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Clinical Trials with PEA: overview

Recent review of palmitoylethanolamide including many clinical trials via this link. 

Overview of all clinical trials:

Clinical studies: PEA in chronic painsyndromes

PEA in general painsyndromes

1. DiPaolo A et al. Palmitoylethanolamide (PEA) as a treatment for vaious chronic painstates. Presented at the 34 AISD congress in Riccione, 2011|

n= 610, two arms, open study, comparing standard treament with standard and PEA in patients suffering from sciatic pain (hernia) (n=331), artrotic pains (n=54), post herpetic pain (n=44), diabetic pains (n=32), failed back (n=76), cancer induced pains (n=72) and mixed painstates (n=51) mean VAS 6.5 at T0. 

Indication: pains due to various painconditions. Two arms: standard care (with or without analgeics) and palmitoylethanolamide twice daily 600 mg.

Results: decrease of pain from mean VAS 6.5 to mean VAS 2.5 for placebo, in both groups, irrespective of co-administred other analgesics. No relevant side-effects, no drug-drug interactions

Conclusion: Palmitoylethanolamide 600 mg twice daily is effective in many painstates (irrespective of concomitant analgesics), and no safety issues arose.

2. Desio P, Pregabalin and Palmitoylethanolamide in the treatment of neuropathic pain. Pathos 2010l17:9-14 |

n=30 treatment refractory chronic pain patients suffering from neuropathic pain. 30 patients which were refractory to painkillers including Lyrica were treated with a slow taper in scedule of Lyrica on top of twice daily een PEA-houdend product.

Results: this combined treatment decreased pain from above 7 to below 3 on the VAS. Lyrica combined with twice daily 600 mg is a effective analgesic coctail for treatment refractory neuropathic pain patients!

This important clinical trial was conducted in 30 treatment refractory neuropathic pain patients, sufferng from either diabetic neuropathic pain, or postherpetic neuralgia. No drug-drug interaction. Further details on the movie under the link.

PEA in pain in Costen syndrome (TMJD)

3. Bortolotti F,Russo M, Bartolucci ML, Alessandri Bonetti G, Gatto MR, Marini I. Palmitoylethanolamide vs NSAID in the treatment of TMJD Pain | Journal of Dental Research | 2010: 89(Special Issue B)

In a head to head comparison study the Italian research group from the Department of Orthodontics, of the School of Dentistry, at the University of Bologna, could demonstrate that treatment with the natural analgesic compound palmitoylethalonamide (een PEA-houdend product®) was superior over the treatment with a classical NSAID in temporomandibular joint disorder (TMJD), or Costen syndrome.

25 patients affected by osteoarthritis and synovitis, who had been classified in Axis I, group III of the Research Diagnostic Criteria for TMD(RDC/TMD) entered a a blind randomized clinical trial.

Group A(13 patientsw) were treated with palmitoylethanolamide ( een Italiaans bedrijfGroup, Padova) and Group B (12 patients ) were randomized to treatment with a NSAID(ibuprofen 600mg) 3 times a day for 2 weeks. Pain decrease after two weeks of treatment was significantly higher in group A (een PEA-houdend product ) than in group B (NSAID) (p=0.0001). And also the masticatory functions improved significantly more in group A than in Group B (p=0.0001).

een PEA-houdend product in lumbosciatic pain (Hernia) and low back pain

4. G. Guida, A. de Fabiani, F. Lanaia, A. Alexandre, G.M. Vassallo, L. Cantieri, M. de Martino, M. Rogai, S. Petrosino | La palmitoiletanolamida en el dolor neuropatico cronico por lumbociatalgia de tipo compresivo: estudio clinico multicentrico.  Dolor 2010, 25:35-42

n= 636, placebo-controlled, double blind, randomised study in patients suffering from sciatic pain (hernia), mean VAS 6.5-7 at T0.

Indication: pains due to lubosciatic problems. Three arms: placebo, palmitoylethanolamide 300 mg/day, palmitoylethanolamide 600 mg/ day.

Results: decrease of pain from mean VAS 6.5 to mean VAS 4.5 for placebo,  VAS 6.5 to 3. 5 for 300 mg and VAS 7.1 to VAS 2.1 for 600 mg.  300 mg was signiicantly better compared to placebo, and 600 mg was significantly better compared to 300 mg and to placebo. No relevant side-effects. 

Conclusion: Palmitoylethanolamide 300 and 600 mg are significantly and clinically better than placebo, and no safety issues arose.

5. Desio,P et al. | Efficacy of palmitoylethanolamide and oxycodon in patients with low back pain. Anesthesia and medicina critica (AMC) 2011, 2: 62-71. 

n= 20, open study in non responders on analgesia.

Indications: sciatic pain, low back pain, hernia and vertebral stenosis of Verbiest. Treatment regime: oxycodin day 1-5 5 mg, after twice daily 5 mg oxycodin; in addition to palmitoylethanolamide, 600 mg twice daily.

Results: decrease of pain from mean VAS 7 to mean VAS 2.5 at day 30 (p<0,001). No side relevant effects, no drug-drug interactions.

Conclusion: Treatment of refractory neuropathic patients with the combination of pregabaline and palmitoylethanolamide seems safe and effective. See also link for movie.

6. Canteri L et al. Reduction of analgesics in patients suffering from lumbosciatic pain, treated with palmitoylethanolamide. Dolor 2010 | 25:227-234 |

n= 111, placebo-controlled, double blind, randomised study in patients suffering from sciatic pain (hernia), mean VAS 9 at T0.

Indication: pains due to lubosciatic problems. Three arms: placebo, palmitoylethanolamide 300 mg/day, palmitoylethanolamide 600 mg/ day. In each group half of all patients were alowed to be treated with NSAIDS, while other half was treated with study medication only.

Results: decrease of pain from mean VAS 9 to mean VAS 6 for placebo (both for NSAID users and NSAID virgins), VAS 9 to 3. 5 for 300 mg (both with/without NSAIDs) and VAS 9 to VAS 1.5 for 600 mg (for both groups with/without NSAIDs).  Decrease of pain in palmitoylethanolamide compared to placebo was significant (p,0,05) No relevant side-effects or drug interactions.

Conclusion: Palmitoylethanolamide 300 and 600 mg are significantly and clinically better than placebo, and no safety issues arose. NSAIDs do not further decrease pain.

7. Palomba R et al. | Efficacy of palmitoylethanolamide as part of multimodal analgesic therapy in patients with low back pain. Presented at 33rd AISD congress, 2010, Florence |

n=81, group comparison study, one group (n=41) recieved PEA on top of standard analgesics (pregabalin, gabapentin, amitriptyline, duloxetine) and the other group recieved just standard analgesics.

Indication: low back pain.

Results: at day 51 (endpoint) PEA treated patients had less pain compared to standard care (p<0,05), no side effects or drug-drug interactions observed.

Conclusion: PEA enhances the analgesic effects of other compounds.

8. Dominguez CM et al. Palmitoylethanolamide on standard care in lumbosciatic pain, a pragmatic trial. Preseted at 8th congres of Pain algologists, Madrid, 2010.

n=85 patients, trial duration 30 days. Clinical significant decrease pain after treatment 300 mg een PEA-houdend product twice daily. No side effects.

Trial design and results: discussed on the next movie

PEA in carpal tunnel syndrome pain

9. Assini A, Laricchia D, Pizzo R, Pandolfini L, Belletti M, Colucci M, Ratto S. | P1577: The carpal tunnel syndrome in diabetes: clinical and electrophysiological improvement after treatment with palmitoylethanolamide | Eur J Neurol | 2010: 17(S3):295.

n= 40, group-controlled randomised study in diabetic patients suffering from carpal tunnel syndrome, with moderate pain (VAS 7-8)

Indication: carpal tunnel syndrome in diabetic patients. Two arms: control (standard care) and palmitoylethanolamide 1200 mg/ day.

Results: significant improvement in pain at endpoint between treatment with PEA and control group, p < 0,0001). All neurophysiological parameters improved on PEA ( SAP, SCV and MLD). No relevant side-effects.

Conclusion: Palmitoylethanolamide 1200 mg/day is significantly and clinically better than standard care and improves nerve functions in carpal tunnel syndrome due to diabetes, and no safety issues arose.

10. Conigliaro R, Drago V, Foster PS, Schievano C, Di Marzo V. | Use of palmitoylethanolamide in the entrapment neuropathy of the median in the wrist. | Minerva Med. | 2011 Apr;102(2):141-7.

n= 26, group-controlled study in patients suffering from carpal tunnel syndrome, with clear neurophysiological abnormalities and pain.

Indication: carpal tunnel syndrome. Three arms: control (standard care), palmitoylethanolamide 600 mg/day, palmitoylethanolamide 1200 mg/ day.

Results: significant improvement in neurophysiological parameters (distal motor latency) in both dose arms, higher dose was more effective, and clinical relevant decrease of pain, as well as less signs of Tinel in treatment groups aftre 30 days of treatment.No relevant side-effects.

Conclusion: Palmitoylethanolamide 600 mg and 1200 mg/day are significantly and clinically better than standard care and improve nerve functions in carpal tunnel syndrome, and no safety issues arose. [1]

PEA is painful neuropathy

11. Biasiotta A, La Cesa S, Leone C, Di Stefano G, Truini A, Cruccu G. | Efficacy of palmitoylethanolamide in patients with painful neuropathy. A clincial and neurophysiological open study. Preliminary results. | , Volume 4, Issue 1, May 2010, Page 77.

n= 30,  open study in patients suffering from neuropathic pain, all non-responders to analgesic therapy.

Indication: treatment refractory neuropathic pain.Treatment: palmitoylethanolamide 600 mg/day (twice daily 300 mg)

Results: significant improvement in neurophysiological parameters (hand-LEP, Foot LEP) and significant reduction of pain.No relevant side-effects.

12. Deslo. P. Combination of pregabalin and palmitoylethanolamide (PEA) for neuropathic pain treatment. | Pathos, 2010, 17,4:9-14

Trial design and results: Presentation of clinical trial data see link.

n= 30, open study in non responders on analgesicsm, including pregabaline.

Indication: diabetic and postherpetic neuropathic pains. Treatment regime step by step increase of pregabaline (150 mg up to 400 mg/day in 30 days; in addition to palmitoylethanolamide, 600 mg twice daily.

Results: decrease of pain from mean VAS 7.6 to mean VAS 1,6 at day 45 (p<0,01). No relevant side-effects, no drug-drug interactions.

Conclusion: Treatment of refractory neuropathic patients with the combination of pregabaline and palmitoylethanolamide seems safe and effective.

PEA in diabetic neuropathic pain and symptoms

13.Schifiliti C, et al. Efficacy of palmitoylethanolamide in pain and neuropathic symptoms in diabetic patients. Presentation at IV congress of European Shock society, Taormina, 2011

n=30, open study in diabetic neuropathic pain patients during 90 days. Score>2 on Michigan neuorpathic scale, dose PEA 300 mg twice daily. 

Results: all symptoms, pain, dysesthesia and parsesthesias decreased as measured on various scales, at endpoint significanly compared to baseline. (p<0,0001) No side effects.

14. Adiletta S et al. Pregabalin and Palmitoylethanolamide in diabetic neuropathic pain: an randomized clinical trial. Presented at the 34th AISD meeting, 2011, Riccione. | Discussion of clinical trail data see: Reported

n=74, patients suffering from diabetic neuropathic pain. Open group comparison. Monotherapie pregabaline (titrated up to 600 mg/day) and pregabaline with added PEA 600 mg twice daily.

Results: significant higher rate of responding on pregabaline plus PEA (73% responders versus 40%) p<0,01. No side effects or interactions.

een PEA-houdend product in neuropathic pain in MS

14. Mancardi GL et al. Palmitoylethanolamide in neuropathic pain in MS patients. Presented at the 15yh Italian neurological meeting in Padua, 2009 |

n=20, open group collection. Patients suffering from MS and neuropathic pain. Treatment; PEA 300 mg twice daily. 14 of 20 patients were full responders. No side effects.

PEA in pain and spasticity after stroke

15. Russo G and Parabita M. Decrease of spasticity and pain after stroke due to treatment with PEA. Presented at 14th congress European Shocj Soc, Taormina, 2011

n=20, open group comparison. Either rehabilitation alone, or rehab and PEA 600 mg twice daily.

Indication: stroke rehab patients. 

Results: Significant decease of spasticity as measured via modified Ashworth scale, and significant decrease of pain in group treated with PEA, p<0,0006, no side effects.

PEA in chemo-induced neuropathic pain

16. Truina A et al. Palmitoylethanolamide improves pain and nerve function in patients suffering from chemotherapy induced neuropathy. CNS and neurological drug target, 2011, submitted. |

n=20, all patients scored 4 or higher on the DN4 en were treated with chemotherapy (talidomide and bortezomib). 

Treatment with PEA 300 mg twice daily, 60 days.

Results: pain significantly decreased and nerve function as measured by laser evoked LEP increased significantly by the end of treatment. No side effects

PEA cream in postherpetic pains

17. Phan NQ, Siepmann D, Gralow I, Ständer S. | Adjuvant topical therapy with a cannabinoid receptor agonist in facial postherpetic neuralgia. | J Dtsch Dermatol Ges. | 2010 Feb;8(2):88-91. Epub 2009 Sep 10.

PEA in Pelvic pains

18. Indraccolo U, Barbieri F. | Effect of palmitoylethanolamide-polydatin combination on chronic pelvic pain associated with endometriosis: preliminary observations. | Eur J Obstet Gynecol Reprod Biol. | 2010 May;150(1):76-9. Epub 2010 Feb 21.

n=4,  patients presenting with endometriosis-related pain intensity  VAS >or=5 were enrolled and monitored during 3 months. Treatment: palmitoylethanolamide 400mg and polydatin 40mg, twice daily for 90 days.

Results:  all patients enrolled experienced pain relief as early as 1 month after starting treatment. Furthermore, a reduction in the analgesic drugs usually employed for pain control was observed in all subjects treated. Additionally, some improvements in endometriotic lesions seemed to be demonstrated by imaging.

Conclusion: palmitoylethanolamide-polydatin combination seems to be very useful in controlling chronic pelvic pain associated with endometriosis.  [2]

19. Calabrò RS, Gervasi G, Marino S, Mondo PN, Bramanti P. | Misdiagnosed chronic pelvic pain: pudendal neuralgia responding to a novel use of palmitoylethanolamide. | Pain Med. | 2010 May;11(5):781-4. Epub 2010 Mar 22.

Case decription [3]

20. Cobellis L, Castaldi MA, Giordano V, Trabucco E, De Franciscis P, Torella M, Colacurci N. Effectiveness of the association micronized N-Palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study. Eur J Obstet Gynecol Reprod Biol. 2011 Sep;158(1):82-6. Epub 2011 May 23.

n= 61. Randomized, double-blind, parallel-group, placebo-controlled clinical trial in patients submitted to a first line laparoscopic conservative surgery, randomized into 3 groups receiving: group A (n=21) the association N-Palmitoylethanolamine-transpolydatin 400 mg + 40 mg twice a day for 3 months; group B (n=20) the placebo for 3 months; group C (n=20) a single course of Celecoxib 200mg twice a day for 7 consecutive days. 

Results: A marked decrease in dysmenorrhoea, dyspareunia and pelvic pain was observed in all groups, and the association between N-Palmitoylethanolamine and transpolydatin resulted to be more effective than placebo (P<.001). Additionally, the treatment with Celecoxib resulted in a decrease in pelvic pain numerically sligthly more effective either than the association N-Palmitoylethanolamine and transpolydatin or placebo.

Conclusion: the association between micronized N-Palmitoylethanolamine and transpolydatin is effective in the management of pelvic pain related to endometriosis after laparoscopy. Additionally, this association seems to be safe, shows an optimal control of pain and can be used in patients who are unable to receive other therapies.

20a. Keppel Hesselink JM. | Effectiveness of the association micronized N-palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain. | Eur J Obstet Gynecol Reprod Biol. | 2011 Jul 14. 

Letter to editor

20b. Cobellis L, Castaldi MA, Giordano V, Trabucco E, De Franciscis P, Torella M, Colacurci N. Reply to "Letter to Editor" by Keppel Hesselink JM "Effectiveness of the association micronized N-palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain". Eur J Obstet Gynecol Reprod Biol. 2011 Dec;159(2):488-9.

Aswer to letter to editor

21. Fulghesu A et al. Pain during menstruation in young adults treated with palmitoylethanolamide and polidatina. Presented at the 16th world congress for child and adolescent gynaecology, Montpellier, 2010 |

n=40, adolescent women suffering from dysmenorhoe, menstual pains, without organic diseases. Open study. Treatment with een PEA-houdend product 400 mg twice daily resulted in a marked decrease of pain in 70% of all women.

22. Murina F. et al. Palmitoylethanolamide and polidatina in the treatment of vestibulodynia, and the reduction of the C fibre activation. Presented at the world congress of pathology of the vulva, Parigi, september 2011 |

n=20, female suffering from vestibulodynia, placebo controlled, randomized trial: arm 1: placebo and TENS, arm 2 een PEA-houdend product (400 mg twice daily) and TENS.  

The active group achieved more pain reduction after 60 days compared to the placebo group, and CPT measurements showed a decrease in hypersensitivity of the C fibres in the een PEA-houdend product group. 

23. Palomba R et al. PEA and polidatin in pelvic pains. Presented at 64th congress SIAART, Parma, 2010.

The study includes 25 female patients aged 25 to 45 years; 15 suffered from endometriosis , 6 from interstitial cystitis, and 4 from dysmenorrea. All patients were non-responders to the classic treatment (hormon therapy, antibiotics) and common analgesics( Non Steroidal Anti-Inflammatory Drugs -NSAIDs and paracetamol).Non-responders were also defined as patients with pain VAS > 5.

Palmitoyl ethanolamide (PEA) + polydatina was administered for 40 days at a dose of 200mg+20mg three times daily . The patients could take NSAIDs or paracetamol as needed. For each patient we recorded the pain intensity through VAS score at recruitment (T0), after15 (T1), 30 (T2), 60 (T3) days. We also considered the weekly subministration mean number of NSAID/paracetamol before the study(T0) and during follow up. Means VAS at T1 T2 T3 were compared to mean VAS at T0.

The results clearly demonstrated a decrease of mean pain as well as a relevant decrease in concommitant medication. Mean VAS pain decreased from above 7 to below 2, a robust > 50% pain decrease, hand in hand with nearly stopping of all other analgesics.

PEA in pain in dentistry

24. Christian Bacci, Giulia Cassetta, Bruno Emanuele, and Mario Berengo | Research Article Randomized Split-Mouth Study on Postoperative Effects of Palmitoylethanolamide for Impacted Lower Third Molar Surgery | Volume 2011: Article ID 917350, 6 pages doi:10.5402/2011/917350

A randomized, split-mouth, single-blind study was conducted on 30 patients between 18 and 30 years of age requiring lower third molar extraction. Patients underwent bilateral extractions in a randomized sequence, one extraction being performed under een PEA-houdend product treatment. The een PEA-houdend product treatment involved 2 tablets a day for 15 days. The parameters assessed at each procedure were trismus, swelling, pain, NSAID consumption, postoperative complications, drug tolerability, and safety.

Results. Perceived postoperative pain was reportedly significantly milder on een PEA-houdend product treatment than control. The trend of the means differed over time ( P < . 0 0 0 1 ) and between the two extraction groups ( P < . 0 2 2 1 )On the other hand, for edema and trismus, the trend differed over time for both groups but did not differ between the two groups.

Conclusions. Administering een PEA-houdend product improves the postoperative course—in terms of pain—after lower third molar extraction. [4]

Palmitoylethanolamide cream in eczemata and dermatology

25. Eberlein B, Eicke C, Reinhardt HW, Ring J. | Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). | J Eur Acad Dermatol Venereol. | 2008 Jan;22(1):73-82.

A multinational, multicentre, observational, non-controlled, prospective cohort study, patients between 2 and 70 years of age were enrolled. All patients were supplied with the palmitoylethanolamide. Outcome was followed in periods between 3 and 7 days and 4 and 6 weeks after study start. Data were gathered from doctor reports and patient self-assessments via patient questionnaires.


Patients reported a reduction of pruritus on visual analogue scales from 4.9 +/- 2.6 to 2.7 +/- 2.4 6 days after treatment start and a further reduction to 2.0 +/- 2.3 at study end (P < 0.001 each). Likewise, sleep quality improved significantly during the study period.

Earlier-used topical corticosteroids were omitted by 56% of all patients (53.4% in adults and 62.5% in children) at study end, and the average weekly application rate decreased by 62% from 7.9 +/- 6.0 to 3.0 +/- 5.1 (P < 0.001). The tolerance was assessed as very good or good in 92% of cases by both patients and doctors.

Conclusion: Palmitoylethanolamide gave substantial relief of objective and subjective symptoms of atopic eczema after regular skin care. The patient-related effectiveness (decline of pruritus and loss of sleep) indicated a gain in quality of life in these patients. The reduced use of topical corticosteroids is important in view of safety and pharmacoeconomic implications in the treatment of atopic eczema. [5]

26. Kircik L. | A nonsteroidal lamellar matrix cream containing palmitoylethanolamide for the treatment of atopic dermatitis. | J Drugs Dermatol. | 2010 Apr;9(4):334-8.  [6]

27. Pulvirenti N, Nasca MR, Micali G. | Topical adelmidrol 2% emulsion, a novel aliamide, in the treatment of mild atopic dermatitis in pediatric subjects: a pilot study. | Acta Dermatovenerol Croat. | 2007;15(2):80-3.

28. Petrosino S, Cristino L, Karsak M, Gaffal E, Ueda N, Tüting T, Bisogno T, De Filippis D, D’Amico A, Saturnino C, Orlando P, Zimmer A, Iuvone T, Di Marzo V. | Protective role of palmitoylethanolamide in contact allergic dermatitis. | Allergy. | 2010 Jun 1;65(6):698-711. Epub 2009 Nov 11. [7]

29. Kemeny L, Koreck A, Kis K, Kenderessy-Szabo A, Bodai L, Cimpean A, Paunescu V, Raica M, Ghyczy M. | Endogenous phospholipid metabolite containing topical product inhibits ultraviolet light-induced inflammation and DNA damage in human skin. | Skin Pharmacol Physiol. | 2007;20(3):155-61. Epub 2007 Jan 17.

30. Jorge LL, Feres CC, Teles VE. | Topical preparations for pain relief: efficacy and patient adherence. | J Pain Res. | 2010 Dec 20;4:11-24.

PEA in glaucoma and eye disease

31. Pescosolido N, Librando A, Puzzono M, Nebbioso M. | Palmitoylethanolamide Effects on Intraocular Pressure After Nd:YAG Laser Iridotomy: An Experimental Clinical Study. | J Ocul Pharmacol Ther. | 2011 Aug 10.

n=15, patients underwent bilateral laser iridotomy for the prevention of primary closed-angle glaucoma. The IOP was measured at the beginning of the study (t-1), after 15 days of pretreatment with placebo or PEA (t0), and at 15, 30, and 120 min after the iridotomy (t1, t2, t3). Pretreatment: 2 tablets of placebo or PEA per day for 15 days.

Results: The t-test did not show a significant difference between the preoperative mean values of IOP t-1 and t0 in both the pretreatments. Analysis of variance/Tukey’s test pointed out a significant increase of the postoperative IOP values in placebo pretreated patients (P≤0.05), but not in those who were pretreated with PEA. The trend analysis confirmed the significant positive trend in placebo pretreatment. The parallelism test between the 2 regressions showed a significant difference for the slopes (P=0.022) and not for the intercepts (P=0.520).

Conclusions: PEA can counteract the increase of IOP that occurs after iridotomy. It is likely that PEA controls the inflammatory process after iridotomy. [8]

32. Caterina Gagliano et al | Ocular hypotensive effect of oral palmitoylethanolamide: a clinical trial. | Invest. Ophthalmol. Vis. Sci. June 24, 2011 iovs.10-7057 |

In a prospective, randomized, double-blind, crossover clinical trial, 42 patients with POAG or OH who were treated with timolol 0.5% and whose IOP was between 19 and 24 mm Hg received oral PEA (300-mg tablets twice a day) or placebo (PEA vehicle tablets twice a day) for 2 months (period 1), and, after a 2-month washout, received the other treatment for 1 month (period 2). IOP, best-corrected visual acuity, and visual field parameters were considered.

Results: After PEA treatment (mean baseline IOP, 21.6 ± 1.7 mm Hg), IOP was reduced by 3.2 ± 1.3 mm Hg at 1 month and by 3.5 ± 1.2 mm Hg (15.9% ± 5.1%) at 2 months,  after placebo (mean baseline IOP, 21.5 ± 1.5 mm Hg), IOP was reduced by 0.4 ± 1.2 mm Hg at 1 month and by 0.3 ± 1.3 mm Hg at 2 months (t-test at both time points, P < 0.001 vs. PEA). No statistically significant vital signs, visual field, visual acuity changes, or adverse events were detected in either group.

Conclusion: PEA reduces IOP in patients with glaucoma and ocular hypertension. [9]

33. Pescosolido N, Puzzono M. | First clinical case of effective medical treatment of the vitreoretinal traction with recovery of the visual acuity. | Clin Ter. | 2010;161(4):e143-7.

Case report: Patient reported a significant eyesight reduction, metamorphopsia and photopsia. He underwent the following investigations, before and after medical treatment: visual acuity evaluation, dilated fundus examination, OCT.

Treatment: two tablets of PEA per day over 7 days. We observed that, while the visual acuity in the right eye was 2/10 compared to the initial 11/10, the dilated fundus examination highlighted a foveal hole. Moreover, the OCT confirmed the presence of a vitreomacular traction due to the incomplete posterior vitreous detachment.

At the end of the treatment with PEA, the visual acuity was equal to 8/10 and the OCT showed a disappearance of the hyperreflective streak with recovery of the physiological retinal and foveal profile. The therapy was eventually carried on for 10 more days with a final visual acuity of 10/10.

Conclusion: PEA orally administered, probably contributed, by anti inflammatory action, to the vitreolysis and thus to the disappearance of the vitreomacular traction and foveal hole with a subsequent recovery of the eyesight and of the metamorphopsia.  [10]


33. Phan NQ, Siepmann D, Gralow I, Ständer S. Adjuvant topical therapy with a cannabinoid receptor agonist in facial postherpetic neuralgia. J Dtsch Dermatol Ges. 2010 Feb;8(2):88-91. Epub 2009 Sep 10. [11]

Appendix: early clinical studies in last century


Findings that egg yolk as a sort of ‘medical diet-food avant la lettre’ could keep away infections stems from more than half a century ago. Research on palmitoylethanolamide (PEA) has been conducted now for more than 50 years. In former Tsjechoslowakia, in the sixties and seventies, research has been done on PEA (under the brand name Impulsin) and its effects on the immune system in the flu, respiratory disorders and rheumatic fever.

Even earlier, in 1957 Kuehl and coworkers showed PEA to be a natural compound and PEA was isolated from foodproducts such as soybean lecithin, egg yolk and peanut meal. Several years earlier, in 1954 the first scientific report of an anti-inflammatory activity of PEA was made quite early by Coburn et al. They found the first food-related therapeutic effect, namely that egg yolk and alcohol-soluble fraction of egg-yolk could protect the guinea pigs from anaphylactic arthritis.

The Impulsin story

Masek4 Impulsin PEA een PEA-houdend productThe first studies on PEA (brandname at that time was Impulsin) have been focusing on respiratory tract infection.

34 and 35 In a paper 2 double blind controlled trials were described with in total 1345 healthy subjects, from which 41 subjects failed to complete the trial. [12]

The goal of these trials was to evaluate the prophylactic efficacy of Impulsin in upper respiratorytract infections. The persons had to take 600 mg PEA 3 times a day or placebo during 12 days. In the first trial 468 employees of the Skoda car fabrik were randomised.

The employees had to register the following symptoms: temperature of 37.5 °C or higher, headache, sore throat, myalgia, nasalstuffiness or discharge, productive or dry cough,malaise and fatigue, the impression to feel sick or healthy. In the second trial 918 voluteers from 16 to 18 years old living in one army unit were included. In this trial medical personel was registering the complaints. In a period of 8 weeks, the complaints in both groups were evaluated. Another analysis was done in the period of 6 weeks in which the first week and the last week was omitted.

Results: t the group of PEA had less numbers of episodes of fever, headache and sore throat, compared with placebo (18 versus 33). PEA had much less effect on symptoms such as nasal stuffiness, discharge and cough. The episodes of fever and pain were significantly reduced by 45.5% in the PEA group compared with the placebo group (p<0.05).

The beneficial effect of PEA was apparent from the second week of the trial. The total number of days was significantly reduced in the PEA group measured in the 6 and 8 week period. Comparable results were obtained in the second trial. In total 901 soldiers completed the trial. The incidence of disease in the PEA group was 40% lower in the 6 week period and 32% lower in the 8 week period (p<0.0005). The incidence rate of influenza A 2 England was 15.4% in the PEA group and 44.9% in the placebo group (p< 0.0002) [13]

Double blind study of palmitoylethanolamide in school children

36. n= 457, placebo controlled study with PEA examining the incidence of acute respiratory tract infections. Preformed in January 1976.[14]

In total 457 childern were divided into 2 groups: PEA 600 mg 2 times 2 tablets a day with an interval of 6 hours and placebo with the same regime. In the PEA 169 children and placebo 224 children were included. The included children had the age between 11 and 15 years. They received 10 days their tablets at school, so that means that in the weekend they didn’t receive the study medication. Childern were excluded when they became ill in the first 5 days, or did not take their medication. In total 64 children were excluded. Blood samples were taken before the study and 8 weeks later in 65% of the children. Also bacteriological examination was preformed form the nose samples.

Results: in the 8 weeks from the start of the study, the children from the PEA group had 15.7% less acute respiratory tract infections than the control group. Younger children (from 11 to 13 years) this difference was even more pronounced: 25.5%. Though these differences were not statistically significant. The reason could be the short duration of the intake and/or not preforming the study in the epidemic flue period The duration of the illness was not influenced by PEA.

37. Even earlier, in 1960, Coburn and Rich conducted a small clinical study evaluating the ability of PEA to prevent rheumatic occurrences in children with rheumatic fever. The results were difficult to interpreted, due to the low incidence of rheumatic occurrences in all the children possibly as a result of a better general diet (not the due to consumption of eggs) during the test period. (ref not in pubmed: Coburn, A.F., Rich, H. Arch. Interam. Rheumatol. 1960, 4, 498-515)

Working mechanism of palmitoylethanolamide according to old studies

It was not clear how PEA works.

37. n= 50. A studie evaluating the effect of PEA on several proteins and the phagocytic activitly of leucocytes, (white blood cells). A group of 50 children, 4 years old, received 30mg per kg PEA a day during 19 days. [15]

The following molecules were measured before and after PEA in the blood: albumin, orosomucoid, ceruloplasmin, transferin, C3 and C4 complements, and G, A, M and D immunoglobulins. Phagocytic activity was measured with the photometric tetrazolium test. Significance (p<0.05) was obtainted for the fall of C3 complement (80.9 ± 13.3 versus 76.4 ± 12.2) and an increase in IgG (75.1 ± 16.1 versus 79.0 ± 16.6)The "spontaeous" metabolic activity of unstimulated neutrophilic granulocytes showed a significant increase after PEA.

38. n=18. A group of 18 children between 5 and 7 years old was given PEA 30mg/kg/day during 12 days. [16]

The T and B lymphocytes were counted in the blood before and after the treatment of PEA. PEA did not affect significantly the absolute numbers of the lymphocytes, but did change the percentual proportion of the lymphocytes. The percetual proportion of the T lymphocytes was significantly reduced (56.84 ± 6.12 versus 50.64 ± 9.24 p<0.05), while the proportion of the B lymphocytes was increased (3.73 ± 1.55 versus 4.62 ± 1.87 p<0.075).

Also animal studies on the effect of PEA have been done. For example the study of PEA in rats with leukemia next to chemotherapy.[17]  This animal study revealed that PEA reduced side effects of the chemotherapy which anabled to give higher dosages. PEA did not have direct effect on cancer. [18]

Further historical sources of PEA as medical active food

Kuehl, F.A.; Jacob, T.A.; Ganley, O.H.; Ormond, R.E.; Meisinger, M.A.P. J.Am.Chem. Soc. 1957, 79, 5577-5578.

Coburn, A.F., Graham, C.E., Haninger, J. J. Exp. Med. 1954, 100, 425-435.

Compiled by prof. dr. Jan M. Keppel Hesselink, MD, PhD, december 2011