WO2021028459A1 - Méthode de prévention ou de traitement de la douleur menstruelle chez des femmes souffrant de dysménorrhée par stimulation électrique - Google Patents

Méthode de prévention ou de traitement de la douleur menstruelle chez des femmes souffrant de dysménorrhée par stimulation électrique Download PDF

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Publication number
WO2021028459A1
WO2021028459A1 PCT/EP2020/072577 EP2020072577W WO2021028459A1 WO 2021028459 A1 WO2021028459 A1 WO 2021028459A1 EP 2020072577 W EP2020072577 W EP 2020072577W WO 2021028459 A1 WO2021028459 A1 WO 2021028459A1
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woman
vest
dysmenorrhea
pain
duration
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PCT/EP2020/072577
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English (en)
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Etienne L'hermite
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Diavein
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Publication of WO2021028459A1 publication Critical patent/WO2021028459A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0456—Specially adapted for transcutaneous electrical nerve stimulation [TENS]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A61N1/36021—External stimulators, e.g. with patch electrodes for treatment of pain

Definitions

  • the invention relates to the prevention and the treatment of menstrual pain in women suffering from dysmenorrhea.
  • Dysmenorrhea is defined as the presence of painful cramps of uterine origin that occur during menstruations. The pain is generally concentrated in the lower abdomen or pelvis. The pain may be also felt in the right or left side of the abdomen and may radiate to the thighs and lower back. Other disorders often co-occur with menstrual pain such as nausea and vomiting, diarrhea or constipation, headache, fatigue, mood disorders and sleep disorders. In certain women, dysmenorrhea can begin before menstruation occurs and even just after ovulation. Dysmenorrhea represents one of the most common causes of pelvic pain and menstrual disorder. The estimated prevalence of dysmenorrhea is high in particular in adolescents. As of today, it is difficult to determine the actual prevalence of dysmenorrhea because pain during menstruation is considered as a normal aspect of the menstrual cycle and therefore women do not consider useful to report it and to seek medical care.
  • dysmenorrhea can be debilitating and psychologically taxing for many women. Indeed, some women have very severe pain, severe enough to render them incapacitated for 1 to 3 days, every menstrual cycle, requiring absence from school or work. Consequently, dysmenorrhea can have a dramatic impact on women’s quality of life (Bernardi M, et ah, FlOOOResearch 2017, 6(F1000 Faculty Rev): 1645).
  • Dysmenorrhea is classified as primary dysmenorrhea (menstrual pain without organic disease) or secondary dysmenorrhea (menstrual pain associated with underlying pelvic pathology).
  • Secondary dysmenorrhea has a specific underlying cause, typically a condition that affects the uterus or other reproductive organs.
  • the most common disorders associated with secondary dysmenorrhea are endometriosis and adenomyosis.
  • Other gynecological conditions can also cause secondary dysmenorrhea and include ovarian cysts, uterine fibroids, uterine or cervical polyps, cervix stenosis and pelvic inflammatory disease.
  • the first line of treatment to manage the menstrual pain is non-steroidal anti-inflammatory drugs (NSAIDs). These medications work through the inhibition of the production and release of prostaglandins which are believed to be responsible for the painful uterine contractions and associated systemic symptoms such as nausea and diarrhea.
  • the second line of treatment is oral contraceptives.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the necessity of daily medication to prevent symptoms for one or two days a month makes them too cumbersome as a first-line choice compared with NSAIDs, unless birth control is sought.
  • Oral contraceptives prevent menstrual pain through a different mechanism than NSAIDs.
  • the action of oral contraceptives is twofold: reduction of menstrual fluid volume and suppression of ovulation. In some refractory cases, AINS and oral contraceptive pills are used in combination.
  • the invention relates to a method for managing dysmenorrhea in a woman, wherein the woman is subjected to vascular electrical stimulation therapy (VEST).
  • VEST vascular electrical stimulation therapy
  • the invention relates to a method for treating or preventing the onset of menstrual pain in a woman suffering dysmenorrhea, which comprises subjecting the woman to vascular electrical stimulation therapy (VEST).
  • VEST vascular electrical stimulation therapy
  • the woman can suffer from primary dysmenorrhea.
  • the woman suffers from secondary dysmenorrhea, preferably associated with adenomyosis, endometriosis, ovarian cysts and/or uterine fibroids.
  • the method of the invention may be an acute treatment, namely the woman is subjected to VEST upon the onset of menstrual pain.
  • the treatment may be performed chronically during the menstrual cycle of the woman.
  • the treatment with VEST may be repeated at least one time during the menstruation of the woman.
  • the woman is treated daily with VEST during the menstruation.
  • VEST treatment may enable to avoid any NSAID intake during the menstruation, for the alleviation of the menstrual pain.
  • VEST treatment may be the sole treatment administered to the woman to alleviate menstrual pain.
  • the woman is subjected to VEST prior to the menstruation, preferably within 15 or 7 days before her menstruation.
  • the woman is chronically treated with VEST, preferably at least once a month, at least once a week, every two days, or daily.
  • VEST may be performed regardless the occurrence of menstruation in the woman.
  • the chronic VEST treatment may be initiated during menses or no later than 7 days after the end of menses, and the woman may be subjected to a VEST session of 15 to 45 min every two days until at least to the next menses.
  • the woman may be chronically subjected to VEST treatment during at least 3 months.
  • the invention also relates to a method for improving the general condition in a woman suffering dysmenorrhea wherein the woman is subjected to a long-term treatment with VEST, preferably over at least three months.
  • a method is preferably for treating menstrual pain and at least one comorbidity disorder selected from nausea, vomiting, mood disorders, sleep disorders, and headache.
  • the woman is administered with an electrical periodic current having a frequency of at most 15 Hz, typically from 0.01 Hz to 15 Hz.
  • the periodic current is typically composed of electric pulses, the duration of each pulse being of at least 0.5 ms with a rise duration (T i) of at least 0.25 ms and a decrease duration (T2) of at least 0.25 ms.
  • Said electrical periodic current may be composed of unidirectional positive pulses, unidirectional negative pulses or streams of pulses which are alternatively negative or positive.
  • the electrical periodic current administered to the woman is composed of pulses and has at least one of the following features : the extinction duration (Ti)of the pulse is from 0.2 to 5-fold the rise duration (T2)of the pulse,
  • the rise duration (T 1) is of at least 0.25 ms and the decrease duration (T2) is of at least 0.25 ms the peak amplitude of the pulse is from -130 V to 130 V, the base width of the pulse is from 0.5 ms to 30 ms, and the period of the electrical current is from 100 ms to 5000 ms.
  • the pulses of the electrical periodic current may have an exponential-type waveform.
  • the electrical periodic current is administered to the woman by transcutaneous route.
  • Any kind of medical device for electrotherapy can be use to implement the methods of the invention.
  • the medical device preferably comprised at least two electrodes, which are disposed on the skin of the woman, in appropriate areas such as calves, wrists, forarms, shoulders, chest, feet and legs.
  • the medical device for electrotherapy comprises two electrodes, each electrode being positioned on a calf or a foot of the woman.
  • the duration of a VEST session is typically from 10 min to 1 hour, preferably from 15 min to 45 min.
  • a further aspect of the invention relates to the use of a nonsteroidal anti-inflammatory drug in combination with VEST for treating or alleviating menstrual pain in a woman suffering from dysmenorrhea.
  • the NSAID is preferably a propionic acid derivative, such as ibuprofen or flurbiprofen.
  • the woman may be subjected to a VEST treatment as defined above.
  • the invention further relates to the use of an electrical periodic current as described above for treating, alleviating or preventing the onset of menstrual pain in a woman suffering dysmenorrhea such as primary dysmenorrhea or from secondary dysmenorrhea preferably associated with adenomyosis, endometriosis, ovarian cysts and/or uterine fibroids.
  • dysmenorrhea such as primary dysmenorrhea or from secondary dysmenorrhea preferably associated with adenomyosis, endometriosis, ovarian cysts and/or uterine fibroids.
  • Figure 1A shows one pulse waveform according to the invention comprising an exponential rise part and an exponential decrease part.
  • U max refers to the amplitude of the pulse in V
  • To refers to the base width of the pulse (namely the duration of the pulse)
  • Ti refers to the rise duration of the pulse
  • T2 refers to the extinction (decrease) duration of the pulse.
  • Xi and X2 are the time constants of the exponential curves.
  • X-axis time (t) in ms.
  • Y-axis voltage (V) in volts.
  • Figure IB shows an example of positive and negative electrical pulses according to the invention for an electrical resistance of 2 1 ⁇ W.
  • the pulses have a base width of 2.8 ms, and an amplitude of +22 V or -22 V.
  • X-axis time (t) in ms.
  • Y-axis voltage (V) in volts.
  • Figure 1C shows an example of positive and negative electrical pulses according to the invention for an electrical resistance of 2 EW.
  • the pulses have a base width of 3.2 ms, and an amplitude of +62 V or -62 V.
  • X-axis time (t) in ms.
  • Y-axis voltage (V) in volts.
  • Figure 2 shows the visual analog scale (VAS) for pain used for assessing pain in the clinical studies.
  • Figure 3 illustrates the decrease of the number of patients treated with VEST still enduring menstrual pain over the time within a group of 22 women from Example 3.
  • VEST vascular electrical stimulation therapy
  • VAS visual analog scale
  • Example 3 the Inventor demonstrated the efficacy of preventive treatment with VEST in women with severe and recurrent dysmenorrhea. Short VEST sessions every two days enable to prevent the onset of severe pain during menses. A significant decrease in the duration and the severity of the pain episodes together with a significant reduction in NSAID consumption were observed in the menstrual cycle occurring after the VEST treatment as compared to that before.
  • VEST was effective to manage secondary dysmenorrhea caused by gynecological conditions such as endometriosis.
  • Example 4 showed that repeated treatment with VEST during the menstrual cycle enables to significantly manage severe menstrual pain in a woman suffering from grade-4 endometriosis.
  • VEST can be used as an “acute treatment” for effectively and quickly managing severe menstrual pain in patients with dysmenorrhea.
  • VEST can also be used as a “chronic”, “preventive” treatment of dysmenorrhea, e.g. in order to prevent the onset of, decrease the intensity and/or the frequency and/or the duration of, menstrual pains in patients suffering from dysmenorrhea, e.g. menstrual pains in patients with primary dysmenorrhea or with secondary dysmenorrhea such that associated with severe endometriosis.
  • VEST can be also used to decrease, and even delete, the consumption of painkillers and NSAIDS during menses in women with severe, recurrent dysmenorrhea.
  • the present invention relates to the use of vascular electrical stimulation therapy (VEST) for treating dysmenorrhea.
  • VEST vascular electrical stimulation therapy
  • VEST vascular electrical stimulation therapy
  • the present invention also relates to a method for treating dysmenorrhea in a woman in need thereof, which comprises subjecting the woman to a vascular electrical stimulation therapy.
  • the present invention also relates to a method for treating ; e.g. alleviating, decreasing the intensity and/or the duration and/or the frequency of, managing ; menstrual pains, preferably acute menstrual pain, in a woman suffering from dysmenorrhea, which comprises subjecting the woman to a vascular electrical stimulation therapy, preferably upon the onset of the menstrual pains.
  • the present invention also relates to a method for preventing the onset and/or decreasing the intensity and/or the frequency of menstrual pains in a woman suffering from dysmenorrhea which comprises chronically subjecting the woman to a vascular electrical stimulation therapy.
  • a further object of the invention is the use of a non-steroidal anti-inflammatory drug (NSAID) and/or oral contraceptive pill in combination with VEST for treating, e.g. alleviating, decreasing the intensity and/or the duration and/or the intensity, of menstrual pain in women suffering from dysmenorrhea.
  • NSAID non-steroidal anti-inflammatory drug
  • oral contraceptive pill in combination with VEST for treating, e.g. alleviating, decreasing the intensity and/or the duration and/or the intensity, of menstrual pain in women suffering from dysmenorrhea.
  • Another object of the invention is the use of a NSAID such as ibuprofen or flurbiprofen in combination with VEST for managing menstrual pain in a woman suffering from dysmenorrhea, wherein VEST enables to decrease the consumption of NS ATP necessary to alleviate menstrual pain over the menses in the woman as compared to that without VEST treatment.
  • VEST enables to decrease the consumption of NS ATP necessary to alleviate menstrual pain over the menses in the woman as compared to that without VEST treatment.
  • the consumption of NS ATP over the menses can be divided by at least 3- fold as compared to that without the VEST treatment.
  • Another object of the invention is the use of periodic electrical periodic current with low frequency (typically less than 15 Hz) to provide vascular electrical stimulation therapy in a woman suffering from dysmenorrhea, wherein vascular electrical stimulation therapy enables to treat, manage, or prevent the onset of, menstrual pains in said woman.
  • periodic electrical periodic current with low frequency typically less than 15 Hz
  • dysmenorrhea refers to a gynecological disorder characterized by the repeated presence of painful pelvic cramps of uterine origin that occur during menstruations. The pain is generally concentrated in the lower abdomen or pelvis. The pain may be also felt in the right or left side of the abdomen and may radiate to the thighs and lower back. Other disorders often co-occur with dysmenorrhea such as nausea and vomiting, diarrhea or constipation, headache, fatigue, mood disorders and sleep disorders. In certain women, the pelvic pain can begin before, and continue during menstruation. In some women, in particular in women with secondary dysmenorrhea (e.g. associated with endometriosis or ovarian cyst), the painful pelvic cramp can also occur around ovulation. In the context of the invention, “menstrual pain” refers to pelvic pain which are characteristic of dysmenorrhea.
  • Dysmenorrhea can be classified into primary dysmenorrhea and secondary dysmenorrhea.
  • Primary dysmenorrhea refers to dysmenorrhea which is not associated with any macroscopic pathology affected the pelvis, in particular the uterus, the ovaries and the cervix.
  • Primary dysmenorrhea occurs in the first few years after menarche. It is believed to affect as many as 50% of post-pubertal females.
  • Secondary dysmenorrhea refers to menstrual pain resulting from anatomic or macroscopic pelvic pathology. Secondary dysmenorrhea is more frequent in women aged 30-45 years. The most common disorders associated with secondary dysmenorrhea are endometriosis and adenomyosis. Other gynecological conditions which can also cause secondary dysmenorrhea include ovarian cysts or tumors, uterine fibroids, uterine or cervical polyps, cervix stenosis or occlusion, intrauterine adhesions, congenital malformations of the uterus, pelvic congestion syndrome and pelvic inflammatory disease.
  • the menstrual pain in women with secondary dysmenorrhea can begin before the period and continue several days during the period. Diagnosis of primary or secondary dysmenorrhea can be routinely performed by gynecological physicians and encompass questioning the patient about her health and family history and performing routine tests such as laboratory tests, abdominal or transvaginal ultrasonography, RMI, and less often hysterosalpingography, hysteroscopy, or laparoscopy.
  • prostaglandin F2a PGF2a
  • Elevated prostaglandins may also play a role in secondary dysmenorrhea, but by definition, concomitant pelvic pathology must be present.
  • a number of factors may be involved in the pathogenesis of secondary dysmenorrhea. Almost any process that can affect the pelvic viscera can produce cyclic pelvic pain.
  • menstrual pain refers to pelvic pain, more precisely to pelvic cramps of uterine origin, occurring around, typically during menstruations.
  • Severe dysmenorrhea refers to dysmenorrhea wherein the menstrual pain is acute or severe.
  • An acute or severe pain refers to a pain for which the subject needs medication.
  • An acute or severe pain generally refers to a pain of at least 4-cm, preferably of at least 6-cm, e.g. of at least 7, 8, 9 or even 10 in the visual analog scale as shown in Figure 2.
  • the pain score may be assessed using Numeric Rating Scale (NRS).
  • NRS Numeric Rating Scale
  • An acute or severe pain generally refers to a pain with a score of at least 4, preferably of at least 6, e.g. of at least 7, 8, 9 or even 10 in the NRS, said NRS being from 0 to 10, with 0 being no pain and 10 being “the worst pain imaginable”. It was shown that such NRS generally correlates well with the VAS.
  • the woman may be any woman of childbearing age suffering from dysmenorrhea, namely experimented repeated menstrual pains.
  • the woman is 12 to 45 aged, preferably from 14 to 45 aged.
  • the woman suffers from severe dysmenorrhea, namely repeated menstrual pains of more than 4, preferably at least 6 in VAS.
  • the woman has being suffered from recurrent dysmenorrhea, i.e. for at least 12 months.
  • the woman suffers from primary dysmenorrhea. In some further embodiments, the woman suffers from primary dysmenorrhea and is 12 to 30 aged.
  • the woman suffers from secondary dysmenorrhea.
  • said women is afflicted with one or more pelvic conditions selected from adenomyosis, endometriosis, ovarian cysts, uterine or cervix polyps and uterine fibroids.
  • the patient with secondary dysmenorrhea suffers from a pelvic pathology selected from adenomyosis, endometriosis, uterine fibroids and combinations thereof.
  • the woman can suffer from endometriosis, e.g. from grade-3 or grade-4 endometriosis.
  • treatment it is meant at least an amelioration of the symptoms associated with the pathological condition afflicting the subject, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., symptom, associated with the pathological condition being treated.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease or symptom thereof.
  • treating dysmenorrhea includes, without being limited to, decreasing the frequency of menstrual pain, decreasing the intensity and/or the duration of menstrual pain preferably to a level bearable for the subject, preventing the onset of menstrual pain, and/or deleting the presence of menstrual pain in the woman.
  • treating menstrual pain includes, without being limited to, alleviating menstrual pain e.g. decreasing the intensity and/or the duration of the menstrual pain, and/or completely curing said menstrual pain in the subject.
  • a reduction in pain or a decrease in pain intensity means decrease in the level or severity of pain experienced by a subject, as assessed by pain assessment tools known in the art, e.g. by the visual analog scale (VAS) as shown in Figure 2.
  • a decrease in pain intensity refers to a decrease of at least 1, e.g. of at least 2, 3, or 4 in VAS.
  • a decrease in pain intensity refers to decrease to a pain level bearable by the subject, e.g. to a pain score of at most 4 in VAS, preferably of at most 3, 2, or 1 in VAS, and even to the elimination of the menstrual pain in the subject.
  • “/he management of menstrual pain” includes the decrease of menstrual pain intensity for which the subject needs medication (e.g. a menstrual pain with a pain score in VAS higher than 4) to a level bearable by the subject without any medication or with a significant lower dose of medication such as NS ATP (e.g. to a pain level of less than 4 in VAS).
  • medication e.g. a menstrual pain with a pain score in VAS higher than 4
  • NS ATP e.g. to a pain level of less than 4 in VAS
  • a “ decrease in pain duration ” means that the duration of the menstrual pain is reduced as compared to previous menstrual pains experimented by the subject suffering from dysmenorrhea. In some embodiments, a decrease in pain duration results in menstrual pain with a pain score higher than 4 in VAS which lasts at most 4 hours, preferably at most 2, or at most 1 hour.
  • a “ decrease in menstrual pain frequency” means that the menstrual pain does not occur during every menstruation, and/or occurs with a magnitude in terms of duration and intensity lower than that previously experimented by the subject suffering from dysmenorrhea without being subjected to VEST treatment.
  • vascular electrical stimulation therapy refers to a therapeutic treatment based on the external and non-invasive administration of low-frequency electrical pulses able to stimulate vascular smooth muscle and/or vascular endothelium in the subject.
  • a low frequency electrical pulses refer to an electrical periodic signal having a frequency from 0.01 to 15 Hz, preferably from 0.1 to 10 Hz such as a frequency from 0.4 to 8.5 Hz, or from 0.5 Hz to 4Hz.
  • An appropriate frequency is for instance 1.6 ⁇ 0.2 Hz.
  • vascular electrical stimulation therapy is distinct from “ transcutaneous electrical nerve stimulation (TENS)” in terms of delivered electrical pulses and the stimulated tissue.
  • TENS transcutaneous electrical nerve stimulation
  • the target tissue is the vascular system, in particular vascular smooth muscle through the sympathetic nervous system and/or the vascular endothelium.
  • TENS the target tissue is the skeletal striated muscles through the somatic nervous system.
  • An electrical current appropriate to provide VEST in the subject according to the invention refers to a periodic current having a frequency and a pulse waveform able to stimulate the smooth muscle and/or the endothelium of the vascular tissue.
  • the electrical signal does not induce a significant stimulation of motor and/or sensitive nerves.
  • the periodic electrical current delivered to the subject can be composed of unidirectional positive pulses or, unidirectional negative pulses.
  • the periodic current is in the form of streams of pulses that are alternatively positive or negative.
  • the current delivered to the subject is composed of identical pulses.
  • alternating unidirectional positive pulses groups and unidirectional negative pulses groups may improve the efficacy in VEST.
  • the electrical current delivered to the subject consists in alternatively positive and negative streams of pulses.
  • Each stream comprises from 2 to 20, for instance from 6 to 10 identical pulses.
  • the periodic electrical current administered to the subject may be composed of the repetition of 8 positive pulses followed by 8 negative pulses.
  • the waveform of the pulses may be of any type with proviso that the duration of the pulse is of at least 0.5 ms with a rise duration (Ti) of at least 0.25 ms and a decrease duration (T2) of at least 0.25 ms.
  • Ti refers to the duration of the rise part of the pulse from the baseline to the pulse maximum peak.
  • T2 refers to the duration of the decrease part of the pulse from the pulse maximum peak to the baseline.
  • the waveform of the pulses is not squared or rectangular.
  • the electrical periodic current delivered to the subject is characterized by one or several of, preferably all, the following features : the pulse has a duration (namely a base width - To) from 0.5 ms to 30 ms.
  • the pulse duration is from 0.5 to 5 ms, for instance from 1.5 ms to 4 ms, or from 2.0 ms to 3.5 ms, such as from 2.1 to 2.8 ms.
  • the extinction (or decrease) duration (T2) of the pulse is from 0.2 to 5-fold, preferably from 0.5 to 1.5-fold the rise duration (Ti) of the pulse.
  • the two durations are equal.
  • the rise duration (Ti) of the pulse is at least 0.25 ms, preferably at least 0.5 ms, such as at least 0.6, 0.8, 1.0, 1.2 and 1.4 ms.
  • the decrease duration (T2) of the pulse is at least 0.25 ms, preferably at least 0.5 ms, such as at least 0.6, 0.8, 1.0, 1.2 or 1.4 ms.
  • the peak amplitude of the pulse (Umax) is from -130 V to 0 V or from 0 V to 130 V, preferably from -100 V to -10 V or 10 V to 100 V, such as from -10 V to -60 V or from 10 V to 60 V, e.g. such as -15 to -30 V or 15 to 30 V.
  • the period of the electrical current is from 100 ms to 5 000 ms, for instance from 120 ms to 2200 ms such as a period from 250 ms to 2000 ms. For instance, the period of the electrical current may be about 560 ms to 720 ms such as about 625 ms.
  • an appropriate electrical periodic current to provide VEST may be characterized by: a pulse duration from 1.5 ms to 4.0 ms a ratio of T2 to Ti from 0.5 to 1.5, a Ti of 0.5 ms to 2.0 ms a T2 of 0.5 ms to 2.0 ms a Umax from - 60 V to -10 V or from 10 V to 60 V, and a period from 560 ms to 720 ms.
  • Umax is from 10 V to 40 V or from -10 V to -40 V.
  • Umax is from 15 to 30 V or from -15 to -30 V such as from 20 to 25 V or from -25 to -20V.
  • the maximum intensity of the current (namely the intensity at the pulse peak) is at most 100 mA.
  • the peak intensity is at most 90 mA, preferably at most 80 mA.
  • the peak intensity may range from 0.5 mA to 60 mA, more preferably from 1 to 20 mA such as from 5 to 10 mA e.g. from 6 to 8 mA.
  • the waveform of the pulse is of the exponential type.
  • the pulse comprises an increase part and a decrease part which correspond to exponential curves.
  • An example of a pulse of the exponential type is shown in Figure 1A.
  • the electrical pulses of the current administered to the subject has : an rise part of formula (I) : a decrease (or extinction) part of formula (II) wherein U refers to voltage, t refers to time, Umax is the amplitude peak of the pulse, Ti is the duration of the rise part of the pulse and Xi and X2 refer to the time constants.
  • Xi is equal to X2.
  • Xi and X2 is from about 0.1 to about 0.8 ms.
  • Preferred Umax is from 15 to 30 V, such as from 20 to 25 V.
  • the invention also relates to the use of an electrical periodic signal having a frequency of at most 15 Hz, preferably from 0.1 to 10 Hz, to treat a subject in need thereof by vascular electrotherapy, so as to treat menstrual pain in a woman suffering from dysmenorrhea.
  • VEST may be performed with any medical device for delivering an electrical current able to stimulate the human vascular smooth muscle and/or the vascular endothelium in the subject though electrodes disposed on specific body area.
  • the medical device comprises at least two electrodes, because at least two electrodes should be positioned to enable the flow of electrical current through the subject’s body.
  • the administration of the electrical pulses is preferably performed by transcutaneous route.
  • the medical device comprises at least two electrode pads which are positioned on appropriate skin area of the subject’s body such as wrists, hands, calves, feet, legs, forearms, shoulders, scapula, chest and the like. For instance, the electrode pads can be positioned on each calf or each foot of the subject.
  • the first electrode pad can be positioned on the wrist (or the hand palm) or the shoulder and the second electrode pad can be positioned on the opposite calf or plant arch in the subject.
  • the first electrode pad can be positioned on the wrist (or the hand palm) or the shoulder and the second electrode pad can be positioned on the homolateral calf or plant arch in the subject.
  • the subject may have an electrode on each calf or on each foot. Such a positioning enables to stimulate the lower limbs and the small pelvis of the patients.
  • the subject may have a first electrode on the shoulder or the scapula and a second electrode on the contralateral foot or calf.
  • the subject may be in a lying position, in particular in supine position.
  • any medical electrotherapy device can be used in the context of the invention, with proviso that the device can deliver an appropriate electrical current as defined above.
  • the medical device may be as described in EP 0 137 007 or in US 5,725,563, the disclosure of which being incorporated herein by reference.
  • the medical device for administering the vascular electrical stimulation comprises an electrical current generator unit including (i) a mean for generating an electrical pulse current and (ii) a mean for controlling the generated electrical current, said electrical current-generating unit being connected to at least two electrodes or electrode pads adapted to be placed on the subject, preferably on the skin, and delivering electrical stimulation to said subject.
  • the mean for controlling the generated electrical current may enable to adjust the intensity, the shape, the frequency and/or the voltage of said current.
  • Said controlling mean may comprise a selector unit enabling to select the frequency, the pulse waveform, the pulse duration, the pulse amplitude, the intensity and/or the energy of the current, and/or preset programs able to control the delivery of preset electrical currents to the subject.
  • the medical device may comprise a measuring unit for measuring the subject-dependent electrical parameters, such as impedance, and a processing unit in communication with said measuring unit and the electrical current generator unit, whereby the electrical current delivered to the subject can be optionally adjusted depending on the measured subject- dependent electrical parameters.
  • a measuring unit for measuring the subject- dependent electrical parameters, such as impedance
  • a processing unit in communication with said measuring unit and the electrical current generator unit, whereby the electrical current delivered to the subject can be optionally adjusted depending on the measured subject- dependent electrical parameters.
  • the electrical current to deliver to the subject may be adjusted depending on the severity of the menstrual pain and the sensitivity of the subject to the vascular electrical stimulation
  • the pulse peak amplitude (Umax) may vary from one subject to another, depending on the subject impedance and the subject sensitivity to electrical stimulation.
  • the subject impedance may vary from 0.5 kW to 4 kW, typically from 1.5 to 2.5 kW.
  • Umax of the electrical pulse is typically less than 50V for an impedance of 2 kW measured between the electrodes.
  • a therapeutic electrical current corresponds to an electrical current able to induce a small muscle tremor at each electrode disposed on the subject.
  • the physician may determine the appropriate voltage of the current to deliver to the subject by gradually increasing the voltage of the electrical current while observing the reaction of the subject. At the beginning of the treatment, the physician may gradually increase the intensity of the electrical stimulations until the subject feels them. Then, the physician may let the subject subjected to said current during few minutes, for instance 10 minutes, to check that the subject does not feel any disorder or significant discomfort. The physician may then increase the stimulation until a very slight muscle tremor is observable at the skin area in the contact with the electrodes.
  • the physician decreases the energy level so as to obtain an electrical stimulation which is comfortable for the subject while providing a small muscle tremor at the electrodes
  • the physician can adjust the energy level of the electrical stimulation at the level previously identified as providing muscle tremor in subjects while being comfortable.
  • the regimen of the treatment depends on the therapeutic effect which is sought.
  • VEST can be used as an acute treatment in order to alleviate a menstrual pain experimented by a patient suffering dysmenorrhea.
  • the method of the invention is performed while the woman experiments menstrual pain.
  • the woman is subjected to VEST upon the onset of menstrual pain.
  • the VEST session may last from 10 min to 2 hours, typically from 15 min to 1 hour, for instance from 15 min to 45 min.
  • the duration of VEST may be adapted depending on the severity of the menstrual pain.
  • VEST may be sufficient to significantly alleviate the menstrual pain in some patients with dysmenorrhea. In some other patients, it may be needed to repeat VEST several times (e.g. 2, 3, 4 or 5 times) on the same day or the other day in order to obtain an appropriate alleviation of the pain (i.e. a menstrual pain score of at most 4-cm in VAS).
  • the subject may be subjected to vascular electrical stimulation treatment during 2 to 7 (e.g. 3, 4, 5 or 6) consecutive days, the daily number of VEST session being, e.g. from 1 to 4 sessions, e.g. in order to prevent the onset of new painful crisis.
  • the woman may be subjected to at least one daily session of VEST during her menstruation.
  • the total duration of VEST therapy per day may vary from a subject to another. However, a total daily VEST duration of at most 4 hours, such as a duration of at most 3 hours, 2 hours, 1 hour or 30 min may be sufficient for most of the subjects.
  • VEST was shown to alleviate menstrual pain in women suffering from severe dysmenorrhea in an effective and rapid manner, without any coadministration of NSAID. Accordingly, in some embodiments, the woman is not administered with any drug for alleviating pain, including NSAID.
  • the women treated with VEST is further administered with a NSAID.
  • the woman may be administered from 1 to 3 doses, preferably at most 1 dose, of NSAID daily until an appropriate alleviation of the menstrual pain is achieved.
  • a NSAID refers to a drug class of non-steroidal compounds able to reduce pain and to decrease fever and inflammation. These compounds can be classified depending on their chemical structure and their capacity to inhibit a cyclooxygenase. Cyclooxygenases 1 and 2 are the two main isoforms. Most NS A TPs are mixed inhibitors of the two isoforms. Five categories of mixed inhibitors may be defined: (1) propionic acid derivatives, (2) acetic acid derivatives; (3) fenamic acid derivatives; (4) salicylate derivatives; and (5) enolic acid derivatives (oxicams).
  • Acetic acid derivatives encompass diclofenac, indomethacin, tolmetin, sulindac, etodolac, ketorolac, aceclofenac, and nabumetone.
  • Propionic acid derivatives encompass ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin and loxoprofen.
  • Oxicams encompass piroxicam, meloxicam, tenoxicam, droxicam, lomoxicam, and phenylbutazone.
  • Fenamic acid derivatives encompass mefenamic acid and meclofenamic acid.
  • Salicylate derivatives encompass acetylsalicylic acid and diflunisal.
  • NS A IDs also encompass selective COX-2 inhibitors such as celecoxib, rofecoxib, and parecoxib, preferably celecoxib.
  • preferred NSAIDs are propionic acid derivatives, in particular ibuprofen and flurbiprofen.
  • the NSAID can be administered to the patient by any conventional routes such as the oral, rectal, or the parenteral route, for example by intravenous, intracutaneous or intradermal injection.
  • the NSAID is administered by oral route
  • the dose administered to the woman is generally from 1 mg to 800 mg, such as from 10 mg to 400 mg.
  • the combination of NSAID with VEST may enable to decrease the total dose of NSAID needed to alleviate menstrual pain.
  • VEST may enable to decrease by at least 3 fold the dose of NSAID to alleviate menstrual pain in a woman with dysmenorrhea.
  • ibuprofen is of at most 3 doses of 400 mg daily and that of flurbiprofen is of at most 3 doses of 100 mg daily.
  • a daily dose of at most 400 mg of ibuprofen or of at most 100 mg of flurbiprofen may be sufficient to alleviate menstrual pain in women with dysmenorrhea, when used in combination with VEST.
  • VEST can be used for prophylactic purpose, e.g. for preventing the onset of menstrual pain and/or decreasing the magnitude in term of intensity and duration of menstrual pain.
  • the subject can be subjected to chronic, long-term treatment.
  • Such chronic treatments may be beneficial in women with recurrent dysmenorrhea, e.g. who has being suffered from dysmenorrhea for at least 12 months.
  • the woman may suffer from secondary dysmenorrhea, with menstrual pains occurring during several consecutive days and beginning before periods.
  • Preferred secondary dysmenorrhea are associated with endometriosis and adenomyosis.
  • the woman is subjected to a long-term treatment for treating dysmenorrhea, which means that the woman is chronically subjected to VEST during at least 2 weeks, 1, 2 or 3 months, e.g. during at least 6 months such as at least 1, 2 or 3 years.
  • the woman suffering from dysmenorrhea is subjected to at least one VEST session within few days before the presence of menstrual pain, e.g. before the expected date of her menstruation.
  • the woman may be subjected to at least one VEST session within 15 days, e.g. within 10, 7, 6, 5, 4, 3, 2 or the day before her expected date of menstruation.
  • the woman may be subjected to at least one VEST session every day or every two days during 14 or 7 days before the expected date of menstruation.
  • Each VEST treatment can last from 10 minutes to 2 hours, preferably from 15 min to 45 min.
  • the position of the electrodes can be changed for each session.
  • the treatment of VEST can be extended during the period. Accordingly, the woman may be further subjected to at least one VEST session during her menstruation.
  • Such an additional VEST session may be prophylactic or may be performed to alleviate a menstrual pain occurring in the woman during said menstruation.
  • the VEST treatment begins few days after the end of menses and is performed until the next menses.
  • the VEST treatment can begin 1, 2, 3, 4, 5, 6, or 7 days after menses.
  • the woman can be subjected to a VEST session every day or every two days until the next menses.
  • the VEST session typically lasts from 10 min to 1 hour, preferably from 15 min to 45 min such as 30 min.
  • the VEST treatment can continue during the menses or restart few days after the end of the menses (e.g. 1, 2, 3, 4, 5, 6, or 7 days).
  • the woman suffering from dysmenorrhea is subjected to VEST treatment chronically, regardless the expected date of her menstruations.
  • the subject is subjected to VEST at least once a month, e.g. at least once a week, at least twice a week, every two days or daily.
  • the treatment can be repeated during at least 1, 2, 3, 4, 6, 8, 10, 12 months or at least 1, 2 or 3 years.
  • the VEST session typically lasts from 10 min to 1 hour. For instance the woman may be subjected to one VEST session every week, twice a week, every two days or every day.
  • a preferred frequency of treatment is every day or every two days.
  • the treatment of the invention comprises subjecting the woman suffering from dysmenorrhea to a VEST session every two days.
  • the VEST session preferably lasts from 10 min to 1 h, more preferably from 15 min to 45 min, e.g. 30 min.
  • the VEST treatment can be initiated preferably during menses or few days after menses (e.g. 1, 2, 3, 4, 5, 6, or 7 days after menses).
  • the VEST treatment can be performed at least until the onset of the next menses.
  • Such a chronic VEST treatment is preferably performed over several months (e.g. during at least 2, 3, 4, 5, or 6 months), preferably without any interruption.
  • the daily duration of VEST depends on the therapeutic effect which is sought.
  • the total duration of VEST therapy per day may vary from a subject to another. However, a total daily VEST duration of at most 4 hours, such as a total daily duration of at most 3, 2 or 1 hour(s) may be sufficient for most of the subjects.
  • the VEST session may last from 10 min to 2 hours, typically from 15 min to 1 hour, for instance from 15 min to 45 min such as about 30 min.
  • Oral contraceptive encompasses progestogen-only pill (e.g. desogestrel pill) as well as combined oral pill comprising an estrogen such as ethinyl estradiol together with a progestogen such as levonorgestrel.
  • progestogen-only pill e.g. desogestrel pill
  • combined oral pill comprising an estrogen such as ethinyl estradiol together with a progestogen such as levonorgestrel.
  • the woman is not subjected to any contraceptive treatment, in particular to any oral contraceptive.
  • the methods of the invention may also enable to alleviate comorbidity disorders occurring with menstrual pain, especially in women with primary dysmenorrhea.
  • Such disorders encompass, without being limited to, nausea and vomiting, diarrhea or constipation, headache, fatigue, mood disorders and sleep disorders.
  • the invention relates to a method for improving the general condition, or for treating one or several comorbidity disorders in a woman suffering from dysmenorrhea wherein the woman is subjected to VEST, preferably chronically as described above.
  • the invention also relates to the use of VEST, an electrical current as defined above or an electrotherapy device as defined above for improving the general conditions and/or one or several comorbidity disorders in a woman suffering from dysmenorrhea.
  • Example 1 General protocol of Vascular Electrical Stimulation Therapy (VEST) for the management of dysmenorrhea
  • the clinical dose of electrical stimulation refers to an electrical stimulation sufficient to induce a small muscle tremor at each electrode while being comfortable for the subject.
  • the treatment is carried out very gradually as regards to the increase in energy.
  • the physician gradually increases the electrical stimulations until the subject feels them.
  • the physician lets few minutes (e.g. minutes) elapse to ensure that the subject feels no disorder or significant side effects.
  • the physician then increases the stimulation until a very slight muscle tremor in tissues located in the contact of the electrodes is observable. If the subject complains about the stimulation, the physician decreases the energy level so as to obtain an electrical stimulation which is comfortable for the subject.
  • the physician can adjust the energy level of the electrical stimulation at the dose identified as providing muscle tremor in subjects while being comfortable (clinical dose).
  • the medical device used to deliver the Vascular Electrical Stimulation Therapy is a Diavein device commercialized by the company CT Sciences SA (Switzerland).
  • CT Sciences SA Scwitzerland
  • the current delivered to the subject for treating dysmenorrhea ranges from 20 to 30V at a 1.6Hz on a 1500 to 2500W impedance measured between the electrodes.
  • the intensity is from 6 to 8 mA.
  • the electrical pulse of the signal has an exponential-type waveform as defined in Figure 1A.
  • the duration of the pulse is from 2.3 ms to 2.7 ms.
  • the electrical current comprises unidirectional positive pulses group followed by unidirectional negative pulses group.
  • the VEST treatment begins upon the onset of the menstrual pain.
  • the patient is in supine position.
  • An electrode is positioned on each calf of the patient.
  • the VEST treatment typically lasts from 25 min to 45 min.
  • Example 2 Preliminary controlled clinical trial to assess the efficacy of VEST in the relief of menstrual pains in patients suffering from severe dysmenorrhea.
  • the objective of the clinical study was to assess the efficacy of VEST in the management of menstrual pains in patients suffering from severe dysmenorrhea.
  • VAS pain visual analog scale for pain
  • - VEST group 32 women: the women were treated with VEST as described above in Example 1 upon the onset of menstrual pains. The VEST session lasted 25 mins. If the menstrual pain remained higher than 4 on the VAS after 2 hours, the patient was administered an NS AID (ibuprofen, 400 mg). These NSAID doses could be repeated up to three times daily until pain was considered managed (VAS below or equal to 4).
  • NS AID ibuprofen, 400 mg
  • These NSAID doses could be repeated up to three times daily until pain was considered managed (VAS below or equal to 4).
  • - Control group 29 women: the women were not treated with VEST but with NSAIDs only. The women were administered a first dose of NSAID (ibuprofen, 400 mg) upon the onset of menstrual pains. These NSAID doses could be repeated up to three times daily until pain was considered managed (VAS below or equal to 4).
  • Pain in each patient was assessed on a scale of 10 using the visual analog scale (VAS) for pain (e.g. as shown in Figure 2A) over 72 hours following the onset of the dysmenorrhea and recorded. The number of NSAID doses administered to each patient was also recorded. Results
  • VEST was shown to be highly effective in the management of menstrual pains.
  • menstrual pains were managed (pain score below 4) without any intake of NSAIDs in 24 women.
  • menstrual pains were significantly decreased within 30 mins after the end of VEST treatment, and managed in all women 90 mins after the end of VEST, without any administration of NSAIDs.
  • three women were administered one dose of NSAIDs and two women were administered two doses of NSAIDs to alleviate the menstrual pain.
  • NSAIDs In the control group, more doses of NSAIDs were administered to manage menstrual pains: 9 women were administered one dose, 12 women were administered 2 doses and 5 women 3 doses. The three remaining women were poor responders to NSAIDs and were administered 5 or 6 doses over 2 days.
  • Example 3 phase II controlled, non-blinded clinical trial to demonstrate the superiority of the combination of NS AID + VEST over NS AID alone in the management of dysmenorrhea.
  • Patients were eligible for inclusion if they were females with median age 25 (18-37) years, had recurrent intense dysmenorrhea (>12months), pain intensity on NRS>4 the first cycle, had at least primary level education and had given informed consent to participate.
  • Exclusion criteria included women who were pregnant or breastfeeding, had chronic pelvic pain not related to menses, recurrent epigastric pain, allergies to NSAIDs, renal, cardiac or pulmonary comorbidities, or any psychological disorder, sociological conditions or geographic locations that could hinder compliance with the study procedures or monitoring schedules. Study Design
  • the primary study endpoint was the number of days spent with pain.
  • the secondary endpoints were number of Ibuprofen tablets consumed, number of hours spent with intense pain (NRS >4) from onset management, the proportion of patients with pain, the proportion of fully satisfied patients after treatment and documentation of any side effects. Onset of management was defined as the time at which patient effectively started receiving pain follow-up and management at the hospital.
  • a urinary pregnancy rapid diagnostic test was performed at onset of menses.
  • preventive treatment with VEST before menses enables to manage menstrual pain while decreasing the consumption of AINS in women with recurrent and intense dysmenorrhea.
  • the treatment was well tolerated.
  • the women was fully convinced about the efficacy of VEST in the management of menstrual pain.
  • Example 4 Case report - management of dysmenorrhea in a patient diagnosed with endometriosis
  • the patient was treated with VEST every two days for 25 minutes. Treatment was started 15 days before the onset of menses. One electrode pad was placed on the right calf and one electrode pad on the left shoulder the first day and repeated on day 5, 9 and 13. On day 3, 7, 11 and 15, a different method was used which consisted in placing one electrode pad on the left calf and the other one on the right shoulder. The patient resorted to daily treatment during menses.

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Abstract

L'invention concerne la prévention et le traitement de la dysménorrhée chez une femme qui consiste à administrer un traitement de type thérapie vasculaire par stimulation électrique (TVSE).
PCT/EP2020/072577 2019-08-13 2020-08-12 Méthode de prévention ou de traitement de la douleur menstruelle chez des femmes souffrant de dysménorrhée par stimulation électrique WO2021028459A1 (fr)

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US5725563A (en) 1993-04-21 1998-03-10 Klotz; Antoine Electronic device and method for adrenergically stimulating the sympathetic system with respect to the venous media
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