Giorn. It. Ost. Gin. Giornale Italiano di Ostetricia e Ginecologia CIC Edizioni Internazionali 2014 March-April; 36(2): 353–358. ISSN: 0391-9013
Published online 2014 May 30.

Use of micronized palmitoylethanolamide and trans-polydatin in chronic pelvic pain associated with endometriosis. An open-label study

A. DI FRANCESCO and D. PIZZIGALLO

Hospital “F. Renzetti”, Lanciano (CH), Italy

Corresponding author: Antonio Di Francesco, e-mail: a.di.francesco@alice.it

Summary

Aim.
The purpose of this pilot study was to evaluate the efficacy of treatment with micronized palmitoylethanolamide (PEA-m®)+trans-polydatin (food for special medical purpose) on chronic pelvic pain related to endometriosis, in comparison to usual hormonal therapies. The chance to get pregnant during PEA-m®+ trans-polydatin treatment was also evaluated.

Methods.
Thirty outpatients of reproductive age with a history of chronic pelvic pain associated to endometriosis were randomly assigned to three groups of 10, who underwent a 6-month treatment with: PEA-m®+trans-polydatin, leuprorelin acetate or ethinylestradiol + drospirenone. Chronic pelvic pain, dysmenorrhea, dyspareunia and Quality of Life were assessed monthly using the Numeric Rating Scale (NRS) and the SF12 questionnaire.

Results.
Painful symptom intensity significantly decreased over time in all three groups, irrespective of the treatment applied. In the PEA-m® + trans-polydatin group one patient withdrew due to pregnancy.

Conclusions.
In spite of the study’s limited sample size, the data demonstrate that PEA-m®+trans-polydatin is as effective as hormonal therapy in reducing painful symptomatology related to endometriosis in patients of reproductive age, without anti-ovulatory effects. While further investigation is warranted, these results suggest the therapeutic use of PEA-m®+trans-polydatin in chronic pelvic pain due to endometriosis, especially in patients who wish to conceive.

The treatment of chronic pelvic pain due to endometriosis in reproductive-age women with PEA-m® + trans-polydatin reduces pain intensity as the hormonal agents without suppressing ovulation, allowing to conceive where possible and showing excellent tolerability.

Keywords: Endometriosis, Chronic Pelvic Pain, Micronized Palmitoylethanolamide + trans-Polydatin, Pregnancy

Keywords: Endometriosi, Dolore Pelvico Cronico, Palmitoiletanolamide micronizzata + trans-Polidatina, Gravidanza

Introduction

Endometriosis is an estrogen-dependent pathological disorder with multifactorial etiology, affecting 15–20% of child-bearing age women (1). Clinically, endometriosis is characterized by chronic, non-cyclic pelvic pain, deep dyspareunia, dysmenorrhea, and perimenstrual, intestinal or urinary painful symptoms caused by chronic inflammatory reactions. This condition can often make it harder to conceive. While women with endometriosis are more likely to experience difficulty in becoming pregnant, the exact cause of infertility remains unknown (2). Endometriosis is treated by conservative surgical removal of the endometrial tissue or, alternatively, with hormonal agents to induce hypoestrogenism and atrophy of ectopic endometrial implants. Oral contraceptives, androgenic agents, progestins, and gonadotropin releasing hormone (GnRH) analogs, aromatase inhibitors, and anti-inflammatory drugs have all been used successfully in reducing the pain symptoms associated with endometriosis (3, 4) with an overall improvement in the quality of life. However, such therapies carry the risk of undesirable, sometimes severe, side-effects, and there is no evidence for benefit of ovulation suppressants in sub-fertile women with endometriosis who wish to naturally conceive (5, 6).

Among new therapeutic strategies aiming to control the symptomatic pain associated with endometriosis, micronized palmitoylethanolamide (PEA-m®; particle size 2,0÷10,0)+trans-polydatin (a Food for Special Medical Purpose) has been proposed. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the family of fatty acid ethanolamides. The latter is a class of lipid mediators which exert analgesic, anti-inflammatory and neuroprotective effects on several molecular targets in both the central and peripheral nervous systems, as well as in the immune system (7, 8). Three non-mutually exclusive mechanisms have been proposed to explain the analgesic and anti-inflammatory effects of PEA. The first suggests that PEA acts by down-regulating mast-cell degranulation (9). The “entourage effect” instead, postulates that PEA acts by enhancing the anti-inflammatory and anti-nociceptive effects exerted by anandamide, which is often produced together with PEA, and activates cannabinoid CB1 and CB2 receptors and/or transient potential vanilloid receptor type 1 channels. Finally, it has been demonstrated that some anti-inflammatory actions of PEA are mediated by a direct activation of the nuclear peroxisome proliferator-activated receptor alpha and cell membrane receptors (1012).

Clinical studies have shown that micronized PEA (PEA-m®) and ultra-micronized PEA (PEA-um®; particle size 0,8÷6,0) reduces chronic pain in patients suffering from various pathological conditions (1318). Importantly, PEA-m® in association with trans-polydatin [a natural glucoside of resveratrol, endowed with anti-oxidant properties (19, 20)] markedly reduced chronic pelvic pain associated with endometriosis either alone or in combination with hormonal or anti-inflammatory drugs (16, 17). Its analgesic effect was more effective than placebo (18).

These observations prompted us to verify the effectiveness of PEA-m®+trans-polydatin in controlling the painful symptomatology associated with endometriosis, in comparison to hormonal drugs. This study was also intended to explore if this treatment could adversely affect ovarian function in women with endometriosis who wish to naturally conceive.

Materials and methods

The study was conducted as an open-label, randomized three-arm trial with PEA-m® +trans-polydatin compared to traditional hormone therapies used for treatment of chronic pelvic pain associated with endometriosis. Its purpose was to compare efficacy of treatment with PEA-m®+trans-polydatin against that obtained following administration of estroprogestinics and/or GnRH analogues. Thirty women of reproductive age with a history of chronic pelvic pain associated with endometriosis diagnosed according to ESHRE (Special Interest Group for Endometriosis and Endometrium) guidelines (21) and based upon localization, extent and severity of the endometrial lesions, and histological examination of samples, were recruited. The study was conducted in the outpatient clinic of the Division of Obstetrics and Gynecology, Lanciano Hospital (Chieti, Italy) between December 2009 and January 2011.

Patient selection was based on a diagnosis of endometriosis made by an accurate clinical evaluation to assess the presence of symptoms (chronic pelvic pain, dysmenorrhea, deep dyspareunia, pain associated with ovulation, perimenstrual symptoms) and signs (pelvic tenderness, fixed retroverted uterus, tender uterosacral ligaments or enlarged ovaries), and by a laparoscopic examination performed after a period of at least three months without therapies. Furthermore, the inclusion required a score ≥ 5 for at least one painful symptom on the Numeric Rating Scale (NRS).

For the purpose of understanding the “responder” status of the patient, information concerning the outcome of the previous therapies for endometrial pain was collected.

Exclusion criteria included patients with: i) uncertain diagnosis of endometriosis; ii) presence of concomitant pathological conditions unrelated to chronic pelvic pain of endometriosis; iii) menopause. Patients who had participated in other clinical studies in the preceding 3 months were also excluded.

After being fully informed as to the purpose of the study, written consent for participation was obtained from each patient. The study was conducted according to the ethical principles as stated in the Declaration of Helsinki. The study protocol, together with documentation indicating adherence to Good Clinical Practice was communicated to the Hospital’s Health Authority.

Prior to inclusion in the study, all patients underwent a detailed evaluation of the intensity of pelvic pain, dysmenorrhea, dyspareunia, dyschezia and dysuria by the NRS and of Quality of Life using the SF-12 questionnaire. The NRS is a very simple but useful instrument to monitor pain intensity and its modification with time. It consists of a 11-point grading scale (0–10), where a score of 0 represents total absence of pain and 10 corresponds to the presence of the worst pain imaginable. All patients were asked to rate their pain intensity on a scale of 0 to 10. The SF-12 questionnaire is intended to rate patient quality of life, both mental (Mental Component Summary: MCS-12) and physical (Physical Component Summary: PCS-12), both of which change over time. This questionnaire reports patient state of health perception; all patients were instructed on how to carry out self-evaluation for the questionnaire, and were reminded upon every control visit. Patients were divided into 3 groups of 10 each, using a computer-generated randomization list with the following treatment regimens. Group A patients received PEA-m®+trans-polydatin (PELVILEN®400mg +40mg - Epitech Group S.r.l.), 1 tablet/twice daily, for 6 months; group B patients received leuprorelin acetate (Enantone®11.25mg/2ml -Takeda Pharmaceutical Company), one vial every three months (so as to cover the entire observation period equal to 6 months); group C patients received 1 tablet/day of ethinylestradiol + drospirenone (Yasmin® 0.03mg +3mg - Bayer S.p.A.) for 6 months.

During the entire period of treatment patients were subjected to monthly follow-up. Outcome parameters were the NRS and SF-12 questionnaire. At each follow-up, patients were also assessed for treatment tolerability, possible side effects, and adherence to the protocol.

Statistical analysis on ITT (Intention To Treat) patient was carried out using repeated measures ANOVA for unequal variance.

Results

All enrolled patients completed the 6-month treatment with exception of one patient in group A, who left the study due to pregnancy.

Patients with diagnosis of mild or moderate endometriosis (stage II or III) ranged in age from 21 to 44 years. Average ages were 33.9±1.6, 27.9±1.5 and 31.4±0.9 years for groups A, B and C, respectively. Patient characteristics are summarized in Table 1. Mean age was statistically different among the three groups (p<0,0178), and was always included as covariate in all analyses although showing no significant effect.

TABLE 1TABLE 1
BASELINE CHARACTERISTICS OF PATIENTS.

Fifty-three percent of the patients had previously undergone one or more cycles of hormone therapy for chronic pelvic pain associated with endometriosis, while 36% had used anti-inflammatory drugs. These symptoms showed a significant improvement compared to baseline over the 6-month treatment course in all groups treated with PEA-m®+trans-polydatin, leuprorelin acetate and ethinylestradiol + drospirenone, respectively (p<0.0004, p<0.0001 and p<0.0356). These symptomatology improvements did not correlate of age, type of treatment and time of onset of pathology. Moreover, the effects over time of the three treatments did not differ significantly from each other (Figure 1).

Figure 1Figure 1
Painful symptom scores in women suffering from endometriosis.

The scores obtained in questionnaire SF-12 showed that in PCS-12 (physical activities) were significantly improved in all the 3 groups at treatment end in comparison to baseline (p<0.0001; Figure 2) while MCS-12 (mental and emotional component) appeared to be significantly reduced (p < 0.0001) at treatment end only in group A. In fact, the ANOVA analysis of MCS-12 showed a significant difference (p<0.0453) across all groups over time in favor of group A (Figure 2). This difference was also confirmed by the Tukey Kramer adjusted test.

Figure 2Figure 2
Quality of Life (SF-12 questionnaire) of women suffering from chronic pelvic pain due to endometriosis.

No relevant adverse events were observed in the course of this study in any treatment group.

Discussion and conclusions

The results obtained in the present study demonstrate that pain relief elicited by treatment with PEA-m®+trans-polydatin is similar to that obtained with hormonal therapy. The occurrence of pregnancy in one patient under treatment with PEA-m®+trans-polydatin suggests that this therapy does not interfere with ovulation.

Endometriosis is a complex and chronic disease that manifests as pelvic inflammatory reactions, chronic pelvic pain and sub-fertility. Current therapeutic approaches are hormone-based and intended to introduce a hypo-estrogenic state. These include GnRH analogues and oral contraceptives, progestogens and anti-progestogens, all of which produce an efficacious, albeit temporary reduction in endometrial tissue mass and pelvic pain. Because these therapies inhibit ovulation and interfere with the cyclic remodeling of the endometrium, the onset of pregnancy is impossible (22).

PEA-m®+trans-polydatin treatment is known to act mainly on mast cell-induced neuroimmune dysregulation. Increasing evidence points to chronic pelvic pain associated with endometriosis, being characterized by a strong involvement of mast cell distribution and function, with the potential for associated spinal and supraspinal alterations, as well (2326).

PEA-m®+trans-polydatin, by regulating mast cell recruitment/activation and microglia activation, may control peripheral inflammation together with both peripheral and central sensitization (26, 27). The present data confirm that targeting mast cell hyperactivity may reduce the intensity of painful symptomatology in patients with endometriosis as effectively as hormonal therapies, likely without interfering with ovulation processes.

In addition, the comparison with other therapies allow to establish that beneficial effects of PEA-m®+trans-polydatin are comparable to those obtained with the other two treatments, namely ethinylestradiol + drospirenone and leuprorelin acetate. Moreover, treatment with PEA-m®+trans-polydatin, unlike hormonal treatment, improves both quality of life components. These results, in line with experimental results obtained in a model of neuropathic pain (28, 29) suggest that PEA behaves not only as symptomatic but as a disease-modifying agent, capable of reducing the nervous tissue alterations responsible for pain.

Finally, the data obtained reveal that therapy with PEA-m®+trans-polydatin can control pain and allow pregnancy, given that one patient became pregnant during the treatment period. This patient experienced a problem-free pregnancy to term and gave birth to a healthy baby.

These results validate the high safety profile of PEA-m®+trans-polydatin, also when administered for long periods, as shown in previous clinical trials (16, 18).

In conclusion, the data reported here demonstrate that PEA-m®+trans-polydatin is as effective as hormonal therapy in reducing chronic painful symptomatology related to endometriosis in patients of reproductive age while devoid of anti-ovulatory effects. Given their preliminary nature, these observations merit confirmation with a larger sample size.

Acknowledgments

The Authors would like to thank Dr. Stephen D. Skaper for critical reading of the manuscript.

Footnotes

Disclosure

The Authors declare that no conflict of interest and no disclosure of information are associated with this manuscript.

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