Chronic PainCOEDNCT04801498
Chronic Pain, Opioid Use, and Epidermal Nerve Fiber Density
An observational study of Chronic Pain and Opioid Use, run by University of Kansas Medical Center at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Chronic Pain, Opioid Use, Nerve Disorders
- How many people
- 38 participants
- Where
- 1 siteUnited States
- Study dates
- 7 Dec 2020to 25 Jun 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: 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.
Who may be able to join
- 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:
Show all 10Show fewer
- 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
Who cannot join
- 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
Show all 18Show fewer
- 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)
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Kansas Health System
Kansas City, Kansas, 66160
About this study
Official title: Chronic Opioid Use and Epidermal Nerve Fiber Density
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.
Read the detailed description
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.
- Conditions
- Chronic Pain, Opioid Use, Nerve Disorders
- Medical subject headings
- Chronic Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Healthy controls | Men and women ages 18-65 years old with no major medical problems and no history of chronic pain or opioid use. | |
| Chronic pain patients not taking opioids | Diagnosis of non-cancer chronic pain syndrome (persistent pain lasting longer than 3 months) that have not used any opioid medication within the past one year. | |
| Chronic pain patients taking opioids | Diagnosis of non-cancer chronic pain syndrome (persistent pain lasting longer than 3 months) using chronic daily opioid use for longer than 3 months duration and taking stable doses of opioid medications for at least 30 days prior to study visit. |
What is being measured
The primary outcome is the main question the study is designed to answer.
IENFD
Intraepidermal Nerve Fiber Density
Measured: Baseline
Secondary outcomes (16)
Fibromyalgianess
FMness is a measure of pain and co-morbid symptom extensiveness and severity. It is calculated from the 2011 FM Survey27 to derive a continuous metric of CNS pain amplification.
Measured: Baseline
Clinical Pain Severity
Pain severity and interference will be assessed using the Brief Pain Inventory (BPI). The BPI asks patients to rate their worst, least and average pain intensity (0-10 NRS).
Measured: Baseline
Neuropathic Pain Descriptors
The PainDETECT is a 9-item measure of sensory descriptors and spatial and temporal characteristics that indicates neuropathic pain
Measured: Baseline
Stress
The Perceived Stress Scale (PSS) is used to measure levels of stress.
Measured: Baseline
Catastrophizing
Coping Strategies Questionnaire(CSQ-CAT) will quantify traits associated with pain progression and catastrophizing
Measured: Baseline
Physical Functioning
The PROMIS short forms will be used for Fatigue, Sleep Disturbance, Sleep-Related Impairment, Physical Function, Anxiety and Depression
Measured: Baseline
Sleep Disturbance
The PROMIS short forms will be used for Fatigue, Sleep Disturbance, Sleep-Related Impairment, Physical Function, Anxiety and Depression
Measured: Baseline
Sleep Related Impairment
The PROMIS short forms will be used for Fatigue, Sleep Disturbance, Sleep-Related Impairment, Physical Function, Anxiety and Depression
Measured: Baseline
Fatigue
The PROMIS short forms will be used for Fatigue, Sleep Disturbance, Sleep-Related Impairment, Physical Function, Anxiety and Depression
Measured: Baseline
Anxiety
The PROMIS short forms will be used for Fatigue, Sleep Disturbance, Sleep-Related Impairment, Physical Function, Anxiety and Depression
Measured: Baseline
Depression
The PROMIS short forms will be used for Fatigue, Sleep Disturbance, Sleep-Related Impairment, Physical Function, Anxiety and Depression
Measured: Baseline
Impulsivity
Using the Kirby Delay Discounting Task, a type of impulsivity can be measured by determining the value participants see in rewards if they are offered at different time points (eg. $25 now OR $60 in 21 days).Impulsivity is a measure of a person's propensity towards reward-based behaviors. Patients in chronic pain and on opioids have been shown to have changes in their reward pathways.
Measured: Baseline
Pressure Pain Sensitivity
Using the Multimodal Automated Sensory Testing (MAST) System, a computerized QST device, an ascending series of 5-s duration stimuli at 25-s intervals will be delivered beginning at 0.50 kg/cm2 and increasing in 0.50 kg/cm2 intervals up to tolerance or a maximum of 10 kg/cm2. Pain intensity and pressure pain threshold will be determined.
Measured: Baseline
Conditioned Pain Modulation (CPM)
CPM is a measure of the integrity of descending analgesic pathways. CPM will be evaluated using two MAST pressure actuators positioned on opposite thumbnails. A reduction in test stimulus rating by conditioning stimulation implies functional (inhibitory) CPM.
Measured: Baseline
Temporal Summation (TS)
TS is the perceived increase in pain intensity to repeated stimulation at a constant stimulus intensity and is reflective of CNS sensitization. A 256 mN pinprick stimulus (MRC Systems, Heidelberg, Germany) will be applied once to the forearm or hand, followed by a train of 10 identical stimuli (1 Hz). The series will be repeated three times. Participants report the pain intensity and the mean pain rating is used to calculate a wind-up ratio (WUR); a WUR >1 indicates temporal summation.
Measured: Baseline
Pain genetics
A number of genes will be analyzed that have previously been studied for their role in pain sensitivity as well as susceptibility to the development of chronic idiopathic low back pain. Subsequent analysis will be performed based on research findings and other published data.
Measured: Baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2021
- Study start7 Dec 2020
- Primary completion25 Jun 2024
- Study completion25 Jun 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Chronic PainStudies of the same condition, open and under way.
- More trials run by University of Kansas Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Kansas Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Andrea Chadwick, MD, MSc, FASA, University of Kansas Medical Center
- Investigators
- Andrea L Chadwick, MD, MSc, FASA, Principal investigator, University of Kansas School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04801498
- Sponsor's protocol ID
- STUDY00144620
- Acronym
- COED
- Status last verified
- Nov 2024
- First submitted
- 11 Mar 2021
- Last updated
- 6 Nov 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 6 Nov 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Chronic Opioid Use and Epidermal Nerve Fiber Density
- ClinicalTrials.gov ID
- NCT04801498
- Acronym / sponsor ID
- COED / STUDY00144620
- Conditions
- Chronic Pain, Opioid Use, Nerve Disorders
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 38 participants (actual)
- Lead sponsor
- University of Kansas Medical CenterUniversity, hospital or other
- Study start
- 7 Dec 2020 (actual)
- Primary completion
- 25 Jun 2024 (actual)
- Study completion
- 25 Jun 2024 (actual)
- First posted
- 17 Mar 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Healthy controls | – | –Men and women ages 18-65 years old with no major medical problems and no history of chronic pain or opioid use. |
| Chronic pain patients not taking opioids | – | –Diagnosis of non-cancer chronic pain syndrome (persistent pain lasting longer than 3 months) that have not used any opioid medication within the past one year. |
| Chronic pain patients taking opioids | – | –Diagnosis of non-cancer chronic pain syndrome (persistent pain lasting longer than 3 months) using chronic daily opioid use for longer than 3 months duration and taking stable doses of opioid medications for at least 30 days prior to study visit. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- 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.
Key inclusion criteria (10 listed)
- 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:
Key exclusion criteria (18 listed)
- Pregnancy
- Prisoner
- Current clinically significant cardiac, or neurologic disease
- Significant skin disorders in lower extremities
- Circulatory insufficiency
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
IENFD
Time frame: Baseline
Intraepidermal Nerve Fiber Density
16 secondary outcomes
Fibromyalgianess
Time frame: Baseline
Clinical Pain Severity
Time frame: Baseline
Neuropathic Pain Descriptors
Time frame: Baseline
Stress
Time frame: Baseline
Catastrophizing
Time frame: Baseline
Physical Functioning
Time frame: Baseline
Sleep Disturbance
Time frame: Baseline
Sleep Related Impairment
Time frame: Baseline
Fatigue
Time frame: Baseline
Anxiety
Time frame: Baseline
Depression
Time frame: Baseline
Impulsivity
Time frame: Baseline
Pressure Pain Sensitivity
Time frame: Baseline
Conditioned Pain Modulation (CPM)
Time frame: Baseline
Temporal Summation (TS)
Time frame: Baseline
Pain genetics
Time frame: Baseline
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Nov 2024.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andrea L Chadwick, MD, MSc, FASA principal investigator
University of Kansas School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Chronic Pain and Opioid Use, run by University of Kansas Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
IENFD (time frame: Baseline). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Nov 2024.