Neuropathic Pain

More than 100 types of peripheral neuropathy have been identified.

Globally, the most common cause of neuropathic pain is leprosy.

Various studies suggest that 1.5% of those in the U.S., and 7.5% of those in Europe, suffer with neuropathic pain.

Approximately 65% of diabetes patients are reported to have neuropathic pain.

Nearly half of all women experience post-mastectomy (neuropathic) pain at 3 years.

For half of those (about 25%) that pain was found to remain at 9 years post-surgery.

Up to 70% of post-amputation patients suffer with neuropathic pain.

By 2018 there will be an estimated 6 million people in the U.S. with chronic neuropathic pain.

Neuropathic pain results from inflammation.

Let’s get better.

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Neuropathic pain is caused by peripheral nerves that continue sending pain signals even when there is no obvious tissue damage.

There is now overwhelming evidence that inflammation is the cause of, or at least a substantial contributor to, neuropathic pain.

Introduction to Banjo

Banjo provides fast, effective relief from pain and inflammation because it enables your body’s immune system to function properly. It works just like the fruits and vegetables you eat every day – by naturally inhibiting NF-kB, the inflammation Master Switch.

Banjo works better because it combines the most effective natural extracts and delivers them in a form that ensures maximum bio-availability. You get the full spectrum of phytonutrients your body needs to turn off excess inflammation.

Thoughts on Neuropathic Pain

Neuropathic pain is a good model of chronic pain in general.

In fact neuropathic pain may be the best chronic pain model, because it is not associated with any other disease. So it provides the best view of ‘pain itself’.

‘Neuropathic’ pain almost certainly plays a role in most painful conditions. But when pain results from some other identified condition (e.g. a broken bone,) we simply attribute all the pain to the broken bone. As inflammation decreases, so does the pain. It’s only when the inflammation associated with the broken bone goes away, but the pain doesn’t, that we call that remaining pain “neuropathic pain.”

But that pain was there all along. It’s microscopic inflammation associated with local nerve fibers. The microscopic inflammation usually resolves at the same time as the gross (visible) inflammation – which is why we don’t usually end up with neuropathic pain.

Microscopic inflammation may be preceded by obvious inflammation (e.g. limb amputation or mastectomy – the surgery produces a gross inflammatory response at the wound and these surgical procedures commonly result in chronic neuropathic pain.) Or microscopic inflammation may develop in the absence of any preceding gross inflammation, as is most likely the case in fibromyalgia and diabetic neuropathy.

Neuropathic pain results from (and is a disease of) inflammation.

According to the theory advanced on this site (in brief) every ‘disease of inflammation’:

  1. Is caused by inflammation;
  2. That results from over-activation of NF-kB;
  3. Which can be treated by administering NF-kB inhibitors – especially natural (plant derived) NF-kB inhibitors.

The following – if true – would support (not ‘prove’) the theory in regard to neuropathic pain:

  • Neuropathic pain is associated with inflammation.
  • Neuropathic pain is associated with excess NF-kB activation.
  • There is evidence that neuropathic pain is associated with a defect (especially genetic) or vulnerability that results in excess activation of NF-kB.
  • There is evidence that inhibiting NF-kB is beneficial in the treatment of neuropathic pain.
  • There is evidence that natural NF-kB inhibitors are beneficial in treating or preventing neuropathic pain.
  • There is an explanation for the cause and progression of neuropathic pain that is consistent with the theory.

Over the course of time, as more research is accumulated, it should be possible to demonstrate that neuropathic pain adheres well to the theory.

As such, the initial expectation is that natural NF-kB inhibitors might prove useful in the treatment of neuropathic pain.

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ALL NEUROPATHIC PAIN POSTS

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December 16, 2009

NF-kB inhibition reduces inflammation & pain, increases GABA after spinal cord injury

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Spinal cord injury is often followed by increased pain perception. There is both immediate gross inflammation and chronic micro-inflammation.

Treatment with an NF-kB ‘decoy’ effectively blocks (inhibits) NF-kB activation, and was shown to improve outcome after spinal cord injury. Inflammation and pain were reduced, and an increase in GABA neurotransmitter was evidenced.

The publication:

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J Neurosci Res. 2008 Feb 15;86(3):566-80.

Nuclear factor-kappaB decoy amelioration of spinal cord injury-induced inflammation and behavior outcomes.

Rafati DS, Geissler K, Johnson K, Unabia G, Hulsebosch C, Nesic-Taylor O, Perez-Polo JR.

Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.

Summary of the abstract

Spinal cord injury (SCI) results in a pathophysiology that includes altered nociception (pain perception) and hyperalgesia (lower pain threshold and increased pain sensation). SCI triggers an early and prolonged inflammatory response, with increased interleukin-1beta levels.

Transient changes are observed in NF-kB.

There were significant early increases in COX-2 and inducible nitric oxide synthase after SCI.

We used synthetic double-stranded “decoy” deoxyoligonucleotides containing selective NF-kB protein dimer binding consensus sequences. Decoys targeting the p65/p50 binding site on the COX-2 promoter decreased SCI-induced cell losses, NF-kappaB p65/p50 DNA-binding activity, and COX-2 and iNOS protein levels. NF-kappaB p65/p50 targeted decoys improved early locomotor recovery after moderate but not severe SCI, yet ameliorated SCI-induced hypersensitization after both moderate and severe SCI.

To determine whether changes in GABA activity played a role in decreased hypersensitivity after SCI and p65/p50 targeted decoy, we counted gamma-aminobutyric acid (GABA)-containing neurons in laminae 1-3. There were significantly more GABAergic neurons in the p65/p50 targeted decoy-treated group at the level of injury.

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December 15, 2009

NF-kB exaggerated pain states

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NF-kB over-activation accounts for a substantial portion of back pain, especially neuropathic pain.

NF-kB over-activation was found to account for exaggerated pain states such as are common in conditions such as back pain, especially neuropathic pain. In this case sciatic nerve pain in particular was studied.

The publication:

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Eur J Neurosci. 2005 Oct;22(8):1977-86.

Involvement of spinal cord nuclear factor kappaB activation in rat models of proinflammatory cytokine-mediated pain facilitation.

Ledeboer A, Gamanos M, Lai W, Martin D, Maier SF, Watkins LR, Quan N.

Department of Psychology & Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA.

Summary of the abstract

Proinflammatory cytokines, such as interleukin-1beta and tumour necrosis factor-alpha, are released by activated glial cells in the spinal cord and play a major role in pain facilitation.

These cytokines exert their actions, at least partially, through the activation of the transcription factor, nuclear factor kappaB (NF-kB). In turn, NF-kappaB regulates the transcription of many inflammatory mediators, including cytokines.

This study investigated whether NF-kB is involved in neuropathic pain induced by sciatic nerve inflammation.

The results obtained demonstrated that spinal cord NF-kB activation is involved, at least in part, in exaggerated pain states.

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November 18, 2009

NF-kB: Autoimmunity Master Switch

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A review of NF-kB and autoimmune disease

The abstract below is a quick overview. It suggests the central importance of NF-kB and then lists a few of the autoimmune conditions related to excess NF-kB activation.

The full text article provides a more thorough review, and is available free online.

The full article includes a number of challenges and potential dangers associated with pharmaceutical inhibition of NF-kB. Please note, however, that on this site I’m mainly discussing NF-kB inhibition by means of natural extracts. You’re already doing that – every day – it’s just that you might not be doing enough of it, especially since we’re all exposed to more inflammation promoters every day.

Of course natural extracts are not necessarily safe. Some can have side effects at high doses, and some are outright poisonous.

So as an added safety precaution, Banjo uses only those ingredients that have at least a 1,000 year history of safe use and for which no dose, however great, has ever been found unsafe. Then Banjo uses a relatively small amount of each extract, but in combination with a unique “trans-mucosal” delivery system, it’s very effective.

So yes – NF-kB inhibition by synthetic pharmaceuticals will probably cause all sorts of side effects.

But the natural extracts? If it was possible to overdose I’d be long gone. I drink a lot of coffee.

The publication:

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Acta Biochim Pol. 2008;55(4):629-47. Epub 2008 Dec 16.

The role of nuclear factor-kappaB in the development of autoimmune diseases: a link between genes and environment.

Kuryłowicz A, Nauman J.

Summary of the abstract (or you can read the free full text online)

Although autoimmune diseases are relatively common, mechanisms that lead to their development remain largely unknown.

Nuclear factor-kappaB (NF-kappaB), as a key transcription factor involved in the regulation of immune responses and apoptosis, appears to be a good candidate for studies on the pathogenesis of autoimmunity.

This review presents how perturbations of the NF-kappaB signaling pathway may contribute to self-tolerance failure, initiation of autoimmune inflammatory response as well as its persistent maintenance and therefore to the development of common autoimmune diseases including:

  • rheumatoid arthritis
  • multiple sclerosis
  • diabetes
  • thyroid autoimmune diseases
  • lupus
  • inflammatory bowel diseases
  • and psoriasis

A special emphasis is put on the genetic variations in the NF-kappaB related genes and their possible association with susceptibility to autoimmune diseases, as well as on the therapeutic potential of the NF-kappaB targeted strategies in the treatment of autoimmunity.

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November 14, 2009

NF-kB inhibitor: a great pain drug

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Inhibition of NF-kB would result in great benefits to humanity – but how can it be done?

What’s surprising, or not, is that neither in the abstract nor in the full article are any of the useful NF-kB inhibitors found in nature mentioned. You would think the author would at least give a hat tip to resveratrol, or green tea, or beets, turmeric, chocolate, ginger…

NF-kB inhibitors are all around us.

The publication:

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FASEB J. 2008 Oct;22(10):3432-42. Epub 2008 Jun 17.

The IKK-NF-kappaB pathway: a source for novel molecular drug targets in pain therapy?

Summary of the abstract (or you can read the entire publication free online)

Several studies indicate that the nuclear factor-kappa B (NF-kappaB) -activation cascade plays a crucial role not only in immune responses, inflammation, and apoptosis but also in the development and processing of pathological pain (neuropathic pain.)

Accordingly, a pharmacological intervention into this pathway may have antinociceptive (anti-pain) effects and could provide novel treatment strategies for pain and inflammation.

In this review we summarize the role of NF-kappaB in the nervous system, its impact on nociception (pain perception,) and several approaches that investigated the effects of various modulators.

The results indicate that NF-kappaB has an impact on nociceptive transmission and processing and that a number of substances that inhibit the NF-kappaB-activating cascade are capable of reducing the nociceptive response in different animal models.

Therefore, a modulation of specific participants in the NF-kappaB signal transduction might exert a useful approach for the development of new painkillers.

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Comments:

NF-kB is the Master Switch controlling not only inflammation, but pain as well

By selecting from among the most potent NF-kB inhibitors and then combining those in an effective delivery system, pain and inflammation can be effectively treated with very little risk of side effects.

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November 14, 2009

NF-kB in neuropathic pain

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NF-kB activation is responsible for causing the inflammation that results in neuropathic pain

Neuropathic pain has sometimes been referred to as non-inflammatory pain. But there is now overwhelming evidence that inflammation is a crucial, probably essential, contributor to neuropathic pain – and NF-kB is the Master Switch controlling that inflammation.

The publication:

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Eur J Pain. 2009 Sep;13(8):794-806. Epub 2008 Oct 19.

Tumor necrosis factor receptor 1 induces interleukin-6 upregulation through NF-kappaB in a rat neuropathic pain model

Summary of the abstract

Peripheral nerve injury resulting in neuropathic pain induces the upregulation of interleukin (IL)-6 and tumor necrosis factor-alpha, which binds to tumor necrosis factor receptor 1 (TNFR1) and induces NF-kappaB and p38 MAPK activation in the spinal cord and dorsal root ganglia (DRG).

We here investigated whether TNFR1 regulates IL-6 expression through NF-kappaB or p38 MAPK.

NF-kappaB decoy, but not p38 MAPK inhibitor, reduced elevated IL-6 expression in the spinal cord and DRG. Therefore, these data suggest that TNFR1 induces IL-6 upregulation and neuropathic pain through NF-kappaB, but not p38 MAPK activation in the spinal cord and DRG.

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Comments:

In neuropathic pain, NF-kB is the critical pathway, not MAPK

IL-6 is here presumably acting as a pro-inflammatory mediator that is responsible, at least in part, for promoting the continuation of pain signals in neuropathic pain.

It was found to be regulated by NF-kB.

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November 14, 2009

NF-kB in neuropathic pain model

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Blocking NF-kB in this model of neuropathic pain eliminated the pain stimulus

The publication:

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Mol Pain. 2009 May 28;5:26.

NF-kappaB mediated enhancement of potassium currents by the chemokine CXCL1/growth related oncogene in small diameter rat sensory neurons

Summary of the abstract or you can read the free full text article

BACKGROUND: Inflammatory processes play important roles in both neuropathic and inflammatory pain states, but the effects of inflammation per se within the sensory ganglia are not well understood.

We examined the direct effects of GRO/KC on small diameter DRG neurons, which are predominantly nociceptive (pain receptors.)

RESULTS: The increase in K currents was completely blocked by co-incubation with protein synthesis inhibitor cycloheximide (CHX) or NF-kappaB inhibitors pyrrolidine dithiocarbamate (PDTC) or quinazoline (6-Amino-4-(4-phenoxypheny lethylamino;QNZ).

CONCLUSION: The results suggest that GRO/KC has important effects in inflammatory processes via its direct actions on sensory neurons, and that activation of NF-kappaB is involved in the GRO/KC-induced enhancement of K currents.

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Comments:

Blocking NF-kB prevented the pain fibers from working

This is a technically challenging abstract and much of the jargon has been removed. Nonetheless, it is clear that “GRO/KC” is a key player in the inflammation and pain signals sent by these pain fibers – the “enhanced K currents.”

Activation of NF-kB is “involved” in this GRO/KC effect. So much so, in fact, that by turning off (blocking) NF-kB the effect was eliminated.

Bottom line: in this model, blocking NF-kB blocks pain.

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November 12, 2009

Anti-depressants for pain

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Anti-depressants are effective in treating pain because they decrease NF-kB activation in the brain

In the study summarized below, mirtazapine (an anti-depressant) is found to inhibit NF-kB activation in the brain, thereby reducing inflammation and the mediators of inflammation in the brain.

The publication:

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Neurosci Lett. 2008 Mar 5;433(1):33-7. Epub 2008 Jan 14.

Repeated administration of mirtazapine inhibits development of hyperalgesia/allodynia and activation of NF-kappaB in a rat model of neuropathic pain

Summary of the abstract

Antidepressants have been widely used to treat neuropathic pain for many years. (Some benefit has also been reported in fibromyalgia patients.) However, the mechanisms of their analgesic actions are little known and remain controvertible.

Recent studies indicate that cytokines in central nervous system (CNS) play a critical role in the pathological states of pain. The present study was designed to explore the effects and most appropriate dosage of mirtazapine in treating neuropathic pain and its possible neuroimmune mechanisms.

The inflammatory cytokines production such as TNFalpha, IL-1beta, IL-10 and nuclear factor kappa B (NF-kappaB) activity in brain was determined. We found that mirtazapine can markedly attenuate mechanical and thermal hyperalgesia (excessive pain) produced by nerve transection (cutting the nerve), most significantly on the 14th day.

The elevated TNFalpha, IL-1beta and NF-kappaB in brain were accordingly reduced, while the expression of increased IL-10 were even stimulated after repeated mirtazapine administration.

Our data could conclude that mirtazapine suppressed neuropathic pain partially through inhibiting cerebral proinflammatory cytokines production and NF-kappaB activation in CNS.

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November 10, 2009

Better by Christmas – with Frankincense

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Frankincense inhibits NF-kB, which accounts for its efficacy against cancer, arthritis, chronic colitis, ulcerative colitis, Crohn’s disease, and bronchial asthma

It might be difficult to believe that a single agent could effectively treat a large number of inflammatory conditions, including:

  • cancer (prevention actually, not treatment)
  • arthritis
  • chronic colitis
  • ulcerative colitis
  • Crohn’s disease
  • asthma, and
  • many other ailments

But that’s what natural NF-kB inhibitors do. Some do it (much) better than others. But they all do it – because they fight inflammation.

So at first it’s hard to believe, but since NF-kB inhibitors fight inflammation, it makes sense. If inflammation contributes to the cause of many conditions (and it does) then whatever relieves inflammation (actually treating the cause, not just masking the symptoms) should be effective in treating many ailments.

So you might want to consider using natural NF-kB inhibitors.

Except that you’re already using them. Every fresh fruit and vegetable is a natural NF-kB inhibitor.

The problem is – you’re probably not using enough of them. That’s because our modern world is filled with so many things that cause inflammation. It might not be enough to ‘only’ eat the recommended 9 portions of fruits and vegetable each day. And if you have an autoimmune disease – or if conditions related to inflammation run in your family – then you probably have a genetic vulnerability to inflammation. If so, you’ll need even more of these NF-kB inhibitors.

Frankincense is a very effective NF-kB inhibitor. Banjo is a combination of many very effective NF-kB inhibitors. And because Banjo uses a unique “trans-mucosal” delivery system, it’s very fast acting and even more effective.

So take your pick. With additional NF-kB inhibitors from fruits and vegetables (a lot for a long time) or frankincense, or Banjo – you can get better. That’s my theory. And it’s consistent with the results from thousands of studies, a few of which are referenced on this site – one of which is briefly summarized below.

The publication:

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J Immunol. 2006 Mar 1;176(5):3127-40.

Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression.

Takada Y, Ichikawa H, Badmaev V, Aggarwal BB.

Summary of the absrtract

Acetyl-11-keto-beta-boswellic acid (AKBA), a component of an Ayurvedic therapeutic plant Boswellia serrata (frankincense) is active against a large number of inflammatory diseases, including cancer, arthritis, chronic colitis, ulcerative colitis, Crohn’s disease, and bronchial asthma, but the mechanism is poorly understood.

AKBA was found to inhibit NF-kB. AKBA suppressed NF-kB activation in tumor cells. It also countered inflammation and NF-kB activation induced by cigarette smoke.

Overall, results indicated that AKBA enhances apoptosis induced by cytokines and chemotherapeutic agents, inhibits invasion, and suppresses osteoclastogenesis through inhibition of NF-kappaB-regulated gene expression.

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