Neuropathic Pain Part Two by Jeffrey Dach MD

Neuropathic Pain Part Two by Jeffrey Dach MD

This is part two of a series, click here for part one.


Medicinal Marijuana, Cannabis Sativa – Cannabinoids – Complex Regional Pain Syndrome

Another treatment modality showing success against RSD chronic refractory pain is medicinal marijuana.(21)   “An oral cannabinoid was associated with up to 60% reductions in pain in 10 patients with refractory complex regional pain syndrome (CRPS), according to research presented at the 2010 annual World Congress on Pain in Montreal. The study investigators also reported that most of the patients were able to discontinue long-term opioid therapy and reported signi ficant improvements in quality of life.” (21) from Pharmacy Practice News.  (More on this report)

Here is a review article on use of medicinal cannabis for allodynia, neuropathic pain and other chronic pain syndromes: Cannabinergic Pain Medicine Aggarwal_2013 Clinical Journal of Pain.

Cannabis for Fibromyalgia Pain – works better than prescription medications.  “Medical marijuana is far more effective at treating symptoms of fibromyalgia than any of the three prescription drugs Cymbalta, Lyrica and Savella” (22)

Elaine’s Story – 20 years of opiate refractory RSD, finally better with when Elaine tries medicinal cannabis for pain.


links and References
Beta-Caryophyllene: The Dietary Cannabinoid That Could Make Synthetics Irrelevant
12 Nov, 2013
Beta-caryophyllene is a dietary cannabinoid
PNAS July 1, 2008 vol. 105 no. 26     Jürg Gertsch, Marco Leont, Stefan Raduner
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule (ETH) Zurich, 8092 Zürich, Switzerland;

Although the CB1 receptor is expressed in the central nervous system and in the periphery, the CB2 receptor is primarily found in peripheral tissues.

In particular, CB2 receptor ligands have been shown to inhibit inflammation and edema formation (15), exhibit analgesic effects (16), and play a protective role in hepatic ischemia-reperfusion injury (17). In the gastrointestinal tract, CB2 receptor agonists have been shown to prevent experimental colitis by reducing inflammation (18). Moreover, the CB2 receptor has been described as a potential target for the treatment of atherosclerosis (19) and osteoporosis (20). Consequently, CB2 receptor-selective agonists that are devoid of the psychoactive side effects typically associated with CB1 receptor activation are potential drug candidates for the treatment of a range of different diseases.

CB2 receptor agonists have repeatedly been shown to inhibit the release of cytokines from LPS-stimulated monocytes, such as tumor necrosis factor-α (TNF-α)

“Here, we report that the widespread plant volatile β-caryophyllene (BCP) selectively binds to the CB2 receptor and that it is a functional CB2 agonist. Intriguingly, BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis.”


neuropathic pain

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The role of the cannabinoid receptor 2 in the modulation of neuropathic pain 2012  Dissertation by Anna-Lena Klauke Bonn, Oktober2012

together all findings have clearly demonstrated that CB2 receptor activation alone is sufficient for attenuation of neuropathic pain symptoms and suggest an important role of peripheral and spinal CB2 receptors during neuropathic pain development. The natural source of BCP and the possibility of an oral intake as a dietary factor make BCP and interesting compound that could be clearly advantageous over other synthetic cannabinoid agonists in clinical practice.

BCP reduced glia signals in the spinal cord
Glia cells are thought to contribute to the development of neuropathic pain. Their activation and proliferation in the spinal cord parallels the development of neuropathic pain symptoms (Coyle, 1998). A fast activation and proliferation of microglia cells is seen as early as 4 hours after nerve injury in the dorsal horn of the lumbar spinal cord. This is followed by a late activation of astrocytes, which are gradually up regulated starting around postoperative day four (Tanga et al., 2004). These findings suggest that microglia are mainly involved in the initiation of neuropathic pain by the release of mediators that in turn activate astrocytes and further microglia cells.
Insights into the role of CB2 receptor activation in glia cells during the development of neuropathic pain were given by experiments using CB2 receptor knockout mice. These mice exhibited not only an exaggerated glia response compared to wild type littermates, but the inflammation also spread to the contralateral dorsal horn, which was accompanied by mechanical allodynia and thermal hyperalgesia in the uninjured paw (Rácz et al., 2008b).

Together with the behavioral data the histological analyses suggest that BCP inhibits the formation of allodynia and hyperalgesia by immunomodulatory effects, rather than directly modulating the pain transmission in peripheral or central neurons.\

CB2 receptors only seem to play a minor role under normal, naïve conditions, but are markedly up regulated under various disease conditions at the sides involved in the disease (Pacher and Mechoulam, 2011).

Summarized, the present study is the first demonstration that a common food ingredient is highly effective in an animal model of neuropathic pain at physiologically relevant doses. BCP is the first bioactive, natural CB2 receptor agonist, which is able to reduce neuropathic pain symptoms in mice, without exerting any CB1-associated psychomimetic side effects. Thus, it is likely that BCP belongs to a group of common plant products with a major potential impact on human health.

Eur Neuropsychopharmacol. 2014 Apr;24(4):608-20. doi: 10.1016/j.euroneuro.2013.10.008. Epub 2013 Oct 22.
The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain.
Klauke AL1, Racz I2, Pradier B1, Markert A1, Zimmer AM1, Gertsch J3, Zimmer A1.
The widespread plant volatile beta-caryophyllene (BCP) was recently identified as a natural selective agonist of the peripherally expressed cannabinoid receptor 2 (CB2). It is found in relatively high concentrations in many spices and food plants. A number of studies have shown that CB2 is critically involved in the modulation of inflammatory and neuropathic pain responses. In this study, we have investigated the analgesic effects of BCP in animal models of inflammatory and neuropathic pain. We demonstrate that orally administered BCP reduced inflammatory (late phase) pain responses in the formalin test in a CB2 receptor-dependent manner, while it had no effect on acute (early phase) responses. In a neuropathic pain model the chronic oral administration of BCP attenuated thermal hyperalgesia and mechanical allodynia, and reduced spinal neuroinflammation. Importantly, we found no signs of tolerance to the anti-hyperalgesic effects of BCP after prolonged treatment. Oral BCP was more effective than the subcutaneously injected synthetic CB2 agonist JWH-133. Thus, the natural plant product BCP may be highly effective in the treatment of long lasting, debilitating pain states. Our results have important implications for the role of dietary factors in the development and modulation of chronic pain conditions.
Br J Pharmacol. 2011 Jan;162(2):428-40. doi: 10.1111/j.1476-5381.2010.01046.x.
Central and peripheral sites of action for CB₂ receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats.
Hsieh GC1, Pai M, Chandran P, Hooker BA, Zhu CZ, Salyers AK, Wensink EJ, Zhan C, Carroll WA, Dart MJ, Yao BB, Honore P, Meyer MD.
Cannabinoid CB₂ receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory and neuropathic pain. However, mechanisms underlying CB₂-mediated analgesic effects remain largely unknown. The present study was conducted to elucidate the CB₂ receptor expression in ‘pain relevant’ tissues and the potential sites of action of CB₂ agonism in rats.
EXPERIMENTAL APPROACH:Expression of cannabinoid receptor mRNA was evaluated by quantitative RT-PCR in dorsal root ganglia (DRGs), spinal cords, paws and several brain regions of sham, chronic inflammatory pain (CFA) and neuropathic pain (spinal nerve ligation, SNL) rats. The sites of CB₂ mediated antinociception were evaluated in vivo following intra-DRG, intrathecal (i.t.) or intraplantar (i.paw) administration of potent CB₂-selective agonists A-836339 and AM1241.
KEY RESULTS:CB₂ receptor gene expression was significantly up-regulated in DRGs (SNL and CFA), spinal cords (SNL) or paws (CFA) ipsilateral to injury under inflammatory and neuropathic pain conditions. Systemic A-836339 and AM1241 produced dose-dependent efficacy in both inflammatory and neuropathic pain models. Local administration of CB₂ agonists also produced significant analgesic effects in SNL (intra-DRG and i.t.) and CFA (intra-DRG) pain models. In contrast to A-836339, i.paw administration of AM-1241 dose-relatedly reversed the CFA-induced thermal hyperalgesia, suggesting that different mechanisms may be contributing to its in vivo properties.
CONCLUSIONS AND IMPLICATIONS:These results demonstrate that both DRG and spinal cord are important sites contributing to CB₂ receptor-mediated analgesia and that the changes in CB₂ receptor expression play a crucial role for the sites of action in regulating pain perception.
Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9099-104. doi: 10.1073/pnas.0803601105. Epub 2008 Jun 23.
Beta-caryophyllene is a dietary cannabinoid.
Gertsch J1, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, Altmann KH, Karsak M, Zimmer A.
Author information

The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB(1)) and CB(2) receptors. Although the CB(1) receptor is responsible for the psychomodulatory effects, activation of the CB(2) receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-beta-caryophyllene [(E)-BCP] selectively binds to the CB(2) receptor (K(i) = 155 +/- 4 nM) and that it is a functional CB(2) agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the CB(2) receptor, showing ligand pi-pi stacking interactions with residues F117 and W258. Upon binding to the CB(2) receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB(2) receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB(2) receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis.


Refractory CRPS Patients Discontinue Opiates With Cannabinoid Treatment  by David Wild, Pharmacy Practice News
Montreal—An oral cannabinoid was associated with up to 60% reductions in pain in 10 patients with refractory complex regional pain syndrome (CRPS), according to research presented at the 2010 annual World Congress on Pain in Montreal. The study investigators also reported that most of the patients were able to discontinue long-term opioid therapy and reported significant improvements in quality of life.


Marijuana Rated Most Effective for Treating Fibromyalgia
April 21st, 2014 by Pat Anson, Editor

Medical marijuana is far more effective at treating symptoms of fibromyalgia than any of the three prescription drugs approved by the Food and Drug Administration to treat the disorder.

That is one of the surprise findings in an online survey of over 1,300 fibromyalgia patients conducted by the National Pain Foundation and National Pain Report.

Cymbalta graphThe FDA has approved only three drugs – Cymbalta, Lyrica and Savella — for the treatment of fibromyalgia. Although they generate billions of dollars in annual sales for Pfizer, Eli Lilly, Forest Laboratories and other drug makers, most who have tried the medications say they don’t work.


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