, Pain source

In the paper

“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.”

What the sources say

• Not checked yetcites [46] Strangman, 1999, Cannabinoid WIN 55,212-2 inhibits the activity-dependent facilitation of spinal nociceptive responses, J Neurophysiol source
• Not checked yetcites [47] Liu, 2006, Effects of a cannabinoid agonist on spinal nociceptive neurons in a rodent model of neuropathic pain, J Neurophysiol source

In the paper

“Monoacylglycerol lipase (MGL) is a key enzyme implicated in the hydrolysis of 2-AG.33, 34”

What the sources say

• Not checked yetcites [33] Hohmann, 2005, An endocannabinoid mechanism for stress-induced analgesia, Nature source
• Not checked yetcites [34] Dinh, 2002, Brain monoglyceride lipase participating in endocannabinoid inactivation, Proc Natl Acad Sci U S A source

In the paper

“SR141716, administered acutely, is pro-hyperalgesic and pro-allodynic in this model. 42”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“CB1 receptors are upregulated in the spinal cord following CCI; these effects are believed to be modulated by tyrosine kinase38 and glucocorticoid39 receptors.”

What the sources say

• Not checked yetcites [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 yetcites [39] Wang, 2007, Central glucocorticoid receptors regulate the upregulation of spinal cannabinoid-1 receptors after peripheral nerve injury in rats, Pain source

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [4] Guindon, 2008, Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain, Br J Pharmacol source

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“AEA can also activate the peroxisome proliferator receptor-γ (PPARγ) receptor.32”

What the sources say

• Not checked yetcites [32] Bouaboula, 2005, Anandamide induced PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation, Eur J Pharmacol source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“This basal hypoalgesia is absent in FAAH-/- mice subjected to nerve injury, where genotype differences in evoked neuropathic pain behaviors are not apparent.30”

What the sources say

• Not checked yetcites [30] Lichtman, 2004, Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia, Pain source

In the paper

“However, anti-hyperalgesic effects observed with these compounds are likely to be independent of cannabinoid receptors, and may be mediated through TRPV1.”

What the sources say

• Not checked yetcites [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 yetcites [41] Comelli, 2008, Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved, Phytother Res source

In the paper

“CCI produces mechanical allodynia as well as thermal allodynia and hyperalgesia in the ipsilateral paw as early as two days post-surgery.37”

What the sources say

• Not checked yetcites [37] Bennett, 1988, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain source

In the paper

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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [51] Yao, 2009, J Pharmacol Exp Ther source

In the paper

“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.”

What the sources say

• Not checked yetcites [65] Helyes, 2003, Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat, Life Sci source

In the paper

“The transport inhibitor AM404, administered systemically, suppressed mechanical allodynia in a CB1-dependent manner, without producing motor effects.73”

What the sources say

• Not checked yetcites [73] Mitchell, 2007, Actions of the endocannabinoid transport inhibitor AM404 in neuropathic and inflammatory pain models, Clin Exp Pharmacol Physiol source

In the paper

“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”

What the sources say

• Not checked yetcites [69] Dyson, 2005, Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat, Pain source

In the paper

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

In the paper

“Anti-hyperalgesic effects of AEA and PEA were blocked by a CB1 and CB2 antagonist, respectively.65”

What the sources say

• Not checked yetcites [65] Helyes, 2003, Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat, Life Sci source

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“Additionally both OL135 and URB597 are antinociceptive in FAAH+/+ mice, but fail to produce an effect in FAAH-/- mice.59”

What the sources say

• Not checked yetcites [59] Kinsey, 2009, Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain, J Pharmacol Exp Ther source

In the paper

“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”

What the sources say

• Not checked yetcites [59] Kinsey, 2009, Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain, J Pharmacol Exp Ther source

In the paper

“CB2-/- mice reportedly develop thermal hyperalgesia and mechanical allodynia in the contralateral paw following surgery, whereas CB2+/+ do not.63”

What the sources say

• Not checked yetcites [63] Racz, 2008, Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain, J Neurosci source

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [17] Beltramo, 2006, CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms, Eur J Neurosci source

In the paper

“The FAAH inhibitor URB597, administered locally in the paw,67 but not systemically62 suppressed both thermal hyperalgesia and mechanical allodynia through a CB1 mechanism.”

What the sources say

• Not checked yetcites [62] Jayamanne, 2006, Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models, Br J Pharmacol source
• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [80] LaBuda, 2005, Pharmacological evaluation of the selective spinal nerve ligation model of neuropathic pain in the rat, J Neurosci Methods source

In the paper

“Increases in both AEA and 2-AG have also been reported in the ipsilateral injured L5, but not the uninjured L4 DRG.83”

What the sources say

• Not checked yetcites [83] Mitrirattanakul, 2006, Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain, Pain source

In the paper

“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”

What the sources say

• Not checked yetcites [64] Wallace, 2007, The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy, Br J Pharmacol source

In the paper

“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”

What the sources say

• Not checked yetcites [82] Chapman, 2001, Functional changes in the inhibitory effect of spinal cannabinoid (CB) receptor activation in nerve injured rats, Neuropharmacology source

In the paper

“The fatty-acid analogue of PEA, L-29, also suppressed thermal hyperalgesia and mechanical allodynia in the Seltzer model.”

What the sources say

• Not checked yetcites [64] Wallace, 2007, The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy, Br J Pharmacol source

In the paper

“CB2 mRNA was upregulated in the lumbar spinal cord following SNL,49 coincident with the expression of activated microglia.”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [81] Leichsenring, 2009, Analgesic and antiinflammatory effects of cannabinoid receptor agonists in a rat model of neuropathic pain, Naunyn Schmiedebergs Arch Pharmacol source

In the paper

“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”

What the sources say

• Not checked yetcites [75] Vuong, 2008, Actions of N-arachidonyl-glycine in a rat neuropathic pain model, Neuropharmacology source

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [76] Dani, 2007, The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors, Eur J Pharmacol source

In the paper

“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”

What the sources say

• Not checked yetcites [92] Jhaveri, 2006, Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain, J Neurosci source

In the paper

“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”

What the sources say

• Not checked yetcites [93] Vos, 1991, Behavioral changes following ligation of the infraorbital nerve in rats: an animal model of trigeminal neuropathic pain

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [94] Liang, 2007, The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain, Neuropharmacology source

In the paper

“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.”

What the sources say

• Not checked yetcites [94] Liang, 2007, The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain, Neuropharmacology source

In the paper

“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”

What the sources say

• Not checked yetcites [81] Leichsenring, 2009, Analgesic and antiinflammatory effects of cannabinoid receptor agonists in a rat model of neuropathic pain, Naunyn Schmiedebergs Arch Pharmacol source

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [92] Jhaveri, 2006, Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain, J Neurosci source

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [94] Liang, 2007, The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain, Neuropharmacology source

In the paper

“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”

What the sources say

• Not checked yetcites [101] Decosterd, 2004, Differential analgesic sensitivity of two distinct neuropathic pain models, Anesth Analg source

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [103] Hama, 2007, Antinociceptive effect of cannabinoid agonist WIN 55,212-2 in rats with a spinal cord injury, Exp Neurol source

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“Spinal cord injury (SCI)102 produces mechanical hyperalgesia and allodynia.”

What the sources say

• Not checked yetcites [102] Bruce, 2002, Chronic pain after clip-compression injury of the rat spinal cord, Exp Neurol source

In the paper

“Interestingly, Δ9-THC exhibited enhanced antinociceptive efficacy in diabetic rats whereas morphine showed reduced antinociceptive efficacy.115”

What the sources say

• Not checked yetcites [115] Williams, 2008, Decreased basal endogenous opioid levels in diabetic rodents: effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception, Eur J Pharmacol source

In the paper

“HU-210 did not alter the hyperglycemia index; however, it did normalize cerebral oxidative stress present in diabetic mice.114”

What the sources say

• Not checked yetcites [114] Dagon, 2007, The synthetic cannabinoid HU-210 attenuates neural damage in diabetic mice and hyperglycemic pheochromocytoma PC12 cells, Neurobiol Dis source

In the paper

“Unlike morphine, chronic administration of WIN55,212-2 reduced mechanical allodynia in the SCI model with no decrease in effectiveness over time.104”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [7] Agarwal, 2007, Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors, Nat Neurosci source

In the paper

“Increased levels of endocannabinoids have been found in obese patients suffering from Type II diabetes109”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [114] Dagon, 2007, The synthetic cannabinoid HU-210 attenuates neural damage in diabetic mice and hyperglycemic pheochromocytoma PC12 cells, Neurobiol Dis source

In the paper

“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”

What the sources say

• Not checked yetcites [7] Agarwal, 2007, Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors, Nat Neurosci source

In the paper

“Mechanical allodynia and thermal hyperalgesia were present in the initial study describing this technique105 as well as the study we reviewed.”

What the sources say

• Not checked yetcites [105] Hofmann, 2003, Pharmacological sensitivity and gene expression analysis of the tibial nerve injury model of neuropathic pain, Eur J Pharmacol source

In the paper

“The CB1 antagonist rimonabant (Acomplia®) ameliorates insulin resistance and decreases weight gain in patients suffering from metabolic syndromes.112”

What the sources say

• Not checked yetcites [112] Scheen, 2009, The endocannabinoid system: a promising target for the management of type 2 diabetes, Curr Protein Pept Sci source

In the paper

“Systemic BAY 59-3074 was shown to attenuate both forms of neuropathic nociception, although pharmacological specificity was not assessed.78”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [113] Watanabe, 2009, Rimonabant ameliorates insulin resistance via both adiponectin-dependent and adiponectin-independent pathways, J Biol Chem source

In the paper

“Rats receiving ddc displayed modest levels of gliosis whereas combined treatment with both HIV-gp120 and ddc increased levels of microglial activation.123”

What the sources say

• Not checked yetcites [123] Wallace, 2007, Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain, Brain source

In the paper

“No hypersensitivity to thermal stimuli or motor deficits was observed following ddc treatment.”

What the sources say

• Not checked yetcites [123] Wallace, 2007, Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain, Brain source

In the paper

“Using the paclitaxel dosing paradigm described by Flatters and Bennett,120 mechanical allodynia, but not thermal hyperalgesia, was observed.”

What the sources say

• Not checked yetcites [120] Flatters, 2004, Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy, Pain source

In the paper

“WIN55,212-2 prevented the development of mechanical allodynia induced by cisplatin, but failed to produce an anti-emetic benefit in this study.116”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [123] Wallace, 2007, Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain, Brain source

In the paper

“Thus, both mixed CB1/CB2 agonists and selective CB2 agonists suppress paclitaxel-evoked mechanical allodynia.”

In the paper

“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”

What the sources say

• Not checked yetcites [123] Wallace, 2007, Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain, Brain source

In the paper

“WIN55,212-2 attenuated mechanical allodynia and thermal hyperalgesia in this model and remained efficacious for up to one hour post injection.125”

What the sources say

• Not checked yetcites [125] Wallace, 2003, Focal lysolecithin-induced demyelination of peripheral afferents results in neuropathic pain behavior that is attenuated by cannabinoids, J Neurosci source

In the paper

“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”

What the sources say

• Not checked yetcites [118] Polomano, 2001, A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel, Pain source
• Not checked yetcites [119] Pascual, 2005, A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats, Pain source

In the paper

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

What the sources say

• Not checked yetcites [119] Pascual, 2005, A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats, Pain source

In the paper

“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”

What the sources say

• Not checked yetcites [126] Lynch, 2008, Analysis of nociception, sex and peripheral nerve innervation in the TMEV animal model of multiple sclerosis, Pain source
• Not checked yetcites [127] Buchanan, 2003, Gender analyses of nursing home residents with multiple sclerosis, J Gend Specif Med

In the paper

“Vincristine produced mechanical allodynia, but not thermal hyperalgesia, in a 10 day injection paradigm121.”

What the sources say

• Not checked yetcites [121] Weng, 2003, Changes in sensory processing in the spinal dorsal horn accompany vincristine-induced hyperalgesia and allodynia, Pain source

In the paper

“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.”

What the sources say

• Not checked yetcites [125] Wallace, 2003, Focal lysolecithin-induced demyelination of peripheral afferents results in neuropathic pain behavior that is attenuated by cannabinoids, J Neurosci source

In the paper

“Naguib and colleagues85 demonstrated that a novel CB2-specific agonist, MDA7, suppressed paclitaxel-induced mechanical allodynia, although mediation by CB2 receptors was not assessed.”

What the sources say

• Not checked yetcites [85] Naguib, 2008, MDA7: a novel selective agonist for CB2 receptors that prevents allodynia in rat neuropathic pain models, Br J Pharmacol source

In the paper

“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.”

What the sources say

• Not checked yetcites [134] Svendsen, 2004, Does the cannabinoid dronabinol reduce central pain in multiple sclerosis?, BMJ source
• Not checked yetcites [143] Zajicek, 2003, Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial, Lancet source

In the paper

“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”

What the sources say

• Not checked yetcites [138] Woolridge, 2005, Cannabis use in HIV for pain and other medical symptoms, J Pain Symptom Manage source

In the paper

“Additionally, this drug improved median radiating pain intensity and pressure threshold,134 sleep quality, spasms, and spasticity143 in MS patients.”

What the sources say

• Not checked yetcites [134] Svendsen, 2004, Does the cannabinoid dronabinol reduce central pain in multiple sclerosis?, BMJ source
• Not checked yetcites [143] Zajicek, 2003, Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial, Lancet source

In the paper

“autoimmune encephalomyelitis has been postulated to underlie the development of neuropathic pain in MS.”

What the sources say

• Not checked yetcites [128] Olechowski, 2009, Neuropathic pain behaviours in a chronic-relapsing model of experimental autoimmune encephalomyelitis (EAE), Pain source

In the paper

“Dronabinol (Marinol®) is used to counteract AIDS-related wasting and promote appetite in patients suffering from AIDS-related anorexia.139”

What the sources say

• Not checked yetcites [139] Beal, 1995, Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS, J Pain Symptom Manage source

In the paper

“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”

What the sources say

• Not checked yetcites [144] Mechoulam, 2007, Cannabidiol—recent advances, Chem Biodivers source

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [137] Ellis, 2009, Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial, Neuropsychopharmacology source

In the paper

“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”

What the sources say

• Not checked yetcites [64] Wallace, 2007, The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy, Br J Pharmacol source

In the paper

“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.”

What the sources say

• Not checked yetcites [137] Ellis, 2009, Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial, Neuropsychopharmacology source

In the paper

“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”

What the sources say

• Not checked yetcites [138] Woolridge, 2005, Cannabis use in HIV for pain and other medical symptoms, J Pain Symptom Manage source

In the paper

“The benefits of Δ9-THC and nabilone for the treatment of chemotherapy-induced nausea and vomiting have also been validated.140, 141”

What the sources say

• Not checked yetcites [140] Vincent, 1983, Review of cannabinoids and their antiemetic effectiveness, Drugs source
• Not checked yetcites [141] Tramer, 2001, Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review, BMJ source

In the paper

“It may act as a high potency antagonist of cannabinoid agonists and an inverse agonist at CB2 receptors.144”

What the sources say

• Not checked yetcites [144] Mechoulam, 2007, Cannabidiol—recent advances, Chem Biodivers source

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“The PEA analogue L-29 suppressed mechanical allodynia in this model with an earlier onset relative to gabapentin.”

What the sources say

• Not checked yetcites [64] Wallace, 2007, The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy, Br J Pharmacol source

In the paper

“Additionally, patients did not increase the titration of their dose indicating that no tolerance developed to Sativex®.”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [143] Zajicek, 2003, Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial, Lancet source

In the paper

“Δ9-THC and Sativex®, but not placebo or CBD, reduced the VAS rating of the two worst pain symptoms during the crossover phase.156”

What the sources say

• Not checked yetcites [156] Notcutt, 2004, Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies, Anaesthesia source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“CT-3 has limited CNS availability,69 which translates into fewer CB1-mediated side-effects.”

What the sources say

• Not checked yetcites [69] Dyson, 2005, Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat, Pain source

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“In this study, Sativex® reduced mechanical dynamic and punctate allodynia, and improved sleep disturbances.133”

What the sources say

• Not checked yetcites [133] Nurmikko, 2007, Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial, Pain source

In the paper

“Δ9-THC and Sativex® additionally improved muscle spasms and spasticity severity.159”

What the sources say

• Not checked yetcites [159] Wade, 2003, A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms, Clin Rehabil source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [152] Karst, 2003, Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial, JAMA source

In the paper

“CT-3 binds with high affinity to both CB1 and CB2 receptors and also binds with low affinity to PPARγ receptors.154”

What the sources say

• Not checked yetcites [154] Liu, 2003, Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid, Mol Pharmacol source

In the paper

“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”

What the sources say

• Not checked yetcites [155] Wilsey, 2008, A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain, J Pain source

In the paper

“Fifty-four percent of the patients completed one year and 44% of patients completed two years of the study.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [133] Nurmikko, 2007, Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial, Pain source

In the paper

“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”

What the sources say

• Not checked yetcites [168] Narang, 2008, Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy, J Pain source

In the paper

“One study reported side-effects that were more prominent in older patients and did not correlate with analgesia.164”

What the sources say

• Not checked yetcites [164] Attal, 2004, Are oral cannabinoids safe and effective in refractory neuropathic pain?, Eur J Pain source

In the paper

“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.”

What the sources say

• Not checked yetcites [170] Wang, 2008, Adverse effects of medical cannabinoids: a systematic review, CMAJ source

In the paper

“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.”

In the paper

“The mean dose was 16.6 ± 6.5 mg oral dronabinol in one study164 and 15 ± 6 mg in the other study.165”

What the sources say

• Not checked yetcites [164] Attal, 2004, Are oral cannabinoids safe and effective in refractory neuropathic pain?, Eur J Pain source
• Not checked yetcites [165] Clermont-Gnamien, 2002, The therapeutic use of D9-tetrahydrocannabinol (dronabinol) in refractory neuropathic pain, Presse Med

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“In this study, most forms of neuropathic pain had similar prevalence rates and responsiveness to the different pharmacotherapies evaluated.169”

What the sources say

• Not checked yetcites [169] Toth, 2008, A prospective identification of neuropathic pain in specific chronic polyneuropathy syndromes and response to pharmacological therapy, Pain source

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [170] Wang, 2008, Adverse effects of medical cannabinoids: a systematic review, CMAJ source

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [163] Hagenbach, 2007, The treatment of spasticity with Delta9-tetrahydrocannabinol in persons with spinal cord injury, Spinal Cord source