SPENDD: Quantitative Sensory Testing and Analgesic Response for Painful Peripheral Neuropathy.

The goal of this clinical trial is to determine whether quantitative sensory testing (QST) can be used to classify participants into pain sub-groups and predict who will respond best to certain pain treatments in participants with painful peripheral neuropathy.

The analgesic effect is evaluated by measuring pain intensity and Patient Global Impression of Change (PGIC).

This study is a 3-period cross-over trial. This means researchers will compare 3 different drugs (pregabalin, duloxetine, and placebo) over a period of 19 weeks.

Participants will:

* Undergo a quantitative sensory testing (QST) exam.
* Provide a blood sample.
* Complete questionnaires on the computer.
* Take the study drug as instructed.


Eligibility Criteria:
Inclusion Criteria:

1. Between 18 and 80 years old (inclusive).
2. Have peripheral neuropathic pain based on the following criteria.

   1. A history of a relevant lesion of the peripheral nervous system, disease, toxic exposure, or no known cause (i.e., idiopathic).
   2. Pain distribution in a neuroanatomically plausible distribution consistent with a symmetrical generalized polyneuropathy (i.e., with a "glove and stocking" distal to proximal gradient).
   3. DN4 score≥ 4.4
3. Have at least one of the following sensory signs upon clinical examination: abnormal pinprick perception, allodynia, hyperalgesia, abnormal light touch perception, abnormal vibratory perception, or abnormal proprioception.
4. Have average daily baseline pain worst pain intensity in their feet of 4 or greater and less than 10, on a 0-10 numeric rating scale of pain intensity (0 = "no pain," 10= "most intense pain imaginable") as measured on the daily diary during screening.
5. Able to understand and read English. This requirement is to ensure that participants can provide informed consent and complete PROs.
6. Have been on stable dosages of all pain medications for at least 1 month and willing and able to stay on those dosages (except acetaminophen rescue) throughout the duration of the study.
7. Willing and able to complete electronic patient-reported outcomes at home using a REDCap link.

Exclusion Criteria:

1. Taking any opioid medication with a daily mean morphine equivalent (MME) of greater than 30.
2. Have a different diagnosis of pain including but not limited to central disorders (e.g., demyelinating disease), rheumatological disease (e.g., foot arthritis, plantar fasciitis, lumbosacral radiculopathy), that they rate to be worse than their neuropathic pain in their feet, or that in the opinion of the investigator, precludes the participant from rating their neuropathy pain in their feet.
3. Currently taken or have taken duloxetine in the past 6 months.
4. Currently taken or have taken pregabalin in the past 6 months.
5. Currently taken or have taken pregabalin in the past 6 months.
6. Taking venlafaxine, buproprion, tramadol, or St. John's Wort. Concomitant use of one medication that inhibits the reuptake of serotonin is allowed at certain dosages. (See Appendix A for maximum allowed dosages for common selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs); maximum dosages for other applicable drugs will be decided by the research team leadership composed of a) clinical pharmacist with extensive experience in chronic pain management, b) a physician board-certified in pain medicine and psychiatry, and c) a board-certified neurologist.
7. Taking a monoamine oxidase inhibitor.
8. Taking CYP1A2 inhibitors or thioridazine.
9. Have an active, uncontrolled medical condition (e.g., neurological, gastrointestinal, renal, hepatic, cardiovascular, pulmonary, metabolic, endocrine, hematological, genitourinary or other major disorder), psychotic disorder or any other uncontrolled psychiatric illness that in the opinion of the investigator makes it unsafe to participate or inclusion of the participant will have a negative effect on the study.
10. Had a clinically significant illness or operative procedure within four weeks of screening.
11. Known hypersensitivity to pregabalin.
12. Known hypersensitivity to duloxetine.
13. Known history of chronic kidney disease that in the opinion of the investigator would make it unsafe to participate.
14. Known history of chronic liver disease that in the opinion of the investigator would make it unsafe to participate.
15. Excessive consumption of alcohol (i.e., more than 5 drinks / day for males and more than 4 drinks / day for females).
16. Patients who are at significant risk of suicide, or are a danger to self or others, in the opinion of the investigator, based upon clinical interview and the Columbia-Suicide Severity Rating Scale (C-SSRS) at screening and baseline. Affirmative answer to suicidal ideation questions 4 or 5, within the last 6 months and / or suicidal behavior (actual attempt, interrupted attempt, aborted attempt, and/or preparatory acts/behavior) within the last 2 years are exclusionary.
17. Evidence of cognitive impairment including dementia or a psychiatric condition (e.g., schizophrenia, bipolar disorder) that may interfere with the subject's ability to complete assessments.
18. Any amputation of lower limbs.
19. Pregnant or breastfeeding.
20. Enrolled in another investigational medication trial.
21. Unable or unwilling to provide informed consent.
22. Any additional reason that, in the opinion of the site investigator, would make it unsafe to participate.