Conditioning & Open-Label Placebo (COLP) for Opioid Management in Intensive Inpatient Rehabilitation

Study Overview
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Brief Summary
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The use of the conditioning open-label placebo (COLP) paradigm will be studied as a dose extension method to lower opioid dosage in patients with spinal cord injury, polytrauma, and burn injury. The goal is to provide the same level of pain relief with a reduced opioid intake to diminish side effects as well as the risk of addiction associated with opioid treatment.

Detailed Description
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The study is a randomized controlled trial (RCT) parallel-group, assessor blind with one experimental arm, the conditioning open-label placebo (COLP), and one control group following the regular regimen, treatment as usual (TAU). Tools for assessment: Morphine Equivalent Dose Conversion (MEDC); Pain Pressure Threshold (PPT); Modified Brief Pain Inventory (BPI); PROMIS Pain-Related Measures (PROMIS); Numerical Opioid Side Effects (NOSE); Treatment satisfaction questionnaire for medication (TSQM) and Treatment expectation questionnaire (TEX-Q); Measurements of anxiety, depression - Generalized Anxiety Disorder 7 (GAD7) and Patient Health Questionnaire-9 (PHQ9). Recording of medication changes and side effects. Reported visual analog scale (VAS) for pain assessed by the nursing team and recorded at the electronic medical record (EMR); finally, the qualitative exit interview. Neurophysiological and metabolomic phenotyping, using the following measures, Quantitative electroencephalography (qEEG) for quantitative assessment (EEG), functional near-infrared spectroscopy (fNIRS), and metabolomics assessment. Following enrollment, subjects will be randomized to receive COLP treatment or a standard of care opioid dosage. The study team will perform baseline assessments, and subjects in the COLP group will undergo three consecutive days of prescribed - as needed - pro re nata (PRN) opioid 100% dose + opioid conditioning paired with taste and odorous placebos (pill and smell). Afterward, subjects will receive a 50% dose + COLP for three days. The nursing team will alternate the active opioid medication with total placebo dosages to decrease the therapeutic opioid dose by 50%. Voluntary COLP continuation: After the participants have completed the experimental intervention (day 6), all outcomes have been collected (pre and post-measurements). Patients randomized to the COLP group will be asked to continue the COLP intervention during hospitalization if the participant agrees to continue using COLP. We will re-evaluate the following variables: MEDC, PPT, BPI, PROMIS pain, TSQM, and NOSE once COLP is discontinued (e.g., in case of increased pain and opioid utilization or if the patient is being discharged and transferred to another facility). For subjects allocated in the control group (treatment-as-usual), the customary treatment routine will follow the standard of care for patients suffering from mild to moderate pain, including all pharmacological agents (NSAIDs, narcotics, and combos) used for pain management. The study team will record total narcotic dosages at the beginning and end of the trial.

Official Title
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Conditioning & Open-Label Placebo (COLP) for Opioid Management in Intensive Inpatient Rehabilitation

Conditions
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Spinal Cord Injuries, Polytrauma, Burns

Intervention / Treatment
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* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18 or older with traumatic and non-traumatic SCI (ASIA A-D), polytrauma, or burn injury patients from the Comprehensive Rehabilitation Program at Spaulding Rehabilitation Hospital, SCI, polytrauma, or burn injury patients from the Comprehensive Rehabilitation Program at Spaulding Rehabilitation Hospital and pain of no more than five years of evolution, Patients admitted to the Spaulding Comprehensive Rehabilitation Unit at Spaulding Rehabilitation Hospital, Who have; above, at, or sub-lesional neuropathic pain and nociceptive pain (musculoskeletal or visceral) that is moderate or severe (average VAS scale score of 4 or greater at time of enrollment), Inpatients with polytrauma (defined as having injuries that affect two or more body systems or organs) or patients with burn injuries, amputations, or post-surgical (e.g., orthopedic surgery) Respiratory and hemodynamically stable, With current narcotic use for pain control, Narcotic usage of no more than 120 mg of morphine equivalent Exclusion Criteria: History of alcohol or drug dependence, as self-reported, History of bipolar disorder or psychosis, as self-reported, Any substantial decrease in alertness, language reception, or attention that might interfere with understanding, Current usage of narcotic medication with a dosage higher than 120 mg of morphine equivalent or 80 mg of short-acting oxycodone, or 30 mg of hydromorphone Current use of a ventilator, Compromised medical status due to uncontrolled pathologies such as cancer, heart failure, kidney or liver insufficiency, or any other condition which jeopardizes the patient's participation in the study Pregnancy or breastfeeding. Participants with pregnancy capability will be tested for pregnancy by serum human chorionic gonadotropin (hCG) test.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conditioning Open-Label Placebo<br>Days 1 to 3 will include the acquisition phase where the opioid medication will be prescribed on a schedule of 3-4 times per day and paired with an open-label placebo. Day 4 and 6 will be the evoked phase, and patients will receive only the open-label placebo pill. On day 5 the opioid medication will be re-introduced as pharmacological reinforcement. | Other: placebo<br>* Sugar pill, with an essential-oil smell and of blue color used for conditioning.<br>* Other names: open-label placebo;|
| No Intervention: Treatment as usual<br>Patients in the standard of care group will receive their analgesic treatment through Spaulding Pharmacy as prescribed by their treating physicians. The treatment regime will include an opioid medication at the standard recommended dosage. Participants in this group will receive the treatment orally for 6 consecutive days. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morphine Equivalent Dose Conversion (MEDC) | The opioid morphine equivalent conversion factor is used to standardized opioid usage having as a reference morphine as main indicator for analgesic potency. | 6 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Brief Pain Inventory (BPI) | The BPI is a short self-assessment questionnaire that provides information on various dimensions of pain including how pain developed, the types of pain a patient experiences, and time of day pain is experienced, as well as current ways of alleviating pain. Worst Pain Score: 1 - 4 = Mild Pain Worst Pain Score: 5 - 6 = Moderate Pain Worst Pain Score: 7 - 10 = Severe Pain | 6 days, 3 weeks, 6 weeks. | 
| Numerical Opioid Side Effects (NOSE) | The Numerical Opioid Side Effect (NOSE) assessment tool is a simple, rapid, self-administered instrument which has the potential to be utilized in a busy pain clinic setting in efforts to document and longitudinally follow trends of opioid adverse effects. Each item is 0 to 10, zero being no side effects (better outcome) and 10 worst outcome. | 6 days | 
| PROMIS Pain Behavior | The PROMIS Pain Behavior item banks measure self-reported external manifestations of pain: behaviors that typically indicate to others that an individual is experiencing pain. These actions or reactions can be verbal or nonverbal, and involuntary or deliberate. | 6 days, 3 weeks, 6 weeks. | 
| PROMIS Pain Interference | The PROMIS Pain Interference item banks assess self-reported consequences of pain on relevant aspects of one's life. This includes the extent to which pain hinders engagement with social, cognitive, emotional, physical, and recreational activities. Pain Interference also incorporates items probing sleep and enjoyment in life, though the item bank only contains one sleep item. The pain interference short forms are universal rather than disease specific. All assess pain interference over the past seven days | 6 days, 3 weeks, 6 weeks. | 
| Patient Health Questionnaire 9 (PHQ-9) | The PHQ-9 components of the longer Patient Health Questionnaire offer psychologists concise, self-administered tools for assessing depression. They incorporate the Diagnostic and Statistical Manual 4th Edition (DSM-IV) depression criteria with other leading major depressive symptoms into a brief self-report instruments that are commonly used for screening and diagnosis, as well as selecting and monitoring treatment. | 6 days, 3 weeks, 6 weeks. | 
| Generalized Anxiety Disorder questionnaire 7 (GAD-7) | The Generalized Anxiety Disorder 7 (GAD-7) is a 7-item instrument used to briefly measure or assess one of the most common mental disorders. | 6 days, 3 weeks, 6 weeks. | 
| TEX-Q | TEX-Q, a scale for generically and multidimensionally measuring expectations of medical or psychological treatments. Its fully generic nature enables the comparability of assessments across different treatments and conditions. | 6 days | 
| TSQM-9 | The TSQM is a 14-item psychometrically robust and validated instrument consisting of four scales.The four scales of the TSQM include the effectiveness scale, the side effects scale, the convenience scale, and the global satisfaction scale. | 6 days | 
| Quantitative electroencephalography (qEEG) | stands out as a valuable, non-invasive tool because it provides reliable and relevant information about brain functioning during rest, sensory stimulation and cognitive tasks. In addition, this technique is safe, low-cost, and employs an easy methodology, thus making it an appropriate tool for use in clinical practice. qEEG at rest and during pain processing event-related potentials (ERP's) at the patient's bed side. The qEEG and ERP's recordings will be processed for analytical purposes, standard EEG metrics will be explored (e.g. spectral analysis, connectivity, source localization), while ERP's will provide information related to pain and values of valence and arousal. | 6 days | 
| Functional near-infrared spectroscopy (fNIRS) | This method is based on near-infrared light absorption fluctuations that depend on concentration changes of the chromophores O2Hb and HHb in the tissue under investigation. We will use it to investigate cerebral metabolism of oxygenated (O2Hb), deoxygenated (HHb) and total hemoglobin (tHb) during pain processing ERP's. Changes in tHb, defined as the sum of the changes in O2Hb and HHb, can be used as a measure of blood volume changes. fNIRS can provide the equivalent of cortical blood-oxygen-level-dependent (BOLD) signal, like functional magnetic resonance imaging (fMRI). | 6 days | 
| Qualitative Exit Interview | The main purpose of the exit interview is to explore individual experiences to describe how patients with pain conceive the effects of the experimental interventions (COLP/TAU). | 1 day | 
| Metabolite assessment of 3-Methyl Xanthine | Serum level of metabolite in (ng/mL). | 6 days | 
| Metabolite assessment of Serotonin | Serum level of metabolite in (ng/mL). | 6 days | 
| Metabolite assessment of Uric acid | Serum level of metabolite in (ug/mL). | 6 days | 
| Metabolite assessment of Tyrosine | Serum level of metabolite in (ug/mL). | 6 days | 
| Metabolite assessment of Kynurenine | Serum level of metabolite in (ng/mL). | 6 days | 
| Metabolite assessment of Indole-3-Lactic acid | Serum level of metabolite in (ng/mL). | 6 days | 
| Metabolite assessment of Indole-3-Propionic acid | Serum level of metabolite in (ng/mL). | 6 days | 
| Metabolite assessment of Indole-3-Acetic acid | Serum level of metabolite in (ng/mL). | 6 days | 
| Metabolite assessment of Tryptophan | Serum level of metabolite in (ug/mL). | 6 days | 
| Metabolite assessment of Total indoxyl sulfate | Serum level of metabolite in (ug/mL). | 6 days | 
| Pain Pressure Threshold (PPT) | Pain pressure threshold (PPT) is used to measure deep muscular tissue sensitivity. The test determines the amount of pressure over a given area in which a steadily increasing nonpainful pressure stimulus turns into a painful pressure sensation [19]. A varying pressure is applied from 0.5 to 1 kg/sec in a perpendicular direction relative to the muscle. PPT has been used on a wide variety of patients and conditions, including musculoskeletal and neuromuscular disorders (e.g., Parkinson disease, tension headaches, pelvic pain, low back pain, myofascial trigger points, knee osteoarthritis, shoulder pain). PPT is a quick, objective measure used to quantify pain intensity | 6 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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open-label placebo, Spinal cord injury (SCI), opioid, pain management, addiction prevention, pharmaco-behavioral, rehabilitation, in-patients