Cognitive Function and Addiction Under Opioid Tapering

Study Overview
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Brief Summary
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This study evaluates the effects of opioid dose reduction in the treatment of chronic pain in adults. Participants were divided in two groups: 1) patients that reduced opioid dose and 2) patients that kept the same opioid dose for six months.

Detailed Description
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BACKGROUND The indications for initiating long-term opioid treatment for chronic non-cancer pain are often unclear and may be associated with poor outcomes and problematic use. Few available studies demonstrated that opioids do not provide advantages regarding pain control, quality of life and functional capacity in this population and may have numerous serious adverse effects and consequences. AIMS This study aimed at: evaluating the feasibility of a opioid tapering off program to patients with chronic pain, investigating the influence of opioid tapering off on cognitive function, pain, symptoms of opioid withdrawal, anxiety , depression, and health related quality of life, investigating the prevalence of addiction in chronic pain patients in a long-term treatment, determining the predictive value of the Pain Medication Questionnaire (PMQ) in patients with chronic pain, investigating how opioid tapering off influences PMQ. METHODS Study design This is a prospective, single centre, open-label, parallel-group randomized controlled trial (1:1) conducted at the Multidisciplinary Pain Centre of Rigshospitalet, Copenhagen University Hospital, Denmark. Two phases with nine assessments were planned. The Phase 1 was the stabilization phase and consisted of two assessments: the first assessment (baseline) was done when patients were admitted to the pain centre and the second assessment was done when medical treatment was considered stable for at least three weeks (stable dose levels and regular intervals). In the following patients went through Phase 2 and were randomized to receive the intervention (Taper off Group) or continue the same stable treatment (Control Group). Seven assessments were planned to this phase: third and fourth assessments were done in intervals of two to three weeks and the following assessments (fifth to ninth) with intervals of one month in between. Intervention The taper-off intervention consisted of a reduction of 10% of the daily opioid dose every 1-2 weeks until discontinuation of opioid treatment for up to six months. Clonidine use (25mg - 150mg/day) was allowed in cases of opioid withdrawal symptoms, according to medical prescription. Analysis Statistical analysis will be performed to compare baseline characteristics between groups (patients that complete the study vs. patients that dropped out and intervention vs. control group). Comparative analysis of primary and secondary outcomes between groups will also be performed to identify significant differences associated with the intervention.

Official Title
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Cognitive Function and Addiction in Patients With Chronic Pain Under Opioid Tapering in a Multidisciplinary Pain Treatment

Conditions
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Chronic Pain, Opioid Use

Intervention / Treatment
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* Drug: Opioids taper off
* Drug: Opioid stable treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18 years old or more at least seven years of schooling pain duration of at least six months, treatment with oral opioids for more than three months daily opioid dose ≥ 60 mg of oral morphine equivalent Exclusion Criteria: not fluent in Danish language cancer disease poor general health condition pregnancy, dementia encephalopathy brain damage cranial base trauma enrolled in other studies

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Random assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Taper off<br>Decrease of opioid daily dose until discontinuation for up to six months. | Drug: Opioids taper off<br>* Decrease of 10% of opioid daily dose every one to two weeks until discontinuation for up to six months.<br>* Other names: Morphine, oxycodone, metadone, fentanyl, tramadol;|
| Active Comparator: Control Group<br>No changes on opioids and adjuvant medication for up to six months. | Drug: Opioid stable treatment<br>* No changes on prescribed opioids and adjuvant medication for the next six months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive function - sustained attention | EKHO, computer program that registers the continuous reaction time to respond to the emission of a sound signal. Scores were summarized in milliseconds using 10th (fastest values), 50th and 90th (slowest values) percentiles. More prolonged times mean worse performance. | Through study completion up to 4 years. | 
| Cognitive function - psychomotor speed | Finger Tapping Test, a mechanical device with a key attached was used to record the number of taps. Score was calculated by the numbers of taps, considering the average of each hand and the differences between hands. Higher scores mean better performance. | Through study completion up to 4 years. | 
| Cognitive function - working memory | Digit Span Test, subjects should repeat orally series of numbers of increasing lengths, in forward and backward orders. Scores were calculated separately for forward and backward exercises, considering the number of correct repetitions. Scores range from 0 to 14. Higher scores mean better performance. | Through study completion up to 4 years. | 
| Cognitive function - mental flexibility | Trail Making Test B, numbers and letters written on a paper should be connected in alternated sequence and increasing order. Score was calculated by the total time spent to correctly conclude the test (seconds). Shorter time mean better performance. | Through study completion up to 4 years | 
| Cognitive function - mental state | Mini Mental State Examination, measures orientation to time and place, registration of words, attention, calculation, and word recall, as well as language and visual construction. Total scores range from 0 to 30; scores below 27 were considered indicative of cognitive dysfunction. | Through study completion up to 4 years. | 
| Risk of opioid misuse | Pain Medication Questionnaire, 26 items responded on a 5-point Likert format scale. Scores range from 0 to 104, higher score means higher risk of opioid misuse. Scores equal or above 22 were considered indicative of risk for opioid addiction. | Through study completion up to 4 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain intensity | Verbal numerical scale from 0=no pain to 10= worst pain, to assess pain right now and average pain. | Through study completion up to 4 years. | 
| Sleep | Number of total hours of sleep in the previous night before assessment | Through study completion up to 4 years. | 
| Rest | Rest sensation assessed by the question do you feel rested?. Answers were categorized as yes or no. | Through study completion up to 4 years. | 
| Quality of life | RAND 36-Item Short Form Health Survey version 1.0., 36 items distributed in 8 scales: physical functioning, bodily pain, role limitations due to physical health, role limitations due to emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Each item was scored on a 0 to 100 range. Items in the same scale were averaged together to create the 8 scale scores. A high score defines a more favorable health state. | Through study completion up to 4 years. | 
| Depression and anxiety | Hospital Anxiety and Depression Scale, self-assessment about the last week. It has 14 items divided in anxiety subscale and depression subscale with seven items each one.The maximum score for each scale is 21; cut-off scores for each scale were 8 to 10 for possible and 11 or higher for probable presence of mood disorder. A clinical judgment was also done by the pain specialist physician (possible answers were yes or no) | Through study completion up to 4 years. | 
| Objective symptoms of opioid withdrawal | Objective Opiate Withdrawal Scale, 13 physically observable signs, rated present or absent that reflected common motoric and autonomic manifestations of opiate withdrawal: yawning, rhinorrhea, piloerection, perspiration, lacrimation, mydriasis, hands tremors, hot and cold flashes (shivering), restlessness (frequent shifts of position), vomiting. muscle twitches, abdominal cramps, and anxiety. Scores range from 0 to 13, higher scores mean more opioid withdrawal symptoms. | Through study completion up to 4 years. | 
| Subjective symptoms of opioid withdrawal | Subjective Opiate Withdrawal Scale, self-assessment, 16 items: motoric, autonomic, gastrointestinal, and musculoskeletal opiate withdrawal symptoms and indirectly related psychological symptoms, like anxiety and craving. Answers are scored from 0 to 4 based on how patient is feeling at the time of assessment. Scores range is 0-64, higher scores mean more opioid withdrawal symptoms. | Through study completion up to 4 years. | 
| Addiction - Portnoy's Criteria | Classification according to Portnoy's Criteria (psychological dependence, evidence of compulsive drug use, and evidence of a group of associated behaviors). Subjects were classified in addict and non-addict. | Through study completion up to 4 years. | 
| Addiction - International Classification of Diseases -10. | Diagnostic criteria according to the International Classification of Diseases -10. Subjects should present at least three symptoms associated with addiction in the least month or several times within a year to be considered addict. | Through study completion up to 4 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cognitive function, opioid dependence, opioid withdrawal, quality of life, side effect