Please select the eligibility criteria that correspond to the clinical trial below.
Title: Use of Duloxetine or Pregabalin in Monotherapy Versus Combination Therapy of Both Drugs in Patients With Painful Diabetic Neuropathy "The COMBO - DN (COmbination vs Monotherapy of pregaBalin and dulOxetine in Diabetic Neuropathy) Study"
Brief Summary: This study will investigate the efficacy of a combination treatment of duloxetine + pregabalin compared with the maximal dose of each drug in monotherapy, in patients with diabetic peripheral neuropathic pain (DPNP) who have not responded to the standard recommended dose of either drug. It will provide an answer to a common clinical question, namely, is it better to increase the dose of the current monotherapy or to combine both treatments early on, in patients who do not respond to standard doses of duloxetine or pregabalin.


Options:
A: Inclusion Criteria:

* meet criteria from primary FMS as defined by the ACR: widespread aching pain in all four quadrants of the body and axial skeleton and greater than or equal to 11 of 18 tender points under digital palpation examination
* measure average pain item of the BPI at Visits 1 and 2

Exclusion Criteria:

* have pain symptoms related to traumatic injury, structural rheumatic disease, or regional rheumatic disease that will interfere with interpretation of outcome measures
* have regional pain syndrome, multiple surgeries or failed back syndrome
* have confirmed current or previous diagnosis of rheumatoid arthritis, inflammatory arthritis, or infectious arthritis, or an autoimmune disease (i.e. systemic lupus erythematosus)
* have current primary Axis I diagnosis other than major depressive disorder (MDD), including a current diagnosis of dysthymia
B: Inclusion Criteria:

* HIV infected
* HIV-associated neuropathy
* Able and willing to provide informed consent
* Successful completion of a daily baseline pain diary over 1 week immediately prior to entry with a mean pain intensity of 4 or more on an 11-point Likert scale
* Karnofsky performance score of 60 or more within 45 days prior to entry
* Required laboratory values. More information on this criterion can be found in the study protocol.
* Willing to comply with protocol requirements for the duration of the study, to include daily completion of the pain diary as instructed, attendance at all study visits, and avoidance of prohibited medications
* On stable or no antiretroviral therapy for 30 days prior to entry. Participants on ARV therapy should plan to remain on the same regimen and drug dose for the duration of the study. Participants not on ARV therapy should have no plans to initiate therapy during study enrollment.
* Not pregnant

Exclusion Criteria:

* Conditions that confound a diagnosis of HIV-associated neuropathy or preclude accurate assessment of neuropathy symptoms, at the discretion of the site investigator. More information on this criterion can be found in the study protocol.
* Potential for unstable neuropathy symptoms during study participation due tthe following: (1) discontinuation of dideoxynucleoside nucleoside reverse transcriptase inhibitor (NRTI) within 16 weeks prior to entry, (2)treatment within 120 days prior to entry with any drug that the site investigator considers may contribute to sensory neuropathy
* Current history of significant depression on antidepressant therapy precluding withdrawal from antidepressants, upon impression of site investigator with input from the participant's mental health provider where available
* History of active substance abuse or dependence identified through medical chart review or self-report such that, in the opinion of the site investigator, participation poses undue risk for the participant
* History of alcohol-related complications within 6 months prior to entry that include but are not restricted to alcohol withdrawal seizures, alcoholic hallucinosis, delirium tremens, or being in an alcohol detoxification program - Treatment with tricyclic antidepressants, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors (SNRIs), bupropion, or tramadol that, upon judgment of the site investigator, cannot be tapered and discontinued prior to the pre-entry visit
* Treatment with an analgesic opioid regimen of more than 60 mg oral morphine equivalent per day within 45 days prior to entry
* Cognitive impairment that, in the opinion of the site investigator and based on clinical impression, might impact the ability to comply with the study protocol
* Use of an investigational agent within 45 days prior to entry except for expanded-access drugs or drugs used in an ACTG protocol for HIV treatment or for HIV-associated complications, if the drug is not prohibited by this protocol
* Acute active AIDS-defining opportunistic infection (OI) within 30 days prior to entry. Participants with no evidence of active disease and receiving maintenance therapy of AIDS-related OIs will be eligible
* Serious illness requiring systemic treatment and/or hospitalization within 45 days prior to entry
* End-stage renal dialysis requiring hemodialysis
* History of known or suspected hepatic cirrhosis diagnosed by signs and symptoms, radiography, or prior liver biopsy with Metavir score of more than 2
* Prolonged QTc interval (more than 0.45 seconds) within 90 days prior to entry
* Felt to be at high risk of opioid-induced respiratory compromise. More information on this criterion can be found in the study protocol.
* Diagnosis of a new seizure disorder or seizure within 90 days prior to entry
* History of acute angle-closure glaucoma, at the discretion of the site investigator
* Known allergy/sensitivity or any hypersensitivity to duloxetine, methadone, acetaminophen, or their ingredients
* Breastfeeding
C: Inclusion Criteria:

* Pain due to bilateral peripheral neuropathy (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 more than 3 months \[assessed by questioning patient\]).
* Score of at least 4 on the 24-hour average pain severity score on an 11-point Likert scale \[on Brief Pain Inventory (BPI) Modified Short Form\] at screening and at randomization.
* Patient is currently not receiving treatment for diabetic peripheral neuropathic pain (DPNP) or was receiving treatment for DPNP, with a drug other than pregabalin or duloxetine, and completed the required washout
* Patient has never received treatment with duloxetine or pregabalin. (However, a short course of less than 15 days of treatment, at any time previously, will be allowed.)
* Stable glycemic control, as assessed by a physician investigator, and hemoglobin A1c (HbA1c) less than or equal to 12% at screening.

Exclusion Criteria:

* Have a known hypersensitivity to duloxetine or pregabalin or any of the inactive ingredients or have any contraindication for the use of duloxetine or pregabalin.
* Have uncontrolled narrow-angle glaucoma.
* Have received treatment with a monoamine oxidase inhibitor (MAOI) within 14 days prior to randomization, or have a potential need to use a MAOI during the study or within 5 days after discontinuation of study drug.
* Have received fluoxetine within 30 days prior to randomization.
* Have acute liver injury (such as hepatitis) or severe cirrhosis (Child-Pugh Class C).
* Have a serum creatinine greater than or equal to 1.5 milligram per deciliter (mg/dL) or a creatinine clearance less than 60 milliliter per minute (mL/min), at screening.
* Are judged clinically by the investigator to be at suicidal risk or as defined by a score of 2 or greater on Question 9 of the Beck Depression Inventory-II (BDI-II), at screening or randomization
* Have a historical exposure to drugs known to cause neuropathy (for example, vincristine), or a history of a medical condition, including pernicious anemia and hypothyroidism, that could have been responsible for neuropathy.
* Have pain that cannot be clearly differentiated from or conditions that interfere with the assessment of the DPNP.
* Have serious or unstable cardiovascular, hepatic, renal, respiratory or hematological illness; symptomatic peripheral vascular disease; a history of seizure disorder; or other medical (including unstable hypertension and not clinically euthyroid) or psychological conditions that, in the opinion of the investigator, would compromise participation or be likely to require hospitalization during the course of the study.
* Have received non-pharmacological treatment for pain within 14 days prior to randomization, or do not agree to abstain from non-pharmacological treatment during the study.
* Have a history of frequent and/or severe allergic reactions with multiple medications.
D: Inclusion Criteria:

* Have pain due to bilateral peripheral neuropathy caused by Type I or Type II diabetes with the pain beginning in the feet and present for at least 6 months.
* May not be pregnant and agree to utilize medically acceptable and reliable means of birth control during participation in the study.
* Score of 4 or greater on the Brief Pain Inventory on the 24-hour average pain item.

Exclusion Criteria:

* Glycosylated hemoglobin (A1C) \> 12%
* Severe hepatic disease
* History of substance abuse or dependence within the past year, excluding nicotine and caffeine.
* Serious or unstable cardiovascular, hepatic (acute liver injury such as hepatitis or severe cirrhosis), kidney, respiratory, blood disorder, seizure disorder, problems with peripheral vascular disease, or other medical conditions or psychiatric conditions that would hinder your participation or likely to lead to hospitalization during the course of the study.
* Taking monoamine oxidase inhibitor (MAOI) within 14 days of starting the study or the potential need to take during or within 5 days after discontinuation from the study.
* Treatment of fluoxetine within 30 days of starting the study.
* Unstable blood sugar control and uncontrolled or poorly controlled hypertension.

Answer: C