Dosing Intervals of Opioid Medication for Chronic Pain

Study Overview
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Brief Summary
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This study is to determine the feasibility of an n-of-1, randomized, double blind, placebo controlled case series to examine effects of extended release opioids when used at intervals shorter than recommended by the manufacturer by people with chronic pain.

Official Title
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Examining the Relationship Amongst Opioid Subjective Effects and Pharmacokinetics of Extended Release Opioids at Shortened Dosing Intervals in Patients With Chronic Pain: a Randomized, Blinded, N-of-1 Case Series Feasibility Study

Conditions
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Chronic Pain

Intervention / Treatment
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* Drug: Extended Release Opioid Formulation, Shortened Intervals
* Drug: Extended Release Opioid Formulation, Standard intervals
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: >18 years old willing and capable to give written informed consent diagnosis of chronic pain (> 3 months) current prescription for oxycodone controlled release or hydromorphone controlled release or morphine sustained release for pain Using extended release opioids at intervals less than 12 hours/ more than twice daily Exclusion Criteria: ongoing acute pain episode use of immediate release opioids that contribute to more than 20% of their total daily opioid dose total daily morphine equivalent dose >400mg actively tapering their opioid dose use of multiple extended release opioid products unstable psychological diagnosis (using the Psychosocial Screening Interview Guide) outstanding or planned litigation related to pain pregnancy or lactation in women history of coronary artery disease active tapering or titration of benzodiazepines or cannabinoids positive urine drug screen for amphetamines, barbiturates, cocaine, methamphetamine, methadone, phencyclidine, propoxyphene or unexpected opioids or benzodiazepines using M-Eslon using long acting hydromorphone using Kadian

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: Crossover Assignment
Interventional Model Description: Feasibility study of an n-of-1, within-subject, crossover, randomized, double blind, placebo controlled case series
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Shortened interval extended release opioid<br>Extended release opioid, individualized total daily dose, dosing intervals less than every 12 hours. | Drug: Extended Release Opioid Formulation, Shortened Intervals<br>* Extended release opioid, individualized total daily dose, dosing interval is less than every 12 hours<br>* Other names: morphine slow release;Drug: Placebo oral tablet<br>* Lactose pill manufactured to mimic extended release opioid formulation<br>* Other names: Placebo (for Extended release opioid);|
| Active Comparator: Standard interval extended release opioid<br>Extended release opioid, individualized total daily dose, dosing intervals every 12 hours | Drug: Extended Release Opioid Formulation, Standard intervals<br>* Extended release opioid, individualized total daily dose, dosing interval is every 12 hours<br>* Other names: morphine slow release;Drug: Placebo oral tablet<br>* Lactose pill manufactured to mimic extended release opioid formulation<br>* Other names: Placebo (for Extended release opioid);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants who complete both treatment periods and have evaluable Patient Global Impression and pharmacokinetic data | Feasibility outcome | 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Global Impression of Change | Single-item rating by subjects of their improvement with treatment on a 7-point scale that ranges from the lowest rating of 1= 'very much improved' to the highest rating of 7= 'very much worse'. Higher values are considered to be a better outcome. | 3 weeks | 
| Numerical Pain Rating Scale | A measure of pain intensity. Ten point scale with a minimum of 0= no pain to a maximum of 10 = worst pain imaginable. Higher scores represent a worse outcome. | 3 weeks | 
| Brief Pain Inventory (Short Form) | An inventory of questions about pain, including a pain diagram, pain intensity rating subscales and pain interference rating subscales. The four pain intensity rating subscales are pain at worst, pain at least, pain on average and pain right now. These are 10-point scales with a minimum of 0 =no pain, and a maximum of 10= pain as bad as you can imagine, where higher scores are worse. Pain intensity subscales can be combined as an average on the same scale of 0-10. The eight pain interference subscales measuring interference on general activity, mood, walking ability, work, relations with other people, sleep, enjoyment of life, are 10-point subscales which range a minimum of 0 = pain does not interfere, to a maximum of 10=pain completely interferes with the item. Higher scores are worse outcomes. Pain interference subscales may be combined as an total score out of 80, or divided by eight to get an average of pain interference on the scale of 0-10. | 3 weeks | 
| Subjective Opioid Withdrawal Scale | A self-administered scale for grading 16 opioid withdrawal symptoms on a scale of '0' meaning 'not at all' to '4' meaning 'extremely'. Higher numbers are worse outcomes. | 3 weeks | 
| Addiction Research Centre Inventory (ARCI) - short form | The short version of the ARCI is a well-validated, standardized, self-report questionnaire of 49 true-false items and is used to differentiate subjective effects of drugs. True = 1, False = 0, responses to selected items are added for scores on different scales. Three of the scales are pertinent to opioid abuse liability: MBG (morphine-benzedrine group), a measure of euphoria, minimum = 0, and a maximum = 16); PCAG (pentobarbital-chlorpromazine-alcohol group) a measure of sedation, minimum =0, maximum=15; LSD (lysergic acid diethylamide scale) a measure of dysphoric and psychotomimetic changes, minimum=0, maximum =14. Higher scores are worse outcomes. | 8 hours | 
| Profile of Mood States | A widely used, self-reported questionnaire for assessing drug-induced changes in mood. It has 72 adjectives and phrases describing feelings people have, and ask for the user to describe how you are feeling right now on a 5 point scale of descriptives: with a minimum value = 0 Not at all, to a maximum value of 4= extremely. Total mood disturbance is calculated by adding the results of the 6 subscales, and then subtracting the vigor -activity subscale (range 0-200). Subscales (six) are calculating by adding specific items: tension-anxiety (9 items, range 0-36), depression (15 items, range 0-60), anger-hostility (12 items, range 0-48), vigor-activity (8 items, range 0-32), fatigue (7 items, range 0-28), confusion-bewilderment (7 items, range 0-28). | 8 hours | 
| Visual analogue scale - liking/high | Visual analog scales are 100mm lines, anchored at the ends by opposing adjectives (e.g. like-dislike). Like is at the minimum, 0mm mark, dislike is at the maximum, 100mm mark. Subjects are instructed to rate how they feel along a continuum by making a mark along the line. The measurement of drug liking is considered to be one of the most sensitive and reliable assessments of the likelihood of abuse of a drug. Liking and High at the 100mm marks would be considered worse outcomes in terms of likelihood of abuse of a substance. | 8 hours | 
| Serum opioid concentrations | Serum opioid concentrations at 0,30 mins, 1,2,3,4,5,6 hours post-dose | 6 hours | 
| Peak plasma concentration (Cmax) | The maximum concentration achieved post dose | 6 hours | 
| Time to peak plasma concentration (Tmax) | Time that peak plasma concentration occurs post-dose | 6 hours | 
| Area under the plasma concentration versus time curve (AUC) | Calculated area under the plasma concentration versus time curve, which describes exposure to the drug. | 24 hours | 
| Abuse liability quotient (AQ) | The peak plasma concentration (Cmax) divided by the time to peak plasma concentration, which describes a calculation of the average rate of increase in plasma concentration over the interval between treatment administration and the time of peak plasma concentration. | 6 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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opioid