Please select the eligibility criteria that correspond to the clinical trial below.
Title: Milnacipran in the Treatment of Widespread, Non-Joint Pain in Rheumatoid Arthritis
Brief Summary: The purpose of this study is to determine whether milnacipran reduces widespread, non-joint pain in patients with rheumatoid arthritis (RA). The investigators will conduct a double-blind randomized crossover trial in subjects with RA to test the hypothesis that milnacipran improves widespread, non-joint pain. The investigators will also use data from the trial to determine whether response to milnacipran is associated with pain-modulating mechanisms from the central nervous system. The investigators hypothesize that response to milnacipran will be greater among patients with impaired central pain mechanisms than among patients with intact central pain modulating mechanisms.


Options:
A: Inclusion Criteria:

* Age 21 through 65 years old at registration
* Documentation of delayed gastric emptying on gastric emptying scintigraphy within 2 years of registration, defined as greater than 60% retention at 2 hours or greater than 10% retention at 4 hours
* Symptoms of gastroparesis for at least 6 months (does not have to be contiguous) prior to registration with Gastroparesis Cardinal Symptom Index (GCSI) score of 21 or greater
* Negative upper endoscopy or upper GI series within 2 years of registration

Exclusion Criteria:

* Normal gastric emptying confirmed with scintigraphy
* Diabetic gastroparesis or post-surgical gastroparesis including fundoplication
* Another active disorder which could explain symptoms in the opinion of the investigator
* History of significant cardiac arrhythmias and/or prolonged QTc
* History of seizures
* Use of narcotics more than 3 days per week
* Use of tricyclic antidepressants for refractory symptoms of gastroparesis within 6 weeks prior to randomization
* Use of strongly anticholinergic medications
* Use of calcium channel blockers
* Use of erythromycin
* Clear history of failed trial of nortriptyline use for gastroparetic symptoms
* Symptoms of primary depression or suicidal ideation
* Contraindications to nortriptyline:

  1. hypersensitivity or allergy to any tricyclic antidepressant drug
  2. concomitant therapy with a monoamine oxidase inhibitor (MAOI)
  3. recent myocardial infarction
  4. glaucoma
* Pregnancy or nursing
* Any other condition, which in the opinion of the investigator would impede compliance or hinder completion of the study
* Use of a G tube, J tube,or a central catheter for nutrition
* Use of a gastric electrical stimulator
* Failure to give informed consent
B: Inclusion Criteria:

* Age 24 years or older
* Primary diagnosis of rheumatoid arthritis from a board-certified rheumatologist
* Willing to maintain stable doses of concurrent non-steroidal anti-inflammatory drugs or other acceptable medications or therapies for the duration of the study
* Brief Pain Inventory Average Pain \>= 4 at the screening visit
* Widespread Pain Index \>= 5 at the screening visit
* Able to give informed consent

Exclusion Criteria:

* Diagnosis of primary fibromyalgia
* Diagnosis of cold sensitive conditions such as Raynaud's syndrome, cryoglobulinemia and paroxysmal cold hemoglobinuria
* Diagnosis of psychotic disorders, such as schizophrenia, schizoaffective disorder, delusional disorder and shared psychotic disorder
* Patients being treated with SSRIs, MAO inhibitors or tricyclic, tetracyclic or atypical antidepressants for pain may participate in this study if they are washed off these medications before study entry. Patients currently receiving therapy with SSRIs or tricyclic, tetracyclic or atypical antidepressants for depression may be washed off these medications before study entry pending permission of the prescribing physician and if they have never received a diagnosis of major depressive disorder or had a history of suicidal ideation.
* Patients on thioridazine or MAO inhibitors
* Patients taking codeine or other opioids/opiates. Patients who are taking medications such as pregabalin (Lyrica) and gabapentin (Neurontin) for pain may be enrolled in this study.
* Known hypersensitivity to milnacipran
* Patients with a significant risk of suicide as assessed by the Beck depression inventory form
* Patients with a history of suicide
* Pregnant or breast-feeding women
* Patients with an actively pending worker's compensation claim or auto no-fault claim; patients with current worker's compensation, auto no-fault compensation, or litigation; or any patient with significant secondary gain issues per discretion of the researchers.
* Patients with myocardial infarction within the past 12 months, active cardiac disease (chest pain or evidence of ischemia on stress test), acute congestive heart failure requiring hospitalization in the past 12 months, clinically significant cardiac rhythm or conduction abnormalities requiring hospitalization in the past 12 months
* Patients with severe liver impairment (AST or ALT \> 3 times the upper limit of normal)

  * For patients 2-3 times the upper limit of normal, we will obtain enrollment permission from the patient's hepatologist and monitor values at each study visit. If values increase above 3 times the upper limit of normal, the patient will be discontinued from the study.
  * For patients 1-2 times the upper limit of normal, we will obtain enrollment permission from the patient's physician and monitor per request of the physician.
* Patients with severe or end stage renal disease, defined as a GFR \< 15 ml/min or on dialysis
* Patients with a recent (≤ 12 months) history of seizures.
* Patients with uncontrolled narrow-angle glaucoma.
* Patients who have been treated with an experimental agent within the last three months.
C: Inclusion Criteria:

* Present with pain due to bilateral peripheral neuropathy

  * Participants must have pain caused by Type 1 or Type 2 diabetes mellitus
  * Pain must begin in the feet with relatively symmetrical onset
  * Daily pain should be present for at least 6 months
  * Diagnosis must be confirmed by a score of at least 3 on the Michigan Neuropathy Screening Inventory (MNSI)
* Females must test negative for a serum pregnancy test at Screening. Females of child-bearing potential (who are not surgically sterilized and between menarche and 1 year postmenopause) must agree to use a medically acceptable and reliable means of birth control, during the study and for 1 month following the last study dose.
* Stable glycemic control as assessed by a physician investigator and a glycosylated hemoglobin (HbA1c) \<12% before randomization
* Score of greater than or equal to 4 on the Brief Pain Inventory (BPI) 24-hour average pain item at Screening.
* Full completion of the daily diaries for at least 80% of the days between the second and third time you come to the hospital (Screening).

Exclusion Criteria:

* Currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
* Current (less than or equal to 1 year) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I diagnosis of major depressive disorder, dysthymia, anxiety disorders (excluding phobias), alcohol or eating disorders as determined by the Mini-International Neuropsychiatric Interview (MINI) or a previous diagnosis
* DSM-IV diagnosis of mania, bipolar disorder, or psychosis determined either by participant history or by diagnosis using specific MNSI modules
* Serious or unstable cardiovascular, hepatic, renal, respiratory, or hematologic illness, symptomatic peripheral vascular disease, or other medical condition or psychological conditions that in the opinion of investigator would compromise participation or be likely to lead to hospitalization during the course of the study.
* At Screening alanine transaminase (ALT) greater than 2 times upper limit of normal (ULN), based on central laboratory reference ranges times ULN, based on central laboratory reference ranges
* Prior renal transplant, current renal dialysis, or serum creatinine laboratory value \>1.5 times ULN, based on central laboratory reference ranges at Screening.
* Historical exposure to drugs known to cause neuropathy, or a history of a medical condition, including pernicious anemia and hypothyroidism, that could have been responsible for neuropathy
* Pain that cannot be clearly differentiated from or conditions that interfere with the assessment of the diabetic neuropathy pain. Examples of painful conditions that could be confused with diabetic neuropathy pain include peripheral vascular disease, neurological disorders unrelated to diabetic neuropathy, skin condition in the area of the neuropathy that could alter sensation, other painful conditions
* Participants who have previously completed or withdrawn from this study or have been previously treated with duloxetine, including participants who participated in study F1J-MC-HMEQ (NCT00408993), even those in the placebo arm
* Participants taking excluded medications that cannot be stopped at Screening
* Treatment with a monoamine oxidase inhibitor (MAOI) or fluoxetine within 30 days of the third Screening
* Participants with a positive Hepatitis B surface antigen and/or Hepatitis C antibody are to be excluded if they have any of the following:

  * Hepatic dysfunction as determined by the investigator or
  * Clinical manifestations of liver disease within the previous year such as unexplained pruritus, unexplained dark urine, jaundice, unexplained right upper quadrant tenderness, unexplained "flu-like" symptoms or
  * Aspartate transaminase (AST), ALT, or bilirubin above the normal reference range.
D: Inclusion Criteria:

* Male or female of any race, at least 18 years of age
* Patients must meet the ACR criteria for fibromyalgia (ie, widespread pain present for at least 3 months, and pain in at least 11 of 18 specific tender point sites)

Exclusion Criteria:

* Patients with other severe pain (eg, Diabetic Peripheral Neuropathy and PostHerpetic Neuralgia) that may confound assessment or self evaluation of the pain associated with fibromyalgia
* Patients with any autoimmune rheumatic disorder, non-focal rheumatic disease (other than fibromyalgia), active infection, or untreated endocrine disorder
* A current or recent diagnosis (last 6 months) or episode of major depressive disorder, dysthymia and/or uncontrolled depression
* History of mania, hypomania, other psychotic disorder, or current mood disorder with psychotic features

Answer: B