Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase II Role of Immune-pineal Axis in Fibromyalgia: Noradrenergic Modulation and Chronotherapeutic Aspects
Brief Summary: Fibromyalgia is a common condition in clinical medical practice, characterized by diffuse musculoskeletal pain. Sleep disorders, chronic fatigue, depression, intestinal disorders and headache are also commonly associated with the syndrome .

Although the etiology of this syndrome is not well defined yet, it means involve multiple mechanisms, including low levels of serotonin, increased substance P in cerebrospinal fluid and altered circadian variation in sympathetic - parasympathetic balance, consistent with changes in sympathetic hyperactivity at night .

The immune - pineal system, formed by the integration of the adrenergic and immune systems pineal gland, appears to be involved in the genesis of the dysfunctions found in fibromyalgia. Melatonin is secreted by the pineal gland and has promoter activity of sleep. Studies show that melatonin and its precursors , serotonin and tryptophan are reduced in patients with fibromyalgia.

The present study aims to evaluate the relationship of immune - pineal system in the process of fibromyalgia , since dysfunction of this axis appears to govern the cascading events that participate in the pathophysiological process of this disease.


Options:
A: Inclusion Criteria:

* Women 18-65 years old
* Fibromyalgia according to the criteria of the American College of Rheumatology (Wolfe 2010)
* Sign the informed consent
* Patients can take medication for chronic pain ( antidepressants , antiepileptics, for example), since there are at least two months

Exclusion criteria:

* patients who did not understand the Portuguese
* diagnosis of malignancies, severe psychiatric disorders , sleep disorders not related to fibromyalgia (apnea , sleepwalking , restless leg syndrome), Alzheimer's disease or any disease (rheumatologic, neurological, etc.) that can modify the evaluations or outcomes
* alcohol abuse or drug addiction
* patients who are performing acupuncture
* BMI greater than 35 ( BMI = body mass index) .
* Patients with history of allergy to amitriptyline or/and melatonin or any other contraindication for the use of these drugs
B: Inclusion Criteria:

* To be eligible to participate in the study, patients must meet the following criteria:

  1. Patients may be male or female between the ages of 18 and 70 years, inclusive
  2. Patients must have been diagnosed of primary fibromyalgia, as defined by the 1990 ACR Criteria for the Classification of Fibromyalgia
  3. Females must be either postmenopausal (no menses for at least 1 year), posthysterectomy, postoophorectomy (bilateral), or, if of childbearing potential, must have a negative urine pregnancy test prior to randomization and be using a medically acceptable form of contraception (eg, hormonal birth control, IUD, double-barrier method \[eg, simultaneous use of two of the following: male condom, female condom, diaphragm\], or a barrier method plus a spermicidal agent \[contraceptive foam, jelly, or cream\])
  4. Patients must have the ability to give written informed consent
  5. Patients may have hypertension untreated or treated with a maximum of two antihypertensive medications. (Note: medications contributing to a combination product(s) will each be considered as a separate medication.) If untreated, the patient should be stable, with no expectation of initiating treatment during the study. If treated, the patient must have been on stable doses of antihypertensive medications for at least 2 months, with the expectation that dose adjustments will not be necessary for the duration of the study. A patient will be classified as hypertensive if the patient is taking antihypertensive medication, has a SBP equal to or greater than 130 mm Hg, or has a DBP equal to or greater than 85 mm Hg. A patient will be classified as normotensive if he/she is not on antihypertensive medication and has a SBP less than 130 mm Hg and DBP less than 85 mm Hg
  6. Patients must have a mean of two sitting SBP measurements of less than 160 mm Hg and sitting DBP less than 100 mm Hg at Visit 1 (Screening) and Visit 2 (Baseline/Randomization) using an automatic office blood pressure monitor
  7. Patients must have normal physical examination findings, clinical laboratory results, and electrocardiogram (ECG) results from Visit 1 (Screening) or abnormal findings judged not clinically significant by the Investigator and documented as such in the eCRF
  8. Patients must be willing to withdraw from CNS-active therapies marketed as antidepressants, including monoamine oxidase inhibitors, tricyclics, tetracyclics, selective-serotonin reuptake inhibitors (SSRIs), noradrenaline reuptake inhibitors (NARIs), noradrenaline-serotonin reuptake inhibitors (NSRI), serotonin-noradrenaline reuptake inhibitors (SNRIs), and St. John's Wort
  9. Patients must be willing to withdraw from pregabalin (Lyrica) or gabapentin (Neurontin).
  10. Patients must be willing to withdraw from stimulant medications such as those used to treat attention deficit disorder/attention deficit hyperactivity disorder (eg, amphetamine/dextroamphetamine \[Adderall\], methylphenidate, dextroamphetamine) or the fatigue associated with sleep apnea or shift work (eg, modafinil)
  11. Patients must be willing to withdraw from anorectic agents such as diethylpropion , sibutramine (Meridia), and phentermine (Adipex)
  12. Patients must be willing to withhold certain medications for the 24 hours before, as well as during, any ABPM assessment. These medications include phosphodiesterase type 5 inhibitors (eg, Viagra, Levitra, Cialis, Edex, Muse), decongestants (eg, pseudoephedrine, phenylephrine), and antimigraine therapies (eg, triptans such as Imitrex and Maxalt, ergotamines such as Cafergot and Midrin). If, for any reason, the patient takes any of these medications, the ABPM visit should be rescheduled so that at least 24 hours have transpired since the patient's last use

Exclusion Criteria:

* Patients who meet any of the following criteria will not be eligible to participate in the study:
* Psychological/Psychiatric Criteria

  1. Patients with a significant risk of suicide, according to the Investigator's judgment or based on an answer of 2 or 3 for question 9 of the Beck Depression Inventory (BDI) (regarding suicidal ideation) performed at Visit 1 (Screening) or Visit 2 (Baseline/Randomization)
  2. Patients with a total BDI score greater than 25 at Visit 1 (Screening) or Visit 2 (Baseline/Randomization)
  3. Patients testing positive for illegal substances prior to Visit 2 (Baseline/Randomization) as demonstrated by positive drug screening or based on the Investigator's judgment
  4. Patients with any history or behavior that would, in the Investigator's judgment, prohibit compliance for the duration of the study
* Somatic Criteria

  1. Patients with myocardial infarction and/or stroke within the past 12 months; active cardiac disease (American Heart Association Functional Class 2, 3, or 4); congestive heart failure; hemodynamically significant valvular heart disease (including patients with a prosthetic heart valve); hypertensive cardiovascular disease changes (heart, eyes or kidneys) that in the Investigator's judgment, would preclude patient participation; ischemic changes; and/or clinically significant cardiac rhythm or conduction abnormalities (including atrial fibrillation, left bundle branch block, second- or third-degree heart block)
  2. Patients with a mean of two sitting systolic blood pressure (SBP) readings equal to or greater than 160 mm Hg or sitting diastolic blood pressure (DBP) equal to or greater than 100 mm Hg at Visits 1 (Screening) and 2 (Baseline/Randomization) using an automatic office blood pressure monitor
  3. Patients with pacemakers
  4. Patients with an upper arm circumference less than 24 cm or greater than 42 cm in their nondominant arm
  5. Patients with evidence of active liver disease (levels of aspartate aminotransferase, alanine aminotransferase, and/or alkaline phosphatase \> 1.5× the upper limit of the normal range for the clinical laboratory performing the test)
  6. Patients with renal impairment (estimated creatinine clearance \< 50 mL/min)
  7. Patients with documented autoimmune disease. Patients diagnosed with Hashimoto or Grave disease that has been stable for 3 months prior to Visit 1 (Screening) will be allowed to enroll
  8. Patients with current systemic infection (eg, human immunodeficiency virus, hepatitis)
  9. Patients with active cancer, except basal cell carcinoma. Patients taking prophylactic tamoxifen (or other antiestrogen agents) because of a family history of breast cancer or patients taking tamoxifen (or other antiestrogen agents) but who are at least 1 year post-active treatment of breast cancer, may be enrolled
  10. Patients with a current life expectancy of less than 1 year
  11. Patients with active peptic ulcer disease or history of inflammatory bowel disease or celiac sprue
  12. Patients with pulmonary dysfunction or severe chronic obstructive pulmonary disease that, in the Investigator's judgment, could interfere with study participation and completion
  13. Patients with unstable endocrine disease, including unstable diabetes or thyroid disease. Disorders that have been stable for the preceding 3 months will be acceptable
  14. Male patients with prostatic enlargement or other genitourinary disorders who might be at significant risk for dysuria and/or urinary retention while taking agents with noradrenaline-reuptake inhibition properties
  15. Pregnant or breastfeeding patients
  16. Any other conditions (such as epilepsy) that, in the Investigator's judgment, would indicate that the patient is unsuitable for the study (eg, might interfere with study conduct, confound the interpretation of study results, endanger the patient)
* Treatment-Related Criteria

  1. Patients who have received treatment with an experimental agent within the last 30 days prior to Visit 1 (Screening). Patients who have completed previous milnacipran studies (ie, all respective protocol-related study procedures have been completed by the patient) are eligible to participate. Any patients who failed screening in previous milnacipran studies may be re-evaluated, and eligible patients may enroll. Patients currently enrolled in Study MLN-MD-06 are not eligible to participate
  2. Patients who are receiving concomitant therapy with digitalis (digoxin) preparations. (Note: Patients should not undergo washout of digoxin; therefore, patients on digoxin should not be enrolled in the study)
  3. Patients who are receiving concomitant therapy with monoamine oxidase inhibitors, tricyclics, tetracyclics, SSRIs, noradrenaline or noradrenaline-serotonin (NSRI) reuptake inhibitors, SNRIs, St. John's Wort, and/or other agents marketed as antidepressants and are unable to washout or for whom washout is inadvisable\*
  4. Patients who are receiving concomitant therapy with pregabalin (Lyrica) or gabapentin (Neurontin) and are unable to washout or for whom washout is inadvisable\*
  5. Patients who are receiving concomitant therapy with stimulant medications such as those used to treat attention deficit disorder/attention deficit hyperactivity disorder (eg, amphetamine/dextroamphetamine \[Adderall\], methylphenidate, dextroamphetamine) or the fatigue associated with sleep apnea or shift work (eg, modafinil) and are unable to washout or for whom washout is inadvisable\*
  6. Patients who are receiving concomitant therapy with anorectic agents such as diethylpropion , sibutramine (Meridia), and phentermine (Adipex) and are unable to washout or for whom washout is inadvisable\*
  7. Patients who require the use of agents affecting serotonin pharmacology, such as ondansetron (Zofran), granisetron (Kytril), and/or dolasetron (Anzemet)
  8. Patients who require doses of guaifenesin greater than 2400 mg/d (approximately 24 teaspoons)
* Occupational Criteria

  1. Patients whose occupation requires them to work nocturnal hours (eg, 11 PM to 7 AM)
* ABPM Criteria

  1. Patients whose ABPM results at Visit 2 (Baseline/Randomization) do not satisfy ABPM inclusion/exclusion criteria outlined in the ABPM training manual
C: Inclusion Criteria:

* Participants with present OA.
* Have pain for ≥ 14 days of each month for 3 months prior to study entry.
* Participants must have a score of ≥4 on the BPI average pain score before randomization.
* Females of child-bearing potential must test negative (-) on a pregnancy test.

Exclusion Criteria:

* Participants who cannot appropriately complete the daily diaries.
* Have a score change of ≧3 on BPI 24-hour average pain score between screening and baseline.
* Participants who have serious cardiovascular, hepatic, renal, endocrine, respiratory, or hematologic illness, peripheral vascular disease, or other medical condition or neuropsychiatric conditions or clinically significant laboratory abnormalities or electrocardiographic abnormalities.
* Participants who have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) higher than 100 international units per liter (IU/L) or total bilirubin higher than 1.6 milligrams/deciliter (mg/dL).
* Participants who have serum creatinine level higher than 2.0 mg/dL, or had renal transplantation or are receiving renal dialysis.
* Participants who have a diagnosis of inflammatory arthritis (that is, rheumatoid arthritis) or an autoimmune disorder (excluding inactive Hashimoto's thyroiditis and Type 1 diabetes).
* Participants who have any previous diagnosis of psychosis, bipolar disorder, or schizoaffective disorder.
* Participants who have major depressive disorder as determined using depression module of the Mini-International Neuropsychiatric Interview (M.I.N.I.).
* Participants who have uncorrected thyroid disease, uncontrolled narrow-angle glaucoma, history of uncontrolled seizures, or uncontrolled or poorly controlled hypertension.
* Participants who have received intrarticular hyaluronate or steroids, joint lavage, or other invasive therapies to the knee in the past 1 month.
* Participants who have had knee arthroscopy of the index knee within the past year or joint replacement of the index knee or osteotomy at anytime.
* Participants who have end-stage osteoarthritis or surgery planned during the trial for the index joint.
* Participants have a prior synovial fluid analysis showing a white blood cell (WBC) ≥2000 cubic millimeters (mm3) that is indicative of a diagnosis other than OA.
* Participants taking any excluded medications that cannot be discontinued.
* Participants anticipated by the investigator to require use of nonsteroidal anti-inflammatory drugs that include acetaminophen, opioid analgesics, or other excluded medication for the duration of the study.
* Participants treated with a monoamine oxidase inhibitor (MAoI) within 14 days prior to baseline, or those with the potential need to use MAO inhibitor during the study or within 5 days of discontinuation of investigational drug.
* Participants who answer 'yes' to any of the questions about active suicidal ideation/intent/behaviors occurring within the past month (Columbia-Suicide Severity Rating Scale, suicide ideation section-questions 4 and 5; suicidal behaviors section).
* Participants who have a history of having more than one medical allergy.
* Are non-ambulatory or require the use of crutches or a walker.
* Have frequent falls that could result in hospitalization or could compromise response to treatment.
* Have a primary painful condition that may interfere with assessment of the index joint, i.e., knee.
* Have a history of drug abuse or dependence within the past year, including alcohol and excluding nicotine and caffeine.
* Have a positive urine drug screen for any substances of abuse or excluded medication.
* Have received administration of another investigational drug within the 30 days prior to screening.
* Have had previous exposure to duloxetine or completed/withdrawn from any study investigating duloxetine.
* Pregnant participants, female participants who wish to be pregnant during the clinical study period, or participants who are breast-feeding; or male participants who wish pregnancy of the partner.
D: Inclusion Criteria:

* Participants present with pain due to bilateral, peripheral neuropathy
* Participants who have hemoglobin A1c (HbA1c) ≤9.4% (National Glycohemoglobin Standardization Program \[NGSP\]) at screening
* Participants who have HbA1c that has been measured 42 to 70 days prior to screening, and the range of variation in the values measured, thereafter, is within ±1.0% of the value measured at screening
* Participants who have a score of at least 4 on the mean of the 24-hour average pain score measured using 11-point NRS (Numeric Rating Scale) in the daily diary (should be calculated from records 7 days immediately prior to randomization)
* Participants who have made complete daily diary entries 80% or more of the time from screening to randomization

Exclusion Criteria:

* Participants who have undergone renal transplant, or are currently undergoing renal dialysis
* Participants who have uncontrolled narrow-angle glaucoma, history of uncontrolled seizures, or uncontrolled or poorly controlled hypertension
* Participants whose glycemic control has been poor within 70 days immediately prior to screening (for example, ketoacidosis requiring hospitalization, or hypoglycemia that may cause consciousness disorder)
* Pregnant or lactating female participants, or male participants who are planning for their partners to be or become pregnant during the timeframe of the study
* Participants who have hypersensitivity to multiple medications
* Participants who answered "yes" to either question 4 (active suicidal ideation with some intent to act, without specific plan) or question 5 (active suicidal ideation with specific plan and intent) on the "suicidal ideation" portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) or answered "yes" to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on the "suicidal behavior" portion of the C-SSRS; and the ideation or behavior occurred within the past month
* Participants who have past history of psychiatric diseases, such as depression, anxiety disorder, eating disorder, etc., that required drug therapy in the past 1 year, or who are currently having complications of these diseases or any history of manic psychosis or bipolar disorder
* Participants who have major depressive disorder as determined using the depression module of the Mini-International Neuropsychiatric Interview (MINI)
* Participants who have complications of diseases that are considered to affect the assessment of diabetic peripheral neuropathic pain. For example, nerve diseases with pain other than diabetic peripheral neuropathic pain (cervical spondylosis, carpal tunnel syndrome, spinal canal stenosis, and post-herpetic pain), pain diseases other than nerve diseases (collagen diseases, gout, chronic obstructive arteriosclerosis, and arthritis), and other pain at the site of evaluation (skin diseases and traumatic injury) are excluded
* Participants who have neuropathic pain suspected to be caused by alcohol
* Participants who have been treated with a monoamine oxidase (MAO) inhibitor(s) within 14 days immediately prior to randomization. Participants who visited the investigator site 14 days prior to randomization, those who have been treated with MAO inhibitors(s), thereafter, are excluded
* Participants who have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at a level ≥100 units/liter at screening
* Participants who have total bilirubin at a level ≥1.5 milligrams/deciliter (mg/dL) at screening
* Participants who have creatinine clearance (CrCL), calculated by Cockcroft-Gault, that is \<1.0 milliliters/second (mL/s) (\<60 mL/minute) at screening
* Participants who have a white blood cell (WBC) value \<2500/cubic millimeters (mm3), neutrophils \<1500/mm3, or platelets \<100×103/mm3 on their hematology tests at screening
* Participants who are introduced to any treatments for diabetes, or a change in dosing regimen of any treatments for diabetes (exclude insulin treatment), or resumption of insulin treatment after screening
* Participants who have been treated with prohibited concomitant drug(s), or who have undergone prohibited concomitant treatment(s) after screening
* Participants who have taken restricted concomitant drugs 27 days immediately before screening, with continued use of the restricted concomitant drug prior to screening
* Participants who have taken acetaminophen for 4 days or more 7 days immediately prior to randomization

Answer: A