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Syringomyelia in Cavalier spaniels treated succesfully with palmitoylethanolamide (PEA)

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.

However, in central neuropathic pain different pathomechanistical factors may play a role, one of the reasons why central neuropathic pain is often refractory to the treatment with anticonvulsants and antidepressants. In central neuropathic pain inflammatory and gial pathology might play a more important role than we previously thought. [1] 

PEA in King Charles Spaniels 

Recently in this field new drugtargets emerged and research into the treatment of central neuropathic pain is now slowly unfolding. One of those targets is the glia, and the phrase gliopathic pain has been used to point out the importance of the glia in neuropathic pain. The enodcannabinoid palmitoylethanolamide is a new analgesic compound within this new field. We conducted a pilot trial using palmitoylethanolamide in a animal model for central neuropathic pain, the cavalier KIng Charles spaniel, suffering from Arnold Chiari malformations and syringomyelia, and exposing classical pain behaviour.

Central neuropathic pain is a prominent feature in 50 to 90% of adult human patients with syringomyelia. Recently, a direct relationship has been described between central neuropathic pain and objective markers of spinal cord damage. [2]

Large syrinxes leading to damage to the dorsal part of the spinal cord are leading to abnormal behaviour seen by cavalier King Charles spaniels. This behaviour is likely to be "neuropathic pain," and therefore it is suggested that conventional analgesic medication may be ineffective. [3] [4]

In the Netherlands we conducted an open pilot trial and included 12 Cavalier king Charles spaniels, alle with MRI-scan positive syringomyelia and all suffering from behavioural abnormalities and objective signs related to syringomyelia and neuropathic pain. Syringomyelia, linked to Arnold Chiari malformation, is  serious condition in which fluid-filled cavities develop within the spinal cord near the brain.

It is also known as "neck scratcher’s disease", because one of its common signs is scratching in the air near the neck. [5] Our dogs showed symptoms like these as well as other known behavioural abnormalities, such as scratching behavior and scoliosis or lordosis, yelping, sitting with eyes closed, immobility, walking as on eggs, difficulty swallowing, tongue out of mouth, as well as symptoms of  Primary Secretory Otitis Media (PSOM) as well as signs of conjuctivitis (excessive lacrimation).

All dogs were weaned off their analgesic medication before entering the trial. During 2 months PEA was given in a dose of around 30 mg/kg BW. So most dogs received 150 mg twice daily. 

If dogs are very light (less then 6 kg) we start with PEA 200 mg. Dogs between 6-12 kg mostly get twice daily 150 mg and heavy dogs, and non responders twice daily 200 mg. As the substance isn tolerated very well, a bit more is no problem, up to 40 mg/kg dog.

If dogs get too a higher dose, they start painting and they become restless. 

In the Netherlands PEA is available as 400 mg capsules PeaPure, these capsules are easy to open, and one can devide the 400 mg into 2 portions. 

Palmitoylethanolamide (PEA) in Cavalier spaniels: results from a pilot trial 

A composite scale scored by the dog owners was used, based on whether symptoms were the same, improved a bit or improved a lot. The first item was the overall general impression, the other items were linked to behavioural abnormalities, such as:

cheery, lively (same, better, much better)

headache (eyes closed) (same, better, much better)

lacrimation (same, less, much less)

chewing and swallowing, (same, less, much less)

scratching, licking, rubbing (same, less, much less)

moving around (same, better, much better)

Results:

After 2 months of PEA use in 12 Cavalier spaniels, the results were the following. Of all the 12 dogs, based on the overal general impression the owners could clearly detect improvement within 8 days, and in 5 dogs the improvement was seen already after 3-4 days. Within 4 weeks all dogs showed improvements. More specifically:

General impresison: in 4 dogs better and in 8 dogs much better.

cheery/ lively: same 0, better: 5 much better: 7

headache (eyes closed): same 0, better: 5, much better: 7

lacrimation: same: 3, less: 3 much less: 6

chewing and swallowing,  same: 3, less: 3 much less: 5   (1 not scored)

scratching, licking, rubbing: same: 2, less: 5 much less: 5

moving around: same: 2, better: 2 much better: 7  (1 not scored)

Qualitative statements of owners

One owner states she can pat the dog again, and the dog played again with younger dogs.

Some owner stated that the dog’s skull was less hot. One owner of a dog suffering from chronic ear inflammation (PSOM) could tough the dogs head and ears again. In one dog the owner stated that the lordosis vanished, one other dog showed affective behaviour and touching was again possible, etc, etc.

All dog owners noticed impressive positive changes in behaviour after treatment with PEA. 

Follow-up: meanwhile many dogs are treated for many months, and most dogs are still very much stable. The first signs of efficacy is less inflammation of the eyes, and less lacrimation, already sometimes after some days. 

PEA: dose recommendation 

Best is to start with around 10 mg PEA/ kg bodyweight and increase it if necesseary to 30 mg / kg bodyweight. In the Netherlands the supplement PeaPure contains pure finely powdered palmitoylethanolamide in 400 mg capsules; easy to administer as powder in the mouth or on meat. The capsules can be opened easily and PeaPure contains no other compounds, no fillers, no magnesium stearate or sorbitol. 

Discussion and science

The Cavalier King Charles spaniels are the best model for central neuropathic pain in man. The Arnold Chiari malformation in these spaniels resembles the human condition. [4][7]

Therfore our pilot trial has also implications for the human patients suffering from central neuropathic pain due to syringomyelia. As syringomyelia is a spinal cord condition, is it important to point out that palmitoylethanolamide has been evaluated in other models of spinal cord injury too. And these models supported its therapeutic role. 

Palmitoylethanolamide is the naturally occurring amide of palmitic acid and ethanolamine. In a great number of pharmacological trials this molecule has been shown to reduces pain and inflammation through the nuclear receptor PPAR-alpha. This receptor is activated by PEA.

PEA can reduce secondary damage induced by experimental spinal cord injury (SCI) in a mice model. SCI leads to edema, neutrophil infiltration, and production of inflammatory mediators, tissue damage, and apoptosis. Repeated PEA administration significantly reduced: 

  • 1) the degree of spinal cord inflammation and tissue injury,
  • 2) neutrophil infiltration,
  • 3) nitrotyrosine formation,
  • 4) proinflammatory cytokine expression,
  • 5) nuclear transcription factor activation-kappaB activation,
  • 6) inducible nitric-oxide synthase expression, and
  • 6) apoptosis. 

Hand in hand with these biochemical improvements, PEA ameliorated the recovery of motor limb function. [8] 

In a compression model induced by applying an aneurysm clip to the spinal cord in mice repeated PEA administration (10mg/kg i.p., 6 and 12h after SCI) significantly reduced the degree of the severity of spinal cord trauma through the reduction of mast cell infiltration and activation. PEA also significantly reduced the activation of microglia and astrocytes expressing cannabinoid CB(2) receptor after SCI. PEA also acted as a neuroprotectant via induction of neurotrophic factors. [9][10]

The results of this pilot trial are in line with experimental findings supporting the neuroprotective role of PEA, as well as its role as a anti-inflammatory and analgesic compound. The avaiibility of Normast for human and dog sufferers of central neuropathic pain is a leap forward in the treatment of this difficult to treat pain state. 

Jan M. Keppel Hesselink, MD, PhD, april 2011 

Thanks to Jaennette van Leeuwen 

Literature on PEA and spinal cord injury and pain in pets


Referentie

[1] Grace PM, Rolan PE, Hutchinson MR. | Peripheral immune contributions to the maintenance of central glial activation underlying neuropathic pain. | Brain Behav Immun. | 2011 Apr 7. [Epub ahead of print]

[2] Hatem SM, Attal N, Ducreux D, Gautron M, Parker F, Plaghki L, Bouhassira D. | Clinical, functional and structural determinants of central pain in syringomyelia. | Brain. | 2010 Nov;133(11):3409-22. Epub 2010 Sep 17.

[3] Rusbridge C, Carruthers H, Dubé MP, Holmes M, Jeffery ND. | Syringomyelia in cavalier King Charles spaniels: the relationship between syrinx dimensions and pain. | J Small Anim Pract. | 2007 Aug;48(8):432-6. Epub 2007 Jun 30.

[4] Wolfe KC, Poma R. | Syringomyelia in the Cavalier King Charles spaniel (CKCS) dog. | Can Vet J. | 2010 Jan;51(1):95-102.

[5] Rusbridge C, Jeffery ND. | Pathophysiology and treatment of neuropathic pain associated with syringomyelia. | Vet J. | 2008 Feb;175(2):164-72. Epub 2007 Feb 20.

[6] Wolfe KC, Poma R. | Syringomyelia in the Cavalier King Charles spaniel (CKCS) dog. | Can Vet J. | 2010 Jan;51(1):95-102.

[7] Chandler K, Volk H, Rusbridge C, Jeffery N. | Syringomyelia in cavalier King Charles spaniels. | Vet Rec. | 2008 Mar 8;162(10):324.

[8] Genovese T, Esposito E, Mazzon E, Di Paola R, Meli R, Bramanti P, Piomelli D, Calignano A, Cuzzocrea S. | Effects of palmitoylethanolamide on signaling pathways implicated in the development of spinal cord injury. | J Pharmacol Exp Ther. | 2008 Jul;326(1):12-23. Epub 2008 Mar 26.

[9] de Almeida RP, Roselino RB. | [Electrolytic etching of different alloys. 1. Weight loss of samples]. | Rev Odontol Univ Sao Paulo. | 1990 Oct-Dec;4(4):314-7.

[10] Re G, Barbero R, Miolo A, Di Marzo V. | Palmitoylethanolamide, endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain: potential use in companion animals. | Vet J. | 2007 Jan;173(1):21-30. Epub 2005 Dec 1.