Behandelcentrum Neuropathische Pijn

Many patients suffering from neuropathic pain are currently not optimal treated using the drugs on the market. The total value of the neuropathic pain market is supposed to double from 2006 to reach over $7 billion by 2016. There is a lot of space in the marketplace for  improved pain management.

In our institute we are specialized in the treatment of neuropathic pain and adbvising R&D processes related to the identification of new potential painkillers for neuropathic pain. A short explanation of the experience we have in helping pharmaceutical companies developing new drugs, by professor Jan M. Keppel Hesselink, MD, PhD, consultant.

Syringomyelia is characterized by the presence of spinal cord cavitation and is most commonly seen in association with Chiari I malformation. Central neuropathic pain is a prominent feature in 50 to 90% of adult human patients with syringomyelia. The treatment of this neuropathic pain is not an easy task. Methodological sound clinical trials in the treatment of central neuropathic pain are not available. Treatment recommendations for this variety of pain are heavily depending on clinical trials conducted in peripheral neuropathic pain.

Identification of palmitoylethanolamide (Normast) as regulatory mechanism for the metabolism of mast cells by Nobel Price Laureate Rita Levi Montalcini in 1993, and it's use as a analgesic and anti-inflammatory compound.

Searching for non psychoactive Cannabinoids our clinic identified in 2010 the small molecule palmitoylethanolamide (PEA) as a potent novel and promising analgesic and anti-inflammatory agent. This molecule has been developed based on the work and insights of Rita Levi Montalcini,as an off spin of her work with nerve growth factors.

As PEA, or usingt he trade name Normast is gaining more and more international recognition as a break through molecule in the treatment of chronic pain and inflammation, it is worth while to shortly analyze how the mast cell modulation concept, palmitoylethanolamide and the ALIA concepts came into existence.

Adenosine is a neuromodulator that interacs with four adenosine receptors, A(1), A(2A), A(2B) and A(3). Adenosine receptors are new inroads in treating neuropathic pain. Even better, these compounds are inroads to treating gliopathic pain. Gliopathic pain is a new name for the chronic wind-up state of glia and neurons in chronic painstates we see in diabetic neuropathy, herpes zoster and many related painstates.

Given the fact that most antidepressants are not active in mild to moderate depression, it is a bit odd that the Food and Drug Administration has approved in 2010 the anti-depressant Cymbalta® for a different use, which is just as vague as mild and moderate depression: low back pain and osteoarthritis.  

In our continuing debate with international colleagues we received a letter with the following statement related to our articles on gliopathic pain:

Indeed I believe this new glial field in pain research highly exciting. Furthermore, the aspect you mentioned regarding the mast cells is also very promising as possible potent modulators of peripheral modulation of nerve endings in multiple organs.

This prompted us to look for further support to use and evaluate mast cell stabilisers in clinical practice. One indication we came across was myocardial infarction:

In a recent press release (18-10-2010) it was communicated that the company NeurogesX  U.S.will try to broaden the indications for Qutenza® (capsaicin) 8% patch to include patients with painful HIV-associated neuropathy (HIV-AN, also referred to as HIV-distal sensory polyneuropathy (HIV-DSP)). Following a recent meeting with the U.S. Food and Drug Administration (FDA), NeurogesX plans to submit a supplemental new drug application (sNDA) in the first half of 2011.

Palmitoylethanolamide is hot. It is a body-own compound which seems quite interesting for a number of clinical reasons, and most importantly for its analgesic properties in neuropathic pain. But how does it work? 

The search for the palmitoylethanolamide receptor was the title of a publication in Life Sciences, written by pharmacologists from the Department of Experimental Pharmacology, University of Naples, and the Department of Pharmacology, University of California, Irvine, USA.

Distal axonal degeneration is a hallmark of many neuropathies. Traditionally we tended to think in a simpel degeneration-regeneration model. The celbody of each neuron, based on the functions of its residing nucleus, is key in regeneration, and all regeneration processes are anterograde. Failure of metabolic support for the cellbody causes an impairement in the function of the axon, due to the fact that the axon itself is poorly inhabited by ribosomes and mitochondia and thus the axon is totally dependent on support from its master, the cellbody. In 1997 Spencer at all described the degeneration proces using an analogy of the farthest meaddow, which is the first to be drowned from water support, if the waterpump fails. These analogies and metaphors always play a big role in our understanding and our apporach of scientific problems and clinical problems.     

Most people and neurologist view nerves as 'copper ropes' conducting electricity. If the copper rope breaks, the nerve is damaged, and the damage is for the rest of our life. This creates great nihilism for therapeutic innovations. And even more disturbing, patients feel this metaphore is a desription of reality. The message patients often get from their neurologist is: nothing can be done, what is dead remains dead....

Dexpramipexole is an enantiomer, of the dopamine agonist pramipexole, used in Parkinson disease. It is the right-handed isomere and it is practically devoid from all the dopaminergic effect. Preclinical work indicates dexpramipexole might have neuroprotective properties, probably due to its ability to prevent mitochondria from developing leaky membranes when under stress. Therefore it has been taken into development in an orphan indication, amyotrophic lateral sclerosis, ALS, or Lou Gehring disease as the Americans call it. (Should actually been called Charcot's disease, as he first described ALS more than 100 years ago).

In the internet there is a big community of specialists involved in drug R&D and at LinkedIn there are quite some interesting discussions related to topics worth while considering. The question which haunts many drug developers is: Why is it that so many drugs flunk after phase II trials? That question is also immensly important for the development of drugs in the field of chronic pain. But it is a generic question. 

KRN 5500  (6-[4-Deoxy-4-[(2E,4E)-tetradecadienoylglycyl]amino-L-glycero-ß-L-manno-heptopyranosyl]amino-9H-purine) has been tested in a phase II trial and the results were presented on april 20 2010. More details will be presented in May in Athens, during the neuropathic pain congress.

Ketamine is an old drug, and has been in clinical practice for nearly 40 years, but we should not forget this drug for the treatment of neuropathic pain, and we should not be too conservative exploring ketamine as a treatment for otherwise treatment refractory neuropathic pain patients. Ketamine can be used in various ways, as infusions, oral, rectal, intranasal and transdermal. 

As an analgesic drug, doses used are much lower compared to dose-ranges used in anesthesiological practices. Furthermore, the whole story of S-ketamine being less psychoiactive compared to R-ketamine is based on old literature, with very small groups of patients, non-relaible biological read outs, such as the EEG and animal studies with very little relevance for the human species.  

ADL-5859 is a delta agonist for the opiod receptor family, and it might be of use for the treatment of neuropathic pain, by inducing less side effects as the current opioids. The compound is developed by Adolor Corporation (this is alsoi the Originator) and the compound is in phase II.