Cannaboid, Antinociceptive effects, and Neuropathic Pain-Presentation of Two Studies (Discussion to follow)-MEDLINE (RE-POST)

http://www.ncbi.nlm.nih.gov/pubmed/18618522

Phytother Res. 2008 Aug;22(8):1017-24. doi: 10.1002/ptr.2401.

Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved.

Comelli F, Giagnoni G, Bettoni I, Colleoni M, Costa B.

Source

Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.

Abstract

This study aimed to give a rationale for the employment of phytocannabinoid formulations to treat neuropathic pain. It was found that a controlled cannabis extract, containing multiple cannabinoids, in a defined ratio, and other non-cannabinoid fractions (terpenes and flavonoids) provided better antinociceptive efficacy than the single cannabinoid given alone, when tested in a rat model of neuropathic pain. The results also demonstrated that such an antihyperalgesic effect did not involve the cannabinoid CB1 and CB2 receptors, whereas it was mediated by vanilloid receptors TRPV1. The non-psychoactive compound, cannabidiol, is the only component present at a high level in the extract able to bind to this receptor: thus cannabidiol was the drug responsible for the antinociceptive behaviour observed. In addition, the results showed that after chronic oral treatment with cannabis extract the hepatic total content of cytochrome P450 was strongly inhibited as well as the intestinal P-glycoprotein activity. It is suggested that the inhibition of hepatic metabolism determined an increased bioavailability of cannabidiol resulting in a greater effect. However, in the light of the well known antioxidant and antiinflammatory properties of terpenes and flavonoids which could significantly contribute to the therapeutic effects, it cannot be excluded that the synergism observed might be achieved also in the absence of the cytochrome P450 inhibition.

PMID:

18618522

[PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/16316650

Eur J Pharmacol. 2005 Dec 28;528(1-3):65-72. Epub 2005 Nov 28.

A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833.

Whiteside GT, Gottshall SL, Boulet JM, Chaffer SM, Harrison JE, Pearson MS, Turchin PI, Mark L, Garrison AE, Valenzano KJ.

Source

Purdue Pharma Discovery Research, 6 Cedar Brook Drive, Cranbury, NJ 08512, USA. whitesg@wyeth.com

Abstract

Several recent reports have demonstrated a role for selective cannabinoid CB2 receptor agonists in pain modulation, showing both analgesic and antihyperalgesic activities. While the mechanism of action is poorly understood, it has been postulated that these effects may be indirect, involving release of endogenous opioids. We have previously reported that administration of the selective cannabinoid CB2 receptor agonist GW405833 (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone) to rats elicits potent and efficacious antihyperalgesic effects against neuropathic and inflammatory pain and, at high dose (100 mg/kg), is analgesic and ataxic [Valenzano, K.J., Tafesse, L., Lee, G., Harrison, J.E., Boulet, J., Gottshall, S.L., Mark, L., Pearson, M.S., Miller, W., Shan, S., Rabadi, L., Rotstheyn, Y., Chaffer, S.M., Turchin, P.I., Elsemore, D.A., Toth, M., Koetzner, L., Whiteside, G.T., 2005. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658-672]. In the current study, we confirm these properties using mouse models and investigate the role of cannabinoid CB2 receptors using knockout animals. Furthermore, we provide evidence that the antinociceptive properties of GW405833 are opioid independent. GW405833 elicited robust antihyperalgesic effects in mouse models of inflammatory (Freund's complete adjuvant) and neuropathic (Seltzer) pain. In contrast, GW405833 showed no antihyperalgesic activity against Freund's complete adjuvant-mediated inflammatory pain in cannabinoid CB2 receptor knockout mice. As in rats, high-dose GW405833 (100 mg/kg) showed both analgesic and sedative activities in wild-type mice, activities that were also apparent in cannabinoid CB2 receptor knockout mice. In rats, neither the antihyperalgesic effect in the Freund's complete adjuvant model nor the analgesic effects in tail flick and hot plate assays were inhibited by pre-treatment with the non-selective opioid receptor antagonist, naltrexone. These data demonstrate that the antihyperalgesic effects of GW405833 are mediated via the cannabinoid CB2 receptor, whereas the analgesic and sedative effects are not. Furthermore, these data suggest that the mechanism of action for GW405833 does not depend on the release of endogenous opioids.

PMID:

16316650

[PubMed - indexed for MEDLINE]

Chronic Pain and Medical Marijuana-The Effects on Hyperanalgesia

http://norml.org/library/item/chronic-pain (TEST link)

Chronic Pain

As many as one in five Americans lives with chronic pain.[1] Many of these people suffer from neuropathic pain (nerve-related pain) -- a condition that is associated with numerous diseases, including diabetes, cancer, multiple sclerosis, and HIV. In most cases, the use of standard analgesic medications such as opiates and NSAIDS (non-steroidal anti-inflammatory drugs) is ineffective at relieving neuropathic pain. Further, long-term use of most conventional pain relievers, including acetaminophen, opioids, and NSAIDs, is associated with a host of potential adverse side effects, including stroke, erectile dysfunction, heart-attack, hepatoxicity, and accidental overdose death.
Survey data indicates that the use of cannabis is common in chronic pain populations[2] and several recent FDA-designed clinical trials indicate that inhaled marijuana can significantly alleviate neuropathic pain. These include a pair of randomized, placebo-controlled clinical trials demonstrating that smoking cannabis reduces neuropathy in patients with HIV by more than 30 percent compared to placebo.[3-4] (Additional details on these studies appear in the HIV section of this book.) In addition, a 2007 University of California at San Diego double-blind, placebo-controlled trial reported that inhaled cannabis significantly reduced capsaicin-induced pain in healthy volunteers.[5] A 2008 University of California at Davis double-blind, randomized clinical trial reported both high and low doses of inhaled cannabis reduced neuropathic pain of diverse causes in subjects unresponsive to standard pain therapies.[6] Finally, a 2010 McGill University study finding that smoked cannabis significantly improved measures of pain, sleep quality and anxiety in participants with refractory pain for which conventional therapies had failed.[7]
A review of these and other trials in 2011 in the British Journal of Clinical Pharmacology concluded, "[I]t is reasonable to consider cannabinoids as a treatment option for the management of chronic neuropathic pain with evidence of efficacy in other types of chronic pain such as fibromyalgia and rheumatoid arthritis as well."[8] A separate review published in 2012 in The Clinical Journal of Pain further concluded, “Overall, based on the existing clinical trials database, cannabinergic pain medicines have been shown to be modestly effective and safe treatments in patients with a variety of chronic pain conditions. ... Incorporating cannabinergic medicine topics into pain medicine education seems warranted and continuing clinical research and empiric treatment trials are appropriate."[9]
Preclinical data indicates that cannabinoids, when administered in concert with one another, are more effective at ameliorating neuropathic pain than the use of a single agent. Investigators at the University of Milan reported in 2008 that the administration of single cannabinoids such as THC or CBD produce limited relief compared to the administration of plant extracts containing multiple cannabinoids, terpenes (oils), and flavonoids (pigments).
Researchers concluded: "[T]he use of a standardized extract of Cannabis sativa ... evoked a total relief of thermal hyperalgesia, in an experimental model of neuropathic pain, ... ameliorating the effect of single cannabinoids," investigators concluded. ... "Collectively, these findings strongly support the idea that the combination of cannabinoid and non-cannabinoid compounds, as present in [plant-derived] extracts, provide significant advantages in the relief of neuropathic pain compared with pure cannabinoids alone."[10]
In 2009, an international team of investigators from the United Kingdom, Belgium and Romania affirmed these preclinical findings in a clinical study of intractable cancer pain patients. They concluded: "[I]n this study, the THC/CBD extract showed a more promising efficacy profile than the THC extract alone. This finding is supported by evidence of additional synergy between THC and CBD. CBD may enhance the analgesic potential of THC by means of potent inverse agonism at CB2 receptors, which may produce anti-inflammatory effects, along with its ability to inhibit immune cell migration. ... These results are very encouraging and merit further study."[11]
A 2011 clinical trial assessing the administration of vaporized plant cannabis in chronic pain patients on a daily regimen of morphine or oxycodone reported that inhaled "cannabis augments the analgesic effect of opioids." Authors concluded, "The combination (of opioids and cannabinoids) may allow for opioid treatment at lower doses with fewer side effects."[12]
Based on these findings, some pain experts are now advising that physicians recommend cannabis therapy in addition to or in lieu of opiate medications to "reduce the morbidity and mortality rates associated with prescription pain medications."[13]
REFERENCES
[1] New York Times. October 21, 1994. "Study says 1 in 5 Americans suffers from chronic pain."
[2] Cone et al. 2008. Urine drug testing of chronic pain patients: licit and illicit drug patterns. Journal of Analytical Toxicology 32: 532-543.
[3] Abrams et al. 2007. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 68: 515-521.
[4] Ellis et al. 2008. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 34: 672-80.
[5] Wallace et al. 2007. Dose-dependent effects of smoked cannabis on Capsaicin-induced pain and hyperalgesia in healthy volunteers Anesthesiology 107: 785-796.
[6] Wilsey et al. 2008. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. Journal of Pain 9: 506-521.
[7] Ware et al. 2010. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 182: 694-701.
[8] Lynch and Campbell. 2011. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. British Journal of Clinical Pharmacology 72: 735-744.
[9] Sunil Aggerwal. 2012. Cannabinergic pain medicine: a concise clinical primer and survey of randomized-controlled trial results. The Clinical Journal of Pain [E-pub ahead of print].
[10] Comelli et al. 2008. Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain. Phytotherapy Research 22: 1017-1024.
[11] Johnson et al. 2009. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety and tolerability of THC: CBD extract in patients with intractable cancer-related pain. Journal of Symptom Management 39: 167-179.
[12]Abrams et al. 2011. Cannabiniod-opioid interaction in chronic pain. Clinical Pharmacology & Therapeutics 90: 844-851.
[13] Mark Collen. 2012. Prescribing cannabis for harm reduction. Harm Reduction Journal 9:

Marijuana and the Anxiety & Depression link

Recently, I began considering the possibility that perhaps I had set aside the ability to at least look at controlling some mood, as well as anxiety symptoms with the medically grown marijuana.

There is recent evidence that after a time, things that grow on as, even a habit, or behavior associated with chronic pain, or chronic illness, that do suggest the presence of psychiatric illness or psychological factors that play a role in the idea of pain being chronic over time and mood as well as anxiety.  Anti-anxiety medications all seem to head one way.

To an antidepressant.  When I took those, I grew even sicker.  They lead to a manic-induced psychosis.  However, that does not always mean a person is "bipolar."

You may spend time on it if you choose, and learn to cope with the side effects of the medications that some do need.

Psychiatric drugs I am probably sure,. are heavy hitting medications.  I don't doubt that there are many who do need those medications.  And I know that most of the people I meet who take some medications that I would have questioned as a prescriber as whether or not they needed to be on those kinds of heavy-hitting medications.

Sometimes, many people report after years of troubling side effects, that they would prefer to have never been given the atypical antipsychotics, or even some, anti-depressant medications, and given that the drying effects can right there cause enough damage to the GI system that loss of function can happen.  For myself, I take some small amount of anticonvulsant medications, but there are few that I would agree to at this point.

In alleviating anxiety, I would have to agree that a good Sativa does help with more acute levels of anxiety.  Over time, I also can safely say they can serve as a decent anti-depressant as well.  Balance some of the effects of the THC and d-THC, by using a strong Indica, perhaps.

One cannot go wrong, at least not in people who do well on the marijuana.

Does the pharmeceutical industry have a vested interest in keeping people on medications?  When the care for a person who's life is ruined by the over-use of such medications?  I would advise anyone to tread lightly.

For some, medical marijuana use can undoubtedly be helpful.  For others still, I think modern science has certainly been of benefit.  Knowing one's limits is always of crucial importance for success in doing either.

Use of medical marijuana, however, it does also seem to lower the person's desire to use pain medications, such as the opiates.  I would think the "good doctors" would have appreciated less paperwork.

Beat Depression w/out Psychiatry Antidepressant Drugs

Truth About Antidepressants & Chemical Imbalance, Psychology

Ex-Pharmaceutical Rep. Speaks Out

Pharmaceutical Industry vs. Cannabis