Non-infectious cystitis or Interstitial cystitis can be due to a variety of causes, such as medication, radiation, foreign bodies, autoimmune response, and but cases of non-infectious cystitis end as being idiopathic in nature; we call this interstitial cystitis (IC). IC is a pain-syndrome characterized by urinary bladder pain and irritative voiding symptoms of more than 6 months duration.
The European Society for the study of Interstitial Cystitis (ESSIC) proposed a diffirent name for IC, ‘bladder pain syndrome’ (BPS). Pelvic pain syndrome is also sometimes used.
IC is characterized by infiltration of mast cells and other inflammatory white blood cells, and due to mast cell activation a chronic inflammatory cascade developes, leading to irreversible tissue destruction, dysfunctional pathology such as fibrosis and due to enhanced tissue levels of NGF detrusor overactivity, and hyperalgesia. All the symptoms, voiding problems and pain are characterized by chronic waxing and waning of these symptoms and sadly enough sometimes to generalization the local painsyndrome into a pelvic painsyndrome, or even to irritable bowel disorder or fibromyalgia. Fibromyalgia, irritable bowel syndrome (IBS; 35% cases) and vulvodynia (vulvodynia in 20–51.4% of patients) are often seen hand in hand with IC.
Central in the pathogenesis of IC is the mast cell. The central role of inflammation and the mast cell have been confirmed in both human as well as in animal models.
The overactive mast cells lead to chronic inflammation, due to the presence and a cascade of many inflammatory mediators. As a result of this cascade of events a often treatment resistent, self-reinforcing cycle of persistent inflammation and pan, and recurrent injury to bladder epithelium occurs.
Mast cells release NGF and many important irritative factors, and these pro-inflammatory factors irritate the urothelium itself. The urothelium than releases also number of pro-inflammatory molecules, such as neuropeptides, nerve growth factor, various neurotransmitters and the antiproliferative factor (APF). This all leads to chronic peripheral wind up: activation of submucosal afferent nerves and again activation of the mast cells. Thus a clear vicious circle happens, which is difficult to treat.
More on mast cells in Interstitial Cystitis
An increased number of mast cells is characteristic for IV, and these can be found both in submucosa and detrusor layers. Especially the Hunner’s ulcers are rich in activated mast cells. There is a 6- to 10-fold increase in mast cells in classic/ulcerative IC compared with a 2-fold increase in patients with nonulcerative IC.
It has become clear that a diagnostic cutoff of mast cell counts >20 cells/mm2 in bladder muscle has a 95% diagnostic sensitivity and a 88% diagnostic specificity for IC (Kastrup et al).
Mast cells secrete amongs others tumor necrosis factor-α (TNF-α), which activates the nuclear transcription factor-κB. This is a key regulator of inflammatory gene expression, causing further urothelial inflammation. VEGF, another mast cell mediator, causes vasodilation and may therefore be responsible for the hypervascularity and glomerulations, which are characteristic of IC, leading to chronic pain and voiding problems.
Palmitoylethanolamide: the key to modulate mast cells and inhibit pain and inflammation
Palmitoylethanolamide is the key to suppress overactive mast cells, and this endogenous molecule, available as a nutraceutical, PeaPure (in 400 mg capsules) holds great promise in the treatment of chronic pain states like IC.
Identification of palmitoylethanolamide (PEA) as regulatory mechanism for the metabolism of mast cells can be attributed to the work of the Nobel Price Laureate Rita Levi Montalcini. She was the first to identify PEA as a mast cell inhibitor in 1993 and based on her work PEA has been extensively used as a analgesic and anti-inflammatory compound since the last decade, especially in the countries were PEA is available, Italy, Spain and the Netherlands. Due to the fact that since 2012 PEA is world wide avalable as a nutraceutical (PeaPure) increasingly this compound is used in the treatment of complex, mast cell driven chronic pain states, such as IC.
The beginning of the mast cell modulation concept and the ALIA mechanism of PEA
In 1993 in an article titled ‘ A proposed autacoid mechanism controlling mastocyte behavior’, the Nobelprize laureate Levi-Montalcini presented evidence ‘ supporting the possibility that lipid amides of the N-acylethanolamine type are potential prototypes of naturally ocurring molecules capable of modulating mast cellactivation in vivo.’
Together with some of her co-workers she put forward the following elegant hypothesis:
‘Tissue accumulation of ….free N-acylethanolamines has been reported to occur in pathological degenerative conditions. As such conditions are known to be associated with inflammatory reactions, one attractive hypothesis is that the production of these lipid metabolites may play an autacoid role in controlling mast cell behavior in pathological conditions.’
In this paper she also introduced the term ‘ALIA’ to stipulate the physiological mechanism of action of PEA in various inflammatory and painful states.
ALIA and autocoid physiology of PEA
The acronym ‘ALIA’ stamds for ‘autacoid local inflammation antagonism‘ and is a term Montalchini et al proposed for the novel mast cell modulation mechanism, based on PEA.
Mast cells have been known to be activated by NGF. PEA counteractis this activation.
PEA is formed locally in tissue suffering from inflammation or, as Montalcini puts it, neurogenic pain, and increased PEA concentrations are the body-own mechanisms to cope with pain and inflammation.
From another perspective one could state that this molecule is our natural defense molecule, or self-healing molecule, in case of over-active mast cell behaviour, and activated glia cells, as present in may different painful and inflammatory disorders.
Clinical research on PEA started in the 1960s and 1970s, especially in the Czech Republic. PEA, at that time under the brandname ‘Impulsin’ was indicated for prevention of flu and respiratory diseases and immune system enhancement. Many years have since passed, with PEA being subsequently explored in a variety of pain states: diabetic neuropathy, pelvic pain states, carpal tunnel syndrome, dental and temporomandibular joint pain, arthritic, postherpetic and chemotherapy-induced neuropathic pain. Overall, more than 2000 patients have been successfully treated with PEA, and no adverse effects reported in any of the trials (Keppel Hesselink, 2012)
Effect of PEA on Visceral Pain as in Pelvic pain and Interstitiel Cystitis
PEA benefits somatic pain, from neuropathic to postoperative and mixed pain. Interestingly, also chronic pelvic pain, i.e. visceral pain, has been shown to respond to PEA. In an open study of 25 female patients suffering from endometriosis (n=15), interstitial cystitis (n=6) and dysmenorrhea (n=4) a 60 day-treatment with PEA (200 mg/3 times a day) resulted in a significant decrease of pain, with a VAS score reduction from 6.8 (before treatment) to 3.2 (after 30 days) and 1.7 (after 60 days – study end). Moreover, the combined use of non-steroidal anti-inflammatory drugs significantly decreased.
A further preliminary study on the effect of PEA on dysmenorrhea was presented at the Pediatric and Adolescent Gynecology Congress 2010. Twenty adolescent girls were found to benefit from PEA treatment, with a 70% reduction of dysmenorrhea after a 6-month treatment.
A case series on chronic pelvic pain successfully treated with PEA was recently published. Four patients presenting a endometriosis-related pain intensity >5 on VAS were enrolled and monitored during 3 months of the following treatment: oral PEA 90 days. Chronic pelvic pain intensity due to endometriosis and deep dyspareunia, dyschezia, dysuria or dysmenorrhoea was evaluated on VAS at baseline and during the programmed follow-up after 1, 2 and 3 months of treatment. All patients experienced pain relief as early as 1 month after starting treatment (p < 0.0069). For dyspareunia there was a significant reduction at day 30, which remained constant until the end of the study (p < 0.0132). The reduction in pain intensity was paralleled by a statistically significant (p < 0.0176) reduction in analgesics use.
Based on our knowledge to date, recommended starting treatment dose for PEA is: trice daily 400 mg PEA, and after 2 weeks increase the dose, if the body weight is higher than normal. Maximal dose 2400 mg/day (or 30 mg/kg BW).
Description of PeaPure® 400 mg capsules
PeaPure® is a food supplement based on a natural and fatty-acid like compound.
The substance palmitoylethanolamide (PEA) is a physiologically active molecule that the body produces naturally.
What the user should know prior to ingestion:
• There are no known significant side effects.
• PeaPure® can be taken simultaneously with other medicine. In case of doubt, it is recommended to first consult your doctor or a pharmacist.
• Use during pregnancy is NOT recommended.
• PeaPure® does not contain sugar, yeast, allergens, sorbitol, magnesium stearate, povidone or other ingredients.
Dosage and administration
Administration: During or after the meal, swallow 1 capsule together with water, or sprinkle the content of the capsule on your food.
Dosage: may use 30 mg/kg
First 2 months: 3 times 1 capsule daily
Next 2 months: In case of a positive result, 2 times 1 capsule daily, otherwise increase dose
After 4 months, you can consider the following:
• Continue taking 2 times 1 capsule daily.
• Reduce the ingestion to 1 times 1 capsule daily.
• Stop the ingestion.
In case of regression, it is recommended to increase the dosage to 2 or 3 times 1 capsule daily.
It is possible to continue taking PeaPure® in the correct dosage.
Kastrup J., Hald T., Larsen S., Nielsen V.G. (1983) Histamine content and mast cell count of detrusor muscle in patients with interstitial cystitis and other types of chronic cystitis. Br J Urol 55: 495–500.
Keppel Hesselink JM, Kopsky DJ. Treatment of Chronic Regional Pain Syndrome type 1 with palmitoylethanolamide and topical ketamine cream: modulation of non-neuronal cells” accepted for Journal of Pain Research 2013.
Keppel Hesselink JM, Hekker TA, Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series Journal of Pain Research 2012 Volume 2012:5 Pages 437 – 442
Keppel Hesselink, JM (2012) New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide. Open Pain Journal 2012, 5: 12-23