Palmitoylethanolamide in the Treatment of Neuropathic Pain

Neuropathic pain is quite common. It is associated with severe disability and adversely affects the quality of life of sufferers. Current treatment options for neuropathic are not very effective. Moreover, they are associated with significant adverse effects. A new naturally occurring substance- PALMITOYLETHANOLAMIDE (PEA)- has been found to be effective and safe in treating neuropathic pain. The current presentation looks at the efficacy of PEA in neuropathic pain.

1. THERAPEUTIC UTILITY OF PALMITOYLETHANOLAMIDE IN THE TREATMENT OF NEUROPATHIC PAIN DR SUDHIR KUMAR MD DM CONSULTANT NEUROLOGIST APOLLO HOSPITALS, HYDERABAD

2. NEUROPATHIC PAIN: Epidemiology (1) Prevalence of neuropathic pain is estimated to be 6-8% (UK and France) In primary medical care settings, prevalence of neuropathic pain is between 2-11%, Painful diabetic neuropathy is the commonest cause of neuropathic pain (72%).

3. NEUROPATHIC PAIN: Epidemiology (2) Other common causes of neuropathic pain: Low back pain/disc prolapse, post-herpetic neuralgia, cancer pain, trigeminal neuralgia Comorbidities associated with neuropathic pain: mood disorders/depression, sleep disturbance Neuropathic pain leads to reduced work output, deterioration in personal/social life, and has high economic burden.

4. PATHOPHYSIOLOGY OF NEUROPATHIC PAIN Multifactorial, and has multiple mechanisms: Partial nerve damage-increased firing-increase in number of sodium channels. Ectopic discharges due to enhanced depolarization- spontaneous pain, Impaired inhibitory circuits-enables pain impulses to travel unopposed, Alteration in central processing of pain, Inflammation

5. CURRENT MEDICINES FOR NEUROPATHIC PAIN 1. Anti-epileptics - Pregabalin, Gabapentin, Carbamazepine, Oxcarbazepine 2. SNRIs - Duloxetine, Venlafaxine 3. TCAs - Amitriptyline, Nortriptyline, D osulepin 4. Miscellaneous: Capsaicin cream, lidocaine patch

6. LIMITATIONS OF CURRENT MEDICATIONS Most medicines focus on neuronal system suppressing GABA or other inhibitory receptors . Their use is associated with multiple side effects- dizziness, somnolence, peripheral edema, psychomotor slowing, etc. Prolonged use leads to desensitization of receptors, leading to increase in dose, and more side effects.

7. I NFLAMMATION: THE MISSING LINK Italian Nobel laureate Rita Levi-Montalcini researched extensively on the role of inflammation in the neuropathic pain . In 1977, she discovered that NGF works on mast cells . In 1990, she established that mast cells receive inputs from neurologic and immune systems.

8. I NFLAMMATORY PROCESSES INVOLVED IN NEUROPATHIC PAIN Accumulation of inflammatory cytokines, chemokines and prostaglandins . Modulation of extracellular proteins . Changes in transmembrane receptor expression . Immune cell infiltration,

9. PALMIGES: COMPOSITION Palmitoylethanolamide (PEA)- a fatty acid amide found in human body that restores balance to excessive inflammation . Genistein and Daidzein- naturally occurring fatty acid amide hydrolase (FAAH) inhibitor to counter the effects of FAAH enzyme. MPFAITECH- Micronized PEA FAAH technology to help absorption of the formulation at the site of inflammation.

10. PALMITOYLETHANOLAMIDE It is a natural painkiller produced in the human body . Its efficacy in ameliorating pain has been proved in multiple studies over the past 60 years . More than a million people worldwide have used this to get relief from pain . It is very safe and is not associated with any significant side effects.

11. FATTY ACID AMIDE HYDROLASE (FAAH) INHIBITORS FAAH inhibitors increase endogenous levels of anandamide, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), when and where they are naturally released in the brain.

12. PALMIGES: MECHANISM OF ACTION (1) Anti-inflammatory properties : Stops over-activation of mast cells, Stops production of chemokines and cytokines by binding to PPAR alpha, Stops/inhibits phosphorylation of kinases by binding to enzymes causing phosphorylation, Stops chemostaxis of monocytes to affected areas, May be a COX-2 inhibitor too.

13. PALMIGES: MECHANISM OF ACTION (2) FAAH competitive inhibition : Genistein and Daidzein in Palmiges are natural FAAH inhibitors, which help in maintaining the levels of fatty acid amide PEA in the body . Increased body levels of PEA leads to down regulation of neuropathic pain at a faster rate.

14. PALMIGES: MECHANISM OF ACTION (3) Unique absorption and distribution profile : MPFAITECH (a US based Tech) ensures that the particle size of active material in Palmiges is less than 10 micrometer, and hence are absorbed and distributed in a matter most effective to manage neuropathic pain.

15. CLINICAL EVIDENCE S

16. CLINICAL EVIDENCE (1) LUMBAR DISC DISEASE 636 patients from multiple Italian centers were treated with placebo, or PEA (300 mg or 600 mg/day) for 21 days Pain reduction and quality of life were better in PEA group PEA 600 mg/day was found to be more effective than 300 mg/day (Dolor 2019;25:35-42)

17. CLINICAL EVIDENCE (2) Neuropathic pain due to lumbar radiculopathy 118 patients were treated with standard therapy alone or in combination with PEA 600 mg/day for 30 days Greater pain relief was noted in PEA group PEA was well tolerated. (Pain Manag . 2012;2:119-24)

18. CLINICAL EVIDENCE (3) DIABETIC NEUROPATHIC PAI N Open label study in patients with type II DM and painful neuropathy Treated with PEA 300 mg two tablets daily for 60 days, Significant reduction in pain symptoms No adverse events ( Pain Research & Treatment; 2014:1-5)

19. CLINICAL EVIDENCE (4) CHEMOTHERAPY-INDUCED NEUROPATHIC PAIN 20 patients with multiple on chemotherapy with thalidomide and bortezomib Treated with PEA 300 mg BD Motor and sensory nerve function were assessed over 60 day period Significant restoration of nerve function was noted with PEA treatment. (CNS Neurol Disord Drug Targets. 2011;10:916-20)

20. CLINICAL EVIDENCE (5) TEMPOROMANDIBULAR JOINT INFLAMMATORY PAIN 24 patients with TMJ pain were randomized to receive either PEA or Ibuprofen for two weeks. After two weeks, pain relief as well as mouth opening were better in patients treated with PEA. (J Orofac Pain. 2012;26:99-104)

21. CLINICAL EVIDENCE (6) CHRONIC PAIN OF VARIOUS ETIOLOGIES 610 patients with chronic pain were treated with PEA either alone or along with other analgesic therapies PEA treatment significantly reduced pain score in all patients Pain score also reduced in patients without any concomitant analgesic therapy. (Pain Med. 2012;13:1121-30)

22. CLINICAL EVIDENCE (7) PEA enhances the effect of acupuncture in relieving pain from radiculopathy 30 patients with cervical or lumbar radicular pain were treated with either acupuncture alone or in combination with PEA Both groups had pain relief, however, the pain relief was more significant in the acupuncture + PEA group. (MR Italian Journal of Rehabilitation Medicine. 2013;27:49-54)

23. CLINICAL EVIDENCE (8) CARPAL TUNNEL SYNDROME Patients with moderate CTS were treated with PEA (600 mg or 1200 mg per day) and compared with those that did not receive any treatment. Patients on treatment showed reduction in pain, as well as improvement in median nerve conduction studies. (Minerva Med. 2011;102:141-7)

24. CLINICAL EVIDENCE (9) CHRONIC PELVIC PAIN 24 patients with chronic pelvic pain due to endometriosis were treated with PEA At 90 days, patients reported significant improvement in pain, dysmenorrhea and dyspareunia. Quality of life also imporved . ABDOMINAL PAIN due to IRRITABLE BOWEL SYNDROME - also improved in another study conducted in 54 patients.

25. PALMIGES: SUMMARY Indicated for treating neuropathic and chronic pain of various etiologies, Safe in all age groups, No significant adverse effects noted, No significant drug interactions noted, Usual dose is 2-4 capsules per day, Safe in patients with renal and hepatic disease, Can be prescribed alone or along with other pain-relieving therapies.

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