This pilot study is being performed to examine whether epidermal axons are altered in patients taking opioid therapy for chronic non-cancer pain, and if epidermal axonal changes predict heightened pain sensitivity.

Currently, 1 in 25 adults in the USA regularly uses prescription opioids. Now described as a healthcare crisis, increased prescription opioid use is linked with greater healthcare utilization and its associated negative costs. Prescription opioid use leads to increased mortality due to unintentional overdose, misuse and abuse, transition into illicit opioid use, decreased pain thresholds, and widespread neuropathic pain. In addition, opioid- induced hyperalgesia is a dangerous and paradoxical condition wherein patients on opioids develop increased super- heightened pain. In the USA, the increase in prescription opioid use has followed a similar trajectory of the incidence of overdose due to prescription and illicit opioids. Sadly, even with this drastic escalation in opioid use, there has been no change in the rate or severity of chronic pain conditions.

Quantitative analysis of cutaneous innervation of the epidermis provides an indication of the health of peripheral sensory axons. Studies in various pain conditions (e.g., painful diabetic neuropathy, painful chemotherapy-induced neuropathy, and fibromyalgia) suggest changes in epidermal innervation may underlie pain in the feet and hands. Our preclinical studies reveal that changes in epidermal axons play a key role in the development of pain. Here, we postulate that chronic opioid use in patients with chronic pain due to non- cancer conditions 1) contributes to detrimental changes in epidermal axons, 2) works against pain-relieving actions of opioids to reduce pain, and 3) is possibly linked to opioid-induced hyperalgesia.

Our short-term goals are to determine if epidermal axons are altered in patients taking opioid therapy for chronic non-cancer pain, and if epidermal axonal changes predict heightened pain sensitivity. This pilot study will test whether changes in epidermal axons are "dose-dependent" in patients taking low-dose, moderate-dose, or high-dose opioid therapy. Our long-term goals will determine whether dose-reduction or cessation of opioids can reverse axonal changes, or whether these adverse chances can be prevented with other medications. Our central hypothesis is that patients on opioid therapy for chronic non-cancer pain will exhibit elevated epidermal axon densities, and these elevations are accompanied with hyperalgesia and allodynia.

Aim 1: Do patients on long-term opioid therapy have abnormal intraepidermal nerve fiber (IENF) density? We hypothesize that patients taking chronic opioids for non-cancer pain conditions will exhibit abnormal epidermal nerve fiber density compared to chronic pain patients not taking opioid therapy and healthy controls. We will recruit 20 patients with chronic pain due to non-cancer conditions on opioid therapy, 20 patients with chronic pain not taking opioid therapy, and 20 healthy controls and perform a skin biopsy on the ankle. The skin biopsy will then be assessed to ascertain IENF density and compared to normative density values for sex and age. Next, we will compare quantitative measurements of IENF density to total daily oral morphine equivalents (OME) taken by the patients. We hypothesize that higher daily opioid consumption will correlate with abnormalities in epidermal innervation.

Aim 2: Do patients on long-term opioid therapy have heightened cutaneous pain sensitivity that correlates with IENF density? We will perform quantitative sensory testing (QST) in all patient cohorts to objectively assess pain sensitivity. Patients will undergo QST for pressure pain threshold, temporal summation, and conditioned pain modulation. We will determine whether heightened pain sensitivity, as evidenced by reduced pressure pain thresholds, increased temporal summation, and reduced conditioned pain modulation, is associated with altered IENF from skin biopsies. We hypothesize that heightened pain sensitivity will correlate with reductions in epidermal innervation and that higher daily opioid consumption in chronic pain patients will correlate with abnormalities in epidermal innervation and altered QST parameters.

Inclusion Criteria:

Healthy/All:

• Informed consent provided by the participant
• Able to read and speak in English
• Age 18 to 65 years
• Likely to participate in all scheduled evaluations and study procedures

IF they are a Chronic Non-Cancer Patients who do NOT take opioid medication they must meet all of the above criteria as well as:

Diagnosis of non-cancer chronic pain syndrome (persistent pain lasting longer than 3 months)

IF they are a Chronic Non-Cancer Patients who DO take opioid medication they must meet all of the above criteria as well as:

• Chronic daily opioid use for longer than 3 months duration
• Stable doses of opioid medications for at least 30 days prior to study visit

Exclusion Criteria:

• Pregnancy
• Prisoner
• Current clinically significant cardiac, or neurologic disease
• Significant skin disorders in lower extremities
• Circulatory insufficiency
• Open wounds in lower extremity that may interfere with healing
• Lidocaine allergy
• Currently taking anticoagulation (e.g., Coumadin, Plavix, etc)
• Current litigation for chronic pain
• Active psychotic or suicidal symptoms
• Current drug or alcohol abuse
• Neuropathy in upper extremities (hands specifically, PI discretion).
• Current or recent use of artificial fingernails or nail enhancements (last 6 months)
• Other diagnoses that are not considered minor/stable (PI discretion)
• Current or previous cancer diagnosis
• Current or previous chemotherapy treatment
• No chronic pain conditions (healthy)
• Opioid use in the last year (healthy & non-opioid pts)

A cross-sectional study will recruit a total of 60 men and women in three cohorts (20 each): 1) chronic non-cancer pain patients who are utilizing long-term (greater than 3 months of daily use) opioid medication to treat their chronic pain conditions, 2) chronic non-cancer pain patients who do not take opioid medications, and 3) healthy controls.