Please select the eligibility criteria that correspond to the clinical trial below.
Title: Milnacipran and Neurocognition, Pain and Fatigue in Fibromyalgia: A 13-week Randomized, Placebo Controlled Cross Over Trial
Brief Summary: This study was designed to investigate whether milnacipran is safe and effective in improving cognitive function in fibromyalgia. In addition, this study was aimed to investigate whether improvement in neurocognitive status due to milnacipran correlates with improvements in pain, to investigate whether improvement in neurocognitive status due to milnacipran correlates with improvements in fatigue, and to determine whether treatment with improvement in neurocognitive status, pain and fatigue correlates with functional improvement.


Options:
A: Inclusion Criteria:

* Radiographically defined OA knee changes with knee pain
* Must have self-reported knee pain
* Able to give informed consent
* Over 35 years old
* Male or female
* Females not pregnant or lactating and using effective contraception

Exclusion Criteria:

* People with any known contraindication to MRI like

  * Intraocular metallic foreign bodies;
  * Intracranial aneurysm clips;
  * Cardiac pacemakers and defibrillators;
  * Cochlear implants;
* People with a significant head tremor;
* People with potential metal foreign bodies due to previous accidents;
* Breastfeeding or pregnancy, confirmed by pregnancy test;
* People that are felt to be unfit for the MRI scan according to the judgement of medically qualified personnel, either on the research team, or the patient's clinical team. (eg. due to back pain, claustrophobia, acute sickness etc.) This includes patients with signs of impaired temperature regulation such as an extremely high fever;
* Patients with large tattoos, specifically in the head, neck or shoulder region;
* Persons that do not have the capacity to consent;
* Aged less than 35;
* Major medical, neurological and psychiatric co-morbidities;
* Other significant medical condition;
* Metallic agents embedded within the body (ie. Shrapnel, surgical pins);
* Refusal by participant to general practitioner (GP) being informed;
* Have uncontrolled narrow-angle glaucoma;
* Have recently taken monoamine oxidase inhibitor (MAOI) or Mellaril® (thioridazine);
* Taking fluvoxamine, ciprofloxacin or enoxacin;
* Taking St. John's Wort, a herbal treatment (Hypericum perforatum);
* Taking other medicines containing duloxetine;
* Have liver disease or severe kidney disease;
* Currently on antidepressant treatment, including treatment for pain with tricyclic agents such as amitryptiline;
* Have recently taken monoamine oxidase inhibitor (MAOI) or Mellaril® (thioridazine);
* Taking tramadol;
* Known hypersensitivity, allergy or intolerance to one of duloxetine's components;
* Unwillingness to take caution in relation to use of other centrally active substances such as alcohol and sedative drugs;
* Current treatment with potent inhibitors of CYP1A2 like fluvoxamine;

Participants undergoing acute treatment (remifentanil or placebo) have, in addition to the stated above, the following exclusion criteria:

* Taking morphine
* Known hypersensitivity, allergy or intolerance to one of remifentanil's components or other fentanyl - analogues
* Current treatment with cardiac depressant drugs such as beta-blockers and calcium channel blocking agents
B: Inclusion Criteria:

1. Must be between the ages of 18 to 65 years of age
2. Must have been diagnosed with fibromyalgia by a rheumatologist
3. Must have an overall body pain average score ≥ 4
4. Must be on stable doses of your current medication for at least past four weeks
5. Must report all medication including herbal supplements and over-the-counter medications that you are currently taking to a member of the research team.
6. Must limit any changes in your medication(s)during the 21-week study time period unless medically necessary
7. Must be willing to maintain a medication diary provided to you during the 21-week study period
8. Must be willing to abstain (not take) any fibromyalgia related medication (including over-the-counter)for at least 6-hours prior to each of the three testing visits. (Otherwise, you may take these medication immediately after pain sensitivity testing has been completed and as prescribed in-between visits)
9. Must experience the symptoms of fibromyalgia syndrome (FMS) that decreases (limits) your ability to perform daily activities.

Exclusions Criteria:

1. You have uncontrolled hypertension(high blood pressure) systolic \>160 mm Hg or diastolic blood pressure \> 100 mm Hg)
2. If you have a history of: heart disease, glaucoma, or hepatitis
3. You have been diagnosed with any type of peripheral neuropathy
4. You have a body mass index (BMI) of more than 34
5. You currently or frequently have thoughts of harming yourself or committing suicide.
6. You are in the process of filing, or plan to file for disability benefits within the study timeline.
7. You plan to undergo an elective surgery within the study timeline.
8. You have been diagnosed with another major rheumatic conditions (i.e. rheumatoid arthritis, systemic lupus erythematosus, scleroderma and other connective tissue diseases)
9. You are currently pregnant, are planning to become pregnant, or are breastfeeding
10. You have been diagnosed with schizophrenia or manic-depressive.
11. You are currently taking any of the following medications:

    1. fluoxetine, Brand Names: Prozac, Prozac Weekly, Rapiflux, Sarafem
    2. sertraline, Brand Name: Zoloft
    3. paroxetine, Brand Names: Paxil, Paxil CR, Pexeva
    4. citalopram, Brand Name: Celexa
    5. escitalopram, Brand Names: Lexapro
    6. venlafaxine, Brand Names: Effexor, Effexor XR
    7. mirtazapine, Brand Names: Remeron, Remeron SolTab
    8. duloxetine, Brand Name: Cymbalta NOTE: If you are taking any of the medication(s) listed above and are willing to discontinue its use for the duration of this study, you must first discuss your decision with your primary care physician (or prescribing doctor)regarding the appropriate regimen to wean off your current medication and receive his/her written consent before proceeding with enrollment. We will provide you a "Dear Doctor" letter that explains the study details.
12. If you are currently taking or have ever taken Savella® (milnacipran)
13. You are currently participating in other pain research study or have previously been enrolled in any study or class in which cognitive behavioral therapy or educational formats were used to help control pain or stress related to fibromyalgia
14. You are unwilling or unable to comply with the study guidelines

Note: If you have ever experienced an adverse event while taking any type of antidepressant, please alert the research team, while it may not exclude you from participating in the study, it is important that we are aware of the incident in order to keep you safe.
C: Inclusion Criteria:

1. Men or women at least 18 years or older
2. Diagnosis of fibromyalgia
3. Clinically significant sleep disturbance, defined as difficulty in maintaining sleep (wake after sleep onset and arousal index) at least three times per week for at least one month
4. Understand and willing to cooperate with the study procedures
5. Maintain a normal sleep schedule, with daytime-awake and nighttime-sleep schedule, with customary bedtime between 9 PM and midnight, and rise time 5 AM and 9 AM
6. Patients who are able to speak, read, and understand English language and able to follow the study protocol, and are able to sign the informed consent

Exclusion Criteria:

1. Subject has any of the following medical conditions:

   Liver disease, blood disorder, autoimmune disease, endocrine, cardiovascular, hypertension, renal, hepatic, gastrointestinal, or neurological disorder, active peptic ulcer or inflammatory bowel disease
2. Significant sleep apnea
3. Periodic leg movement disorder (PLMD) or restless legs syndrome (RLS)
4. Any form of severe psychiatric illness, moderate to severe depression, including significant risk of suicide
5. Patients with uncontrolled glaucoma
6. Inability to discontinue the prohibited medications
7. Female of childbearing potential not using birth control measures; or lactating.
8. History of alcohol, narcotic, benzodiazepines or other substance abuse within the past one year.
9. Patient on prohibited medication will include but not limited to:

   * Anxiolytics, anti-convulsants, antipsychotics, lithium, barbiturates, anti-histamines, monoamine oxidase inhibitors, or medications that affect sleep
   * Any prescription or over the counter stimulants
   * Medications that are contraindicated with the use of milnacipran
10. Excessive caffeine use, defined as a consumption of more than 500 mg of caffeine or other xanthines, smoking \>1/2 a pack/day or alcohol use \>14 units/week
11. History of allergy to milnacipran.
D: Inclusion Criteria:

* Age 18 to 65 years.
* Specific diagnosis of FM by the participant's rheumatologist or physician, including written confirmation, from a physician, of the FM diagnosis.
* Confirmation of the FM diagnosis by American College of Rheumatology Criteria and a physical tender point examination.
* Ability to give informed consent.
* If female, nonpregnant/nonlactating.
* If a sexually active female of reproductive potential, must be using adequate contraception (i.e., oral contraceptives, barrier protection, or prior tubal ligation) during the trial.

Exclusion Criteria:

* Bipolar disorders, any psychotic disorder.
* the existence of concomitant rheumatological disorders, including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's disease, Sjogren's syndrome or scleroderma.
* Substance dependence (except nicotine dependence) in the previous 3 months.
* Currently suicidal or high suicide risk.
* Serious or unstable medical disorders.
* Any psychotropic drug treatment in the previous 2 weeks before screening.
* A positive urine pregnancy test.
* Screening laboratory values three times the limits of normal or judged clinically significant by the investigator.
* History of hypersensitivity to milnacipran.
* Seizure disorder, traumatic brain injury, any CNS disorder that affects cognitive status.
* Concomitant meds: A minimum of 30 days on stable dose of analgesics and a minimum of 4 week washout from antidepressants and fibromyalgia specific medication ( e.g. pregabalin, neurontin) and supplements ( St John's wort, SAM-E).
* Narrow angle glaucoma.

Answer: D