Dysmenorrhea, Premenstrual Dysphoric Disorder (PMDD) and Premenstrual Syndrome (PMS); Drugs, Supplements, Current Treatment Options and why Lunapatch is the best solution.

 

A cluster of conditions exist near the end of the luteal phase of the menstrual cycle. Which have been varyingly referred to as “dysmenorrhea,” “Premenstrual Dysphoric Disorder” (PMDD) and “Premenstrual Syndrome” (PMS) by different generations of doctors to describe different levels of severity at different times. These syndromes are likely to have common causes and it is therefore useful to treat them as one group when assessing the efficacy (or lack thereof) of various treatments. What these conditions have in common are symptoms that are linked to changes in hormone levels that occur prior to menstrual bleeding. These symptoms are not caused directly by the hormones, but rather by the physiological changes that they initiate. This article is an overview of current treatment options, and how Lunapatch is a new solution that can ease menstrual pain without unwanted side-effects.

Definition and Description of the Symptoms

The World Health Organization’s 2016 disease classification manual defines dysmenorrhea as “a disorder characterized by abnormally painful abdominal cramps during menses.” [1]  Dysmenorrhea is a condition that has been found in medical studies to affect as many as 72.7% of women between menarche and menopause (Unsal et al.). [2]

The Mayo Clinic defines PMS as:

Premenstrual syndrome (PMS) has a wide variety of symptoms, including mood swings, tender breasts, food cravings, fatigue, irritability and depression. It’s estimated that as many as 3 of every 4 menstruating women have experienced some form of premenstrual syndrome.

Symptoms tend to recur in a predictable pattern. But the physical and emotional changes you experience with premenstrual syndrome may vary from just slightly noticeable all the way to intense.

Still, you don’t have to let these problems control your life. Treatments and lifestyle adjustments can help you reduce or manage the signs and symptoms of premenstrual syndrome.[3] (Staff, Premenstrual Syndrome (PMS), 2014)

 

The Mayo Clinic has listed a number of symptoms for PMS:

Emotional and behavioral symptoms:

  • Tension or anxiety
  • Depressed mood
  • Crying spells
  • Mood swings and irritability or anger
  • Appetite changes and food cravings
  • Trouble falling asleep (insomnia)
  • Social withdrawal
  • Poor concentration

Physical symptoms:

  • Joint or muscle pain
  • Cramping
  • Headache
  • Fatigue
  • Weight gain related to fluid retention
  • Abdominal bloating
  • Breast tenderness
  • Acne flare-ups
  • Constipation or diarrhea”[4](Staff, Premenstrual Syndrome (PMS), 2014)

The Mayo Clinic discriminates between PMDD and PMS as separate conditions, saying:

Premenstrual dysphoric disorder (PMDD) is a severe, sometimes disabling extension of premenstrual syndrome (PMS). Although regular PMS and PMDD both have physical and emotional symptoms, PMDD causes extreme mood shifts that can disrupt your work and damage your relationships. In both PMDD and PMS, symptoms usually begin 7-10 days before menstrual bleeding begins and continues for the first few days of bleeding.

In PMDD, however, at least one of these emotional and behavioral symptoms stands out:

  • Sadness or hopelessness
  • Anxiety or tension
  • Extreme moodiness
  • Marked irritability or anger[5](Thielen, 2015)

 

Treatment of Pain
The most common treatments include over the counter NSAID (Non-steroidal Anti-inflammatory drugs) drugs such as aspirin, ibuprofen (Advil, Motrin IB, etc.), acetaminophen (Tylenol, Excedrin etc.), naproxen (Aleve, Naprosyn, etc.) as well as other more recent drugs that inhibit the Cox family of enzymes. These drugs have significant downsides. A list of side effects includes:

 

  • heart attack
  • stroke
  • high blood pressure
  • heart failure from body swelling (fluid retention)
  • kidney problems including kidney failure
  • bleeding and ulcers in the stomach and intestine
  • low red blood cells (anemia)
  • life-threatening skin reactions
  • life-threatening allergic reactions
  • liver problems including liver failure
  • asthma attacks in people who have asthma

Since many of these side effects are already symptoms of PMS, NSAIDs have the problem of exacerbating the effects of PMS even as they may appear to relieve inflammation and pain.

Opioids are another commonly prescribed class of drugs for pain relief and management. Common side effects of opioid administration include:

  • sedation
  • dizziness
  • nausea
  • vomiting
  • constipation
  • physical dependence (addiction)
  • tolerance
  • respiratory depression

Physical dependence and addiction to opioids are clinical concerns that may preclude prescription and in turn prevent pain management.

 

Less common side effects may include:

  • delayed gastric emptying
  • hyperalgesia
  • immunologic and hormonal dysfunction
  • muscle rigidity
  • [6](WebMD, LLC)

Opioids have more side effects and dangers than are reasonable to use for the treatment of dysmenorrhea, PMS, and PMDD.

Treatment of Bloating
Diuretics are a poor option for the treatment of bloating, as they can lead depletion of essential nutrients like magnesium. Products that combine diuretics with NSAIDs have strong side effects that impair the user’s mental state and alertness.

WebMD lists the common side effects of Pamprin Max[7]:

  • Chronic Trouble Sleeping
  • Conditions of Excess Stomach Acid Secretion
  • Feel Like Throwing Up
  • Heartburn
  • Irritation of the Stomach or Intestines
  • Nervous
  • Stomach Cramps
  • Throwing Up

Treatments for Depression and Mental Distress
SSRI antidepressants are described as a treatment for PMDD, but have an overly broad effect with too little benefit to be practical. Antidepressants have become the prime example of the endemic mismanagement of the medical profession’s arsenal of medications. It is far too common to receive prescription of an antidepressant by the doctor with no plan for eliminating the medication as symptoms are remedied.

The recent Scientific American article entitled, “Are Antidepressants Just Placebos with Side Effects?” more evidence unfolds for the poor choice that antidepressants provide.

After analyzing all the FDA studies, Kirsch concluded that placebos are 82 percent as effective as antidepressants. According to Kirsch, this difference vanishes if antidepressants are compared to “active placebos,” which are compounds such as atropine, an alkaloid that blocks certain nerve receptors and causes dry mouth and other symptoms, which have distinct side effects.

 

Additionally:

Although Prozac was touted for its relatively mild side effects, it causes sexual dysfunction in as many as three out of four consumers. [8] (Horgan, 2011)

Natural Alternatives to Pharmaceuticals

With the dizzying number of side effects for medications commonly prescribed for the physical pain and emotional stress of dysmenorrhea, a new approach is needed without complicated side effects and unreasonable risks.

Magnesium and Vitamin B6 supplementation has been found to improve the symptoms of PMS/PMDD in several studies. We also suggest transdermal administration and naked electron therapy to better aide absorption and control inflammation.

Magnesium

In 1991, 32 women (aged 24-39) with PMS participated in a randomized, double-blind study on the effects of an oral magnesium supplement three times per day for four months, finding:[9]

The Menstrual Distress Questionnaire score of the cluster “pain” was significantly reduced during the second month in both groups, whereas Mg2+ treatment significantly affected both the total Menstrual Distress Questionnaire score and the cluster “negative affect.”

Women in this study showed a significant increase in Mg2+ levels during the second month of treatment but not in the first. The study concludes:

These data indicate that Mg2+ supplementation could represent an effective treatment of premenstrual symptoms related to mood changes. (Facchinetti et al.)

Another study by Walker et. al.[10] again showed no effect in the first month of supplementation, but in the second month found significant impact of magnesium upon bloating:

Analysis of variance for 38 women showed no effect of Mg2+ supplementation compared with placebo in any category in the first month of supplementation. In the second month there was a greater reduction (p = 0.009) of symptoms of PMS-H (weight gain, swelling of extremities, breast tenderness, abdominal bloating) with Mg­2+ supplementation compared with placebo.

Bloating is one of the more difficult to manage symptoms of PMS, since diuretics often produce unwanted side-effects.

In 2006, an American study by Khine et al. reported:

Contrary to prior reports, we found no evidence of Mg2+ deficiency in women with PMDD compared with control subjects. Furthermore, Mg2+ was not superior to placebo in the mitigation of mood symptoms in women with PMDD.

Khine et al. studied the effects of a single injection of magnesium for two days, showing no effect. However, we know from prior research (Walker et al. and Facchinetti et al.) that when women with PMS take magnesium supplements three times daily, statistically significant effects show up during the second month of treatment.  The Khine study’s poorly supported conclusion does a disservice to women by dissuading them from using a simple, safe and effective treatment.

In 2012, Ebrahimi et al. found that at the end of two months of magnesium supplementation all scores of PMS were reduced compared to placebo.[11]  Symptoms of craving, water retention and anxiety achieved a statistically significant drop in severity compared to placebo. Symptoms of depression and somatic changes both were reduced but did not achieve statistical significance at this sample size.

Vitamin B6

Vitamin B6 serves double duty in the body: it is an antioxidant[12] (Bilski, Li, Ehrenshaft, Daub, & Chignell, 2000) and an enzyme cofactor in amino acid, glucose, and lipid metabolism.

The Ebrahimi et al. study also evaluated the effects of vitamin B6, which showed a pattern of symptom relief similar to magnesium supplementation. Vitamin B6 actually had a greater impact upon depression symptoms than magnesium.

Vitamin B6 levels in the blood of women of childbearing age (ages 13-54) were found to be significantly lower than their male peers of approximately the same age in a 2007 study by Morris et al. for the 2004 National Health and Nutrition Examination Survey.[13] Morris also found users of oral contraceptives had extremely low B6 plasma levels, saying:

Three quarters of the women who reported using oral contraceptives, but not vitamin B6 supplements, were vitamin B6 deficient.

Menstruating women who used oral contraceptives in the past showed a 40% rate of vitamin B6 deficiency.

Homocysteine is a marker of blood vessel inflammation that increases in concentration in Vitamin B6 deficient blood. Homocysteine was found by Morris to rise in proportion to Vitamin B6 deficiency in women of childbearing age, especially those who used or previously used oral contraceptives.

A 2014 study by Bertone-Johnson et. al.[14]  demonstrated that markers in the blood of chronic inflammation are linked with menstrual symptom severity and premenstrual syndrome (PMS). While the Bertone-Johnson study did not examine levels of homocysteine, there are excellent data available in the study by Morris et. al.13

Treating Inflammation
Inflammation is typically treated by NSAIDs, but these drugs do nothing to address the cause of the inflammation. Taking NSAIDs is akin to preventing the people at a campground from feeding a campfire, but it does nothing to prevent the blaze all around them. Cigarette smoking, for example, is a well-understood source of inflammatory oxidation and free radicals. NSAIDs can never undo the free radical damage brought on by smoking. They can only stop enzymes in the body from feeding the flames of inflammation. It is no coincidence that smoking is positively correlated to the severity of PMS symptoms as seen in a study by Ju et. al. among Australian women15.

 

Antioxidants like Vitamin B6 can be supplemented to directly eliminate the oxidative effects of free radicals that include pain, protein damage, DNA damage and other physical and psychological discomforts.

Vitamin B6 is also critical to human health as an enzyme cofactor, but in a person suffering from periodic inflammation, it may be destroyed before it can get to its proper locations in an enzyme, instead being consumed as an antioxidant.

A large number of drugs block the oral absorption of Vitamin B6, including:

  • the contraceptive pill
  • alcohol
  • barbituates
  • chemotherapy agents (mainly methotrexate)
  • pancreatic extract

Women who take the contraceptive pill or drink alcohol may experience decreased or irregular absorption of Vitamin B6. Similar drugs block the absorption of Vitamin B9 and Vitamin B12, other crucial vitamins for cell function. Other interactions with mainstream or natural medicines are also possible.[15]

The good news is, a review of typical dosing of B6 reveals a very wide therapeutic index, meaning the difference between the dosage necessary for therapeutic effect and dosage necessary for overdose is very big. The US RDA for B6 is between 1.2 and 1.7mg per day as defined by table 1 from the National Institutes of Health factsheet on vitamin B6.

Table 1: Recommended Dietary Allowances (RDAs) for Vitamin B6 [1]
Age Male Female Pregnancy Lactation
Birth to 6 months 0.1 mg* 0.1 mg*    
7–12 months 0.3 mg* 0.3 mg*    
1–3 years 0.5 mg 0.5 mg    
4–8 years 0.6 mg 0.6 mg    
9–13 years 1.0 mg 1.0 mg    
14–18 years 1.3 mg 1.2 mg 1.9 mg 2.0 mg
19–50 years 1.3 mg 1.3 mg 1.9 mg 2.0 mg
51+ years 1.7 mg 1.5 mg    

* Adequate Intake (AI)  16 (National Institutes of Health, 2011)

The Tolerable Upper Intake Level (UL) of B6 supplementation for adults is 100 milligrams. This is half of the amount found to have no adverse effects on study subjects.

Studies in patients treated with vitamin B6 (average dose of 200 mg/day) for up to 5 years found no evidence of this effect. Based on limitations in the data on potential harms from long-term use, the FNB halved the dose used in these studies to establish a UL of 100 mg/day for adults. [16] (National Institutes of Health)

At a dosage of 500 mg/day toxic effects begin to show up in the form of reversible neuropathy. That’s nearly 500x larger than the recommended daily allowance.

A therapeutic index of 294 shows Vitamin B6 to be an exceptionally safe vitamin by any standard.

Transdermal Administration
Interactions between orally consumed medications and orally consumed vitamins is a common problem. One common complaint prior to menstruation is diarrhea, which can impair absorption of B6, making oral administration a hit and miss. These problems with oral administration have a very simple answer: topical administration.

In 1985, Russian researchers Gurochkina et. al.[17] showed the pyridoxal phosphate form of vitamin B6 was active when applied to the skin of rats. This form of vitamin B6 is therefore likely to have much more reliable absorption and consistent bioavailability compared to other forms of B6 administered orally.

Pyridoxal phosphate has another important advantage over pyridoxine, it has reduced or completely eliminated toxicity when compared to the pyridoxine form. According to studies conducted by Levine and Saltzman:

The coenzyme (pyridoxal 5-phosphate) did not cause clinical signs or lesions similar to those produced by pyridoxine even when injected in maximum tolerated doses. Neither a protein-deficient diet nor bilateral nephrectomy changed the results with the vitamers.[18] (Levine & Saltzman, 2004)

Topical application is therefore an effective and safe means for B6 administration. However, bioavailability of topical applications are typically low, since the only factors driving the movement of these compounds through the skin are the forces of diffusion and translocation by transporters. Enhancing the rate of B6 movement through the skin would allow this route of administration to be much more effective. Penetrating agents can be utilized to enhance delivery, such as glycerin.[19]

Iontophoresis is an additional method of improving permeability of skin to drugs using a flow of ions induced by electrochemical activity. Translocation of pyridoxine phosphate through the epidermis of the skin is predicted to occur for solutions below a pH of 4 (positively charged) and above a pH of 7 (negatively charged). See figure 1 below from dos Santos et. al.[20] (Sci Flo Brazil, 2010)

Iontophoresis of pyridoxine hydrochloride and pyroxidine-5 phosphate should be quite efficient for transport of these vitamers through the skin. Typical iontophoresis utilizes a positive and negative pad with a battery or other power source to create ions under these pads via electrolysis of water to H+ and OH ions. The H+ ions drive the positively charged vitamin into the skin at the anode or positive (+) side of the device and simultaneously drive the negatively charged vitamin into the skin at the cathode or negative (-) side of the device. However, due to the oxidizing environment at the positive side those molecules will almost certainly be degraded and may have unwanted consequences.

 

Figure 1 – Fractional distribution of pyridoxine hydrochloride in its possible forms according to pH values, according to the experimentally determined Ka1 and Ka2 values.

Electron Donation: A New Means of Treating PMS, PMDD and Dysmenorrhea
Electrochemical action by electron donation offers a range of beneficial effects. The electron donating effects of elemental magnesium generates positively charged magnesium ions (Mg2+) at the surface of the skin, and these drive positive ions forward into the body as they migrate. These systems typically use positively charged ions such as sodium (Na+), Potassium (K+) and magnesium (Mg2+), but any positively charged ion or molecule (i.e. pyridoxal 5-phosphate, vitamin B6) placed on the skin will be mobilized into the body by the presence of an active electron donation patch. Further due to the reducing environment created by the naked electrons the molecules will be protected against oxidation and will maintain integrity as they permeate into the body and are able to then perform their desired tasks.

 

These donated naked electrons themselves neutralize oxidizing free radicals, which are the source of much of inflammations negative effects. Naked electrons are essentially pure antioxidants. If it is understood that free radicals are molecules or atoms that have an unpaired valence electron and will go steal it from where they can, cells, DNA, enzymes etc. and a typical molecular antioxidant is simply a molecule that donates an electron to a free radical without needing one in return, then if you eliminate the molecular middle man you are left with naked electrons which are what the free radicals are really after.

The Naked Electron’s Distinct Advantages Over Both Typical Molecular Antioxidants and NSAIDs.

  • They leave no waste material behind – Unlike a molecular antioxidant, which once it donates its electron then the rest of the molecule is waste, a naked electron on the other hand gets wholly consumed by the free radical.
  • They are able to act at a distance – Molecular antioxidants need to come into almost direct contact with a free radical to donate their electron, whereas the naked electron from elemental magnesium can utilize its high reducing potential voltage (2.37V), to push the electrons and neutralize free radicals away from the source.
  • Unlike NSAIDs, they can quench any oxidizing agent regardless of the source – By their nature, NSAIDs can only inhibit enzymes that produce oxidizers. To use an analogy, NSAIDs prevent people at the campground from adding fuel to the campfire, but can do nothing about sources of inflammation that are exogenous. Exogenous sources would be excess sugars, radicals from cigarette smoking, or toxins such as paraquat or pollution. The naked electron doesn’t discriminate when it comes to the source of the radicals, and will neutralize any radicals that occur within the range of the patch.
  • Can bypass the digestive system and provide highly targeted relief and vitamin delivery – Most dietary vitamins and antioxidants get destroyed as they make their way through the digestive system, while the ones that do make it through are distributed diffusely throughout the body, with no strong way to direct where they go. NSAIDs take a heavy toll on the user’s digestive system and liver, plus they create the potential for lots of side effects if taken in excess. The amount of naked electrons being delivered far exceeds any dose of antioxidants that is possible to be eaten and absorbed through the digestive system. As such, the patch is able to provide effects that are not reproducible by normal antioxidant intake and will neutralize the free radicals and create a potent anti-inflammatory effect within the vicinity of the patch. The patch also has the ability to deliver positive ions like magnesium and potassium or molecules such as vitamin B6 or B1 or B12, directly to desired areas to help initiate various enzymatic effects.
  • Allowing vitamins to fulfill their higher purpose – Many vitamins double as antioxidants and play a crucial role as enzyme cofactors. By being in the presence of large amounts of powerful antioxidants via the naked electrons, the vitamins are protected from oxidation and no longer need to be reduced to the role of a simple antioxidant. Naked electron therapy allows vitamins like B6 to fulfill their specialized role as an enzyme cofactor instead thus making them more useful to the user.

Please read our other paper Reactive Oxygen Species (ROS) Their Creation, Interconversion, Detoxification and a New Solution with the Naked Electron found on our website https://heliopatch.com/science-detailed-version/. It will in more detail explain the ability of the naked electron to act at a distance and how it is such a potent antioxidant.

 

 

Final Words
Because Lunapatch provides naked electrons and vitamins in a concentrated manner via transdermal delivery, there is a great deal of pain and symptom relief that can be targeted to the area where the pain occurs. Because menstrual pain from cramps is localized and because the cause of the pain is understood by the user, there is a reduced risk that the source of the pain will be misidentified. This technology has shown itself to be an extremely potent anti-inflammatory, as such, it is important to remember there is actually a protective role of inflammation for conditions such as infection and beneficial immune response. We do not recommend that human half-cell electron donation technology be used for medical conditions or unidentified sources of pain, and if pain does not resolve within 3 days, we strongly suggest that you contact your health practitioner and investigate other underlying medical conditions that might be the real culprit.

Menstrual pain is particularly suited to naked electron therapy because it has a predictable onset as well as a predictable endpoint. If you experience symptoms that continue beyond the end menstrual bleeding, please obtain a healthcare practitioner’s advice and seek a more specific treatment for your condition.

 

 

Works Cited

 

Bertone, E., Ronnenberg, A., Houghton, S., Nobles, C., Zagarins, S., Takashima, B., et al. (2014). Association of inflammation markers with menstrual symptom severity and premenstrual syndrome in young women. U.S. National Library of Medicine National Institutes of Health , 9.

Bilski, P., Li, M., Ehrenshaft, M., Daub, M. E., & Chignell, C. F. (2000). Vitamin B6 (Pyridoxine) and Its Derivatives Are Efficient Singlet Oxygen Quenchers and Potential Fungal Antioxidants. Retrieved from National Science Foundation : https://cals.ncsu.edu/plantbiology/Faculty/mdaub/bilski2000.pdf

Ebrahimi, E., Motlagh, S., Nemati, S., & Tavakoli, Z. (2012). Effects of Magnesium and Vitamin B6 on the Severity of Premenstrual Syndrome Symptoms. U.S. National Library of Medicine National Institutes of Health , 4 (1).

Facchinetti, F., Borella, P., Sances, G., Fioroni, L., Nappi, R., & Genazzani, A. (1991, August). Oral magnesium successfully relieves premenstrual mood changes. U.S. National Library of Medicine National Institutes of Health .

Gurochkina, L., Koroleva, N., Avakumov, V., & Smirnova, T. (1985 ). Comparative study of the vitamin activity of pyridoxal phosphate and pyridoxine used cutaneously. Farmakol Toksikol , 6 (48).

Horgan, J. (2011, July 12). Are Antidepressants Just Placebos with Side Effects? Scientific American .

ICD-10 Version:2015. (2015). Retrieved from International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10)-2015-WHO Version for 2015: http://apps.who.int/classifications/icd10/browse/2015/en#/N94.6

Institute of Medicine. (1998). Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C. , United States of America : The National Academies Press .

Ju, H., Jones, M., & Mishra, G. (2014). Smoking and trajectories of dysmenorrhoea among young Australian women. U.S. National Library of Medicine National Institutes of Health , 2 (25).

Khine, K., Rosenstein, D., Elin, R., Neimela, J., Schmidt, P., & Rubinow, D. (2005, October 4). Magnesium (Mg) Retention and Mood Effects After Intravenous Mg Infusion in Premenstrual Dysphoric Disorder. Biologicla Psychiatry Journal .

Levine, S., & Saltzman, A. (2004, November). Pyridoxine (vitamin B6) neurotoxicity: enhancement by protein-deficient diet. J Appl Toxicol .

Morris, M., Picciano, M. J., & Selhub, J. (2007, December 12). Plasma pyridoxal 5′-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003–2004. The American Journal of Clinical Nutrition .

National Institutes of Health. (2016). Vitamin B6 Fact Sheet for Health Professionals. Retrieved from Strengthening Knowledge and Understanding of Dietary Supplements: https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/

Natura Foundation . (n.d.). VITAMIN B6, B12 AND FOLIC ACID Nutritional therapy. Retrieved from Knowledge Centre for clinical PNI and Nutritional Therapy : http://www.naturafoundation.co.uk/monografie/Vitamin_B6_B12_and_folic_acid.html

Oudi, M., Aouni, Z., Mazigh, C., Khockkar, R., Gazoueni, E., Haouela, H., et al. (2010). Homocysteine and markers of inflammation in acute coronary syndrome. U.S. National Library of Medicine National Institutes of Health , 2 (15).

Sci Flo Brazil. (2010). Potentiometric and conductimetric studies of chemical equilibria for pyridoxine hydrochloride in aqueous solutions: simple experimental determination of pKa values and analytical applications to pharmaceutical analysis . Eclética Química , 35 (4).

Shils, M., Shike, M., Ross, A., Caballero, B., & Cousins, R. (2012). Modern Nutrition in Health and Disease . LWW.

Staff, M. C. (2014, December 14). Premenstrual Syndrome (PMS) . Retrieved March 1, 2016, from Mayo Clinic: http://www.mayoclinic.org/diseases-conditions/premenstrual-syndrome/basics/treatment/con-20020003

Theratech, I. (1993, May 3 ). The use of glycerin in moderating transdermal drug delivery . The use of glycerin in moderating transdermal drug delivery field of invention . USPTO.

Theratech, I. (1993, May 3 ). The use of glycerin in moderating transdermal drug delivery . The use of glycerin in moderating transdermal drug delivery field of invention . USPTO.

Thielen, J. M. (2015, November 14). Premenstrual Syndrome (PMS) . Retrieved 2016, from Mayo Clinic : http://www.mayoclinic.org/diseases-conditions/premenstrual-syndrome/expert-answers/pmdd/faq-20058315

Tufts University, Health Sciences. (2008 , May 23). Trends Of Vitamin B6 Status In US Population Sample Identified. Science Daily .

U.S. Food and Drug Administration. (2007, August ). Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) . Retrieved from http://www.fda.gov/downloads/Drugs/DrugSafety/ucm089162.pdf

Unsal A, A. U. (2010 , May). Prevalence of dysmenorrhea and its effect on quality of life among a group of female university students. Ups J Med Sci. , 115(2):138-45.

Walker, A., De Souza, M., Vickers, M., Abeyasekera, S., Collins, M., & Trinca, L. (1998). Magnesium supplementation alleviates premenstrual symptoms of fluid retention. U.S. National Library of Medicine National Institute of Health , 7 (9).

WebMD, LLC. (n.d.). List Pamprin Max side effects by likelihood and severity. Retrieved from Pamprin Max Side Effects : http://www.webmd.com/drugs/2/drug-151686/pamprin-max-oral/details/list-sideeffects

[1] http://apps.who.int/classifications/icd10/browse/2015/en#/N94.6

[2] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853792/

 

[3] http://www.mayoclinic.org/diseases-conditions/premenstrual-syndrome/basics/definition/con-20020003

[4] http://www.mayoclinic.org/diseases-conditions/premenstrual-syndrome/basics/symptoms/con-20020003

[5] http://www.mayoclinic.org/diseases-conditions/premenstrual-syndrome/expert-answers/pmdd/faq-20058315

[6] http://www.webmd.com/drugs/2/drug-151686/pamprin-max-oral/details/list-sideeffects

[7] http://www.webmd.com/drugs/2/drug-151686/pamprin-max-oral/details/list-sideeffects

[8] http://blogs.scientificamerican.com/cross-check/are-antidepressants-just-placebos-with-side-effects/

[9] http://www.ncbi.nlm.nih.gov/pubmed/2067759/

[10] http://www.ncbi.nlm.nih.gov/pubmed/9861593/

[11] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161081/

[12] http://cals.ncsu.edu/plantbiology/Faculty/mdaub/bilski2000.pdf

[13] http://ajcn.nutrition.org/content/87/5/1446.long

[14] http://www.ncbi.nlm.nih.gov/pubmed/25035435

[15] http://www.naturafoundation.co.uk/monografie/Vitamin_B6_B12_and_folic_acid.html

[16] https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/

[17] http://www.ncbi.nlm.nih.gov/pubmed/4085632

[18] http://www.ncbi.nlm.nih.gov/pubmed/15558839

[19] https://www.google.com/patents/WO1993025168A1?cl=en

[20] http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-46702010000400010&lng=en&nrm=iso&tlng=en#f3