Neuropathic pain, or nerve pain, is most commonly described by patients as a ‘shooting pain’, ‘burning’, or ‘pins and needles’. Neuropathic pain (or its symptoms) affects nearly one in 10 Australians and most sufferers seek professional help within six months of onset because the symptoms are severe enough to interfere with their normal daily routine, sleep or physical abilities.
Chronic pain in general is even more frequently encountered, with 38% of the world’s population being affected. Of all chronic pain conditions, nerve pain is one of the most difficult to treat, with less than half of patients treated achieving partial relief from therapeutics which currently compromise mainly of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). Because this line of pain therapy often remains unsatisfactory and is frequently linked with undesirable side-effects, the use of palmitoylethanolamide (PEA) provides an attractive adjunct or alternative.
PEA performs a great variety of biological functions and is clinically used for its neuroprotective, anti-neuroinflammatory and analgesic properties. Its efficacy has been demonstrated in clinical trials in conditions such as sciatic pain, carpal tunnel syndrome, low-back pain, failed back surgery syndrome, osteoarthritis, chronic pelvic pain, vaginal pains, postherpetic neuralgia, and peripheral neuropathies including diabetic neuropathy and chemotherapy-induced peripheral neuropathy.
What is PEA?
PEA is an endogenous fatty acid amide that belongs to a class of lipid autacoids; the N-acylethanolamines. The term “autacoid” is derived from the Greek ‘autos’ (self) and ‘acos’ (relief, treatment). Autacoids can be defined as locally produced modulating factors which influence the function of the cells and/or tissues in which they are synthesised. Autacoids are produced on demand and are subsequently metabolised in the same cells/tissues as they were produced.
As an autacoid, PEA is synthesised in response to injury or inflammation and acts locally to counteract such pathology. Therefore, PEA could also be considered a natural defence or self-healing molecule. 
In addition to its endogenous origins, PEA is found in several food sources, including soy bean, soy lecithin, tomato, corn, milk, egg yolks and peanuts.
PEA was first described in scientific literature in the 1950s as a non-specific immunologic resistance enhancer and was used successfully in the treatment and prophylaxis of the common cold and influenza. However, due to a lack of insight into its mechanism of action, interest waned, only to be ignited again in the early 90s thanks to the work of Levi-Montalcini, who was awarded the Nobel prize for her work on the role of nerve growth factor (NGF) in inflammation and its activating role in mast cells; showing that positive feedback of NGF on mast cell behaviour could be modulated and inhibited by PEA. While this was the first mechanism to explain the anti-inflammatory effects of PEA, several other mechanisms have since been elucidated and PEA has been the subject of many studies, particularly in relation to chronic inflammation and pain.
How does PEA work?
A growing body of evidence suggests that neuroinflammation, which is characterised by infiltration of immune cells, activation of mast and glial cells, and production of inflammatory mediators in both peripheral and central nervous systems, has an important role in the initiation and maintenance of chronic pain.
PEA has been shown to reduce mast cell migration and degranulation, down-modulate mast cell pathological overactivation8 and control glial cell behaviours. Both mast cells and glial cells shift under the influence of PEA from activated immune cells to resting phenotypes.
Even though PEA is synthesised on demand in many tissues, levels are altered following stress or injury. Altered levels have also been noted in clinical conditions associated with pain. In some pathological situations, the endogenous production of PEA is inadequate to control the inflammatory cascade, and in such instances, exogenously supplied PEA may prove beneficial.
Since the early work of Levi-Montalcini, it has become clear that PEA regulates numerous pathophysiological processes involving neuroinflammation. Many of the biological effects of PEA, including that on mast cells, can perhaps be explained via its affinity for the PPAR.
As an autacoid, PEA has a high affinity for the nuclear factor peroxisome proliferator-activated receptor alpha (PPAR-a). This receptor is a regulator of gene networks which control pain and inflammation, probably by switching off the nuclear factor-kappaB (NFkB) signalling cascade, a key element in the transcription of genes for proinflammatory mediators (cytokines, chemokines and nitric oxide).
In addition, PEA also has affinity for the novel orphan cannabinoid receptor GPR55,6 and acts to desensitise TRPV1 on sensory neurons. GPR55 has recently emerged as a putative target for the treatment of inflammation.7 Activation of TRPV1 (also known as the capsaicin receptor) contributes to pain transmission, inflammation and toxicity; desensitisation on the other hand contributes to the analgesic and anti-inflammatory actions of TRPV1 antagonists.
PEA may indirectly activate the cannabinoid receptors CB1 and CB2. Cannabinoids are found in plants belonging to the genus Cannabis but are also naturally produced in the body.
Cannabinoids act on CB receptors in the central nervous system as well as cells of the immune system. CB1 receptors on primary afferent nociceptors (sensory receptors for painful stimuli) in the dorsal spinal cord may explain the anti-nociceptive (the perception of pain) effects of cannabis. The effects of endocannabinoids on the peripheral CB2 receptors of the immune system suggest that they may also be effective for treating inflammatory pain. PEA is a cannabimimetic compound thought to reduce pain through a variety of endocannabinoid driven activities and reducing inflammation.
Exerting neuroprotective effects, PEA may preserve nerve morphology and prevent nerve degeneration.
Collectively, research shows that PEA does not operate through just one main mechanism of action, but instead relies on synergistic interactions among several mechanisms and can therefore produce important therapeutic effects both in the central and peripheral nervous systems and across a broad range of disorders.
These features distinguish PEA from classical steroidal and NSAIDs that act by inhibiting the arachidonic acid cascade. Both pre-clinical and human studies indicate that PEA, especially in its micronised form, is a promising therapeutic tool for the effective treatment of different pathologies characterised by neurodegeneration, neuroinflammation and pain.
A recent pooled meta-analysis of 12 studies evaluating the efficacy and safety of micronised and ultra-micronised PEA on pain intensity in patients suffering from chronic and/or neuropathic pain, showed that PEA produces a progressive reduction in pain intensity significantly higher than control. The Kaplan-Meier estimator showed a pain score ≤3 in 81% of PEA treated patients compared to only 40.9% in control patients by day 60 of treatment.
Comparing the efficacy of PEA to the NSAID ibuprofen in 24 patients with temporomandibular joint osteoarthritis (TMJ), PEA (300mg in the morning and 600mg in the evening for seven days; then 300mg two times a day, for another seven days) was associated with significantly greater pain reduction compared to the drug (600mg three times a day, for two weeks) and was better tolerated, as three patients in the ibuprofen group reported stomach ache whereas PEA patients did not report any adverse events.2 Joint function (measured as maximum mouth opening) also improved more in the PEA group than in the ibuprofen group.
Unlike most pharmaceutical painkillers and anti-inflammatories, the tolerability of PEA is excellent. In fact, clinicians report that PEA has been used successfully by their patients for many years, without any problems.
There are no known contraindications for PEA and as its metabolism is based on being an autacoid, it is independent on kidney and liver functions, thus patients with reduced renal and hepatic clearance can be safely treated with PEA.
No drug interactions have been reported.
Used for its neuroprotective, anti-inflammatory and analgesic actions, PEA belongs to a new class of analgesic products.
PEA has been evaluated in a number of placebo-controlled randomised clinical trials and has been found effective in various neuropathic pain states and inflammation, as well as in chronic pain.
PEA has an excellent safety profile and is devoid of addiction potential. Drug interactions have not been documented and it may be used together with other analgesics or as a stand-alone therapy.
PEA in a micronised form shows superior oral efficacy in inflammatory pain models when compared to non-micronised PEA.
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