Is there a place for Lithium to reverse or control neurological damage induced by chemotherapy?

The buried, older literature on Lithium continues to amaze me, published in a vast array of peer-reviewed papers.  There seems to be little interaction of the medical community in applying its uses.

One of the most frustrating pains is that of post-chemotherapy neuritis especially of the lower legs.  This pain is extremely distressing as a mixture of sensory disturbances – burning, hypersensitivity, pain etc. together with at times of “epileptic bursts” of pain in the feet.  This is extremely distressing to patients as it seems to occur or is more noticed when attempting to sleep.  The use of the standard AEDs such as Lyrica, Neurontin, and Cymbalta in my experience is of limited use in severe cases.

Many cases of post-chemotherapy neuritis come on after many years, often decades.

One of the most useful treatments is the topical application of 5,10 or 15% Phenytoin in a variety of bases often of a liposomal nature.  This work has been spearheaded and raised to a level of “go to” treatment by a double-blind study by Professor Jan Hesselink.  Time will only tell how well this treatment is accepted.  The main form of topical Phenytoin is patented in Europe.  From my limited use of this product, it is of an outstanding value with continuing effect which may increase with time and break the pain cycle.

In many ways, this article was going to end at this point however readers of the various articles of mine will appreciate that Lithium has a high standing in my present view of medical problems ranging from Alzheimer’s, depression, anxiety, not to mention the potential of cell regeneration in many neurological conditions.

As far as I am aware, Lithium has not been used in the treatment of latent, over 1 or 2 decades, of post-chemotherapy neuritis.  Thus, it was with considerable interest that I read the paper by Petrini “Is Lithium able to reverse neurological damage by vinca alkaloids”.  This was an interestingly crafted paper administering Lithium in the form of carbonate to both humans and mice and measuring the neurotoxicity as in neuropathy.  Both humans and mice showed a marked improvement or abolition of neuropathic toxicity from chemotherapy.  All the human patients started Lithium after they developed symptoms of neurotoxicity.  One wonders if Lithium was given closely associated with the chemotherapy if this would have been avoided? In conclusion to their paper, “both results from animal experiments and human observation show that Lithium administered may counteract the acute or semi-acute neurotoxicity of vinca alkaloids”.  There seems to have been no effect on the decrease in chemotherapy effect on the myeloid disorders that they were treating.

The big question and the study that needs to be done especially since Lithium in the doses that were used cause no concern, the equivalent of 600 mg of carbonate, is should this be used as a routine in a series of patients receiving chemotherapy?  This seems to be no antagonism of Lithium to the chemotherapy.  This paper was mainly concerned with the semi-acute neuropathies but I think a long-term study would be rewarding and needs to be completed.  It seems that the Lithium effect from the past work of this group does not affect the inhibition of the chemotherapy agents on their lymphoid tissue targets.

The simple question to be asked is, is there a place for Lithium during chemotherapy?  I can see little downside!

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– Problems in treating chronic pain – a tale of 2 analgesic groups

Chronic pain is poorly researched, poorly treated, and the economic loss and suffering of patients is not appreciated.

Thomas Sydenham 1680 “among the remedies which has pleased Almighty God to give to man to relieve his suffering, none is so universal and efficacious as opium”

The above saying I have pinned to my notice board and over the past 2 decades I have treated chronic pain aggressively with many agents, perhaps the most effective with less side effects have been opioids.  I assume that all the screening and routine pain evaluation has been undertaken.  In screened patients, in my experience, opioids have been extremely effective and dependency is not uncommon but addiction is extremely rare.  Perhaps one or two cases have been addicted in 20 years and these were patients that had been using street opioids and then presented with a picture of chronic pain.

Ten years ago, the standard teaching, was to use opioids for chronic non-malignant pain (CNP).  The dosage was started low and gradually titrated to an effective dose or abandon it.  There were no limits on the amount of opioids used, it was titrated to effect or side-effect.  In the last few years as a result of external pressure on doctors we now have limits that I believe are far too low – 60 mg per day.  This change and government involvement is due to increased deaths, addiction, etc. but this is not related to the treatment of CNP by physicians but mainly of the illegal importation of such agents such as elephant Fentanyl and other drugs from online sites.  It has puzzled me how patients who in my office would not take a simple medication without asking questions will order drugs from online sources without any qualms.  One afternoon, I was depressed by the adverse press, and I could order more narcotics in an hour than are dispensed in Canada.  Small envelopes under 35 grams are not opened by postal authorities so the importation continues.

It is interesting that all medications seem to go through a swing – a miracle or don’t give it to a dog. 

The question of addiction has many causes but one I believe is due to the lack of emotional education and appreciation of life in the world we live in.  Many addictions are based on boredom – a busy mind and body does not seek further highs.  Our education is becoming neutered, exciting subjects are not taught, the curriculum is bland with everyone passing, and many teachers can not teach.  Even in medical lectures I can number on one hand those that have inspired me – they have been different, aggressive, and well planned.

I wonder how low the guidelines on opioids will drop? At present, there is I believe a witch hunt on the subject with physicians being blamed for what is not in most cases their fault.

Dealing with CNP is the major part of my practice.  I have never thought or dreamed of an agent that might be natural, safe, non-addicting, with few side-effects.  It was by shear chance that I stumbled on the European literature on Palmitoylethanolamide (PEA).  It did not take much research to obtain a clear view on PEA despite the fact that little research has appeared in western literature.

The molecular was first discovered in 1957 and has been used for a number of different conditions over the years.  In 1975 a group of Czech physicians describe a positive study published in The Lancet on joint pain.  Its history was somewhat confused by its use widely in the management of influenza.  PEA reached a new high in research with the work by Dr. Rita Levi-Montalcini.  From this increasing animal work, it was discovered its effect on many forms of pain but particularly nerve root pain.  A very good review of the early work is on Wikipedia. 

A number of well balanced double-blind studies have shown it particularly effective in root and neuropathies.  The focus has been in some cases not so much on the nerve filament but on the supporting astrocytes and MAR cells – the inflammation of which stimulates the pain.  This concept is new and should be further explored.  It is the inflammatory agent bath of fluids around the neuronal fibres that may be the major cause of pain to which PEA is highly effective.

When I first read the articles, I thought I was in heaven (for a pain doctor).  An agent without any significant side-effects, non-addictive, simple dosage, and with little evidence of a development of tolerance.  The only problem with the use of PEA is that it is not marketed, developed, or sold in North America – I wonder why?  Patients can obtain this by prescription from a number of European suppliers.

The literature on PEA is quite extensive with research by eminent physicians covering a wide range of painful conditions. 

The concept that pain is magnified, prolonged by the inflammatory “soup” producing by MAR cells and astrocytes on neuronal fibres needs to be given considerable thought.  It is interesting to note that it was far superior to Lyrica in one study.

What more could one ask for?  Non-toxic, natural, effective, no side-effects of significance.

I was very lucky having read the literature to receive guidance, help, and truth regarding treatment from Professor Jan Hesselink.  It is uplifting to find teachers who are willing to share via the Internet their experiences and deal with my initial use of PEA with patients.

From my limited experience, PEA, may be the wonder agent for many forms of pain with miniscule side-effects.  The only drawback I can see is that it lacks patent protection, profitability etc.

It is like in the advert – pity it is not available in North America

 

Orphan Agents can save lives in pain-patients and increase quality of life!

Prof. dr. Jan MK. Hesselink is another physician interested in how orphan agents/supplements can improve chronic pain.  He has kindly shared an editorial he wrote. Profession Hesselink writes:

There are many orphan agents, natural compounds without patents, who are not pushed by the pharmaceutical industry. These compounds are often not used, due to the fact people are not aware of their existence. In the field of paintreatment the current used painkillers have immens drawbacks, and induce a great number of serious side effects and lead to death. Therefore, in cases of chronic pain, one should be aware of effective compounds without these side effects. This editorial I wrote some years ago to open the eyes of pain-physicians and patients suffering from chronic pain.

Keppel Hesselink JMK (2013) Primum non Nocere: Supplements as Analgesics, a Neglected Area. J Pain Relief 2:e116. doi: 10.4172/2167-0846.1000e116

Primum non Nocere: Supplements As Analgesics, A Neglected Area

Our analgesic armamentarium is rooted in pharmaceuticals. Drugs initially protected by patent, new chemical entities (NCE), molecules which never existed on earth until medical chemists synthesized them. Within the realm of this type of analgesics there are just a handful of variations: non-steroidal anti-inflammatory drugs (NSAID’s such as ibuprofen), opioids (tramadol, oxycontin), antidepressants (amitriptyline, venlafaxin), anti-epileptics (gabapentine, pregabalin), paracetamol/acetaminophen and a waste basket of various old coanalgesics such as baclofen. Cannabinoids are for the courageous pain physicians only, although there are many safety reasons to prefer Cannabinoids over opiates.

Our approach to treatment of pain is very much dictated by efficacy data from RCT’s, the meta-analysis based on these trials, and on the Numbers Needed to Treat (NNT), an efficacy derived parameter. How different our approach would be if we selected treatments not based on efficacy plots but on the ‘Likelihood to be helped or harmed (LHH)’. This is a number based both on the Numbers Needed to Treat (NNT) as well as on the Numbers Needed to Harm (NNH). Without going into the science of calculus, just as a simple physician, I would propose to redefine the ‘Likelihood to be helped or harmed’ as the simple quotient of NNH/NNT. The highest quotient would be preferable, in line with one of the medical axiomata: Primumnon nocere, the Latin phrase that means “first, do no harm.”

Let us first take amitriptyline. Based on literature amitriptyline has a NNT of 4.6 and a NNH of 4.1. The ratio would be 4.1/4.6 makes 0.89 [1]. For Serotonin noradrenaline reuptake inhibitors the NNT is 5.1, and the NNH 16; the ratio would be 3.1 [2].

If we consider alpha-lipoic acid (ALP), a compoundregistered in Germany as drug for neuropathic diabetic pain, the NNT for 600 mg ALP/day is 2.7. As the number of adverse events was not significantly different than placebo, let us define the NNH conservatively as 100 [3]. The ratio ALP would then be 37. Let us now take a second supplement with proven efficacy and safety, palmitoylethanolamide (PEA). A natural compound we often use in our clinic for neuropathic pain, either as a standalone therapy, or as part of a multimodal approach [4]. This endogenous lipid has been explored for its analgesic properties since 35 years. Based on a clinical trial in 636 sciatic patients [5], PEA is in the same ball park as ALP, with NNT below 2 and NNH conservatively defined as 100 [6]. The ration would be approximately 50. Both quotients are far out better compared to the 0.89 and 3.1 of the tricyclic antidepressants.

Palmitoylethanolamide, alpha-lipoic acid and other molecules from the class of dietary supplements are not generally seen as analgesics. There are much more compounds in this forgotten or neglected class, for instance curcumin (diferuloylmethane), a component of turmeric (Curcuma longa). This has been referred to as very inexpensive, orally bioavailable and highly safe in humans. The compound is able to block the action and production of TNF-α in vitro model, in animal models and in humans. Curcumin is much cheaper compared to the manmade infliximab’s ($15 000-20 000 per person per year) and Aggarwal et al. boldly state: “With health-care costs and safety being major issues today, this golden spice (Curcuma) may help provide the solution” [7].

Natural compounds, even with higher NNTs, deserve to be considered more often for our patients suffering from pain. We should not focus only on pharmaceuticals and efficacy, but also on analgesic supplements and safety.
References

1. Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ (2012) Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 12: CD008242.

2. Finnerup NB, Otto M, Jensen TS, Sindrup SH (2007) An evidence-based algorithm for the treatment of neuropathic pain. Med Gen Med 9: 36.
3. Tang J, Wingerchuk DM, Crum BA, Rubin DI, Demaerschalk BM (2007) Alpha-lipoic acid may improve symptomatic diabetic polyneuropathy. Neurologist 13: 164-167.
4. Keppel Hesselink JM (2012) New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide. Open Pain Journal 5: 12-23.
5. Guida G, de Martino M, de Fabiani A (2010) La palmitoiletanolamida (Normast) en el dolorneuropaticocronicoporlumbociatalgia de tipocompresivo: estudioclinicomulticentrico. Palmitoylethanolamide treatment of sciatic pain: results form a multicenter study Dolor25: 35-42.
6. Keppel Hesselink JM (2011) Palmitoylethanolamide in sciatic pain-result fron a RCT in sciatic pain-NNT, presented at SIAARTI (SocietàItaliana di Anestesia Analgesia Rianimazione e TerapiaIntensiva).
7. Aggarwal BB, Gupta SC, Sung B (2013) Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. Br J Pharmacol 169: 1672-1692.