Trial of Dronabinol and Vaporized Cannabis in Chronic Low Back Pain

Study Overview
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Brief Summary
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This study will involve treating low back pain associated with nerve injury with oral delta-9-tetrahydrocannabinol (Δ9-THC) or whole plant cannabis for eight weeks. Research subjects will consume either oral Δ9-THC (dronabinol), vaporized 3.7% Δ9-THC/5.6% CBD, or placebo. An analysis will then be determined to assess the risk--benefit ratio of dronabinol and vaporized 3.7% Δ9-THC/5.6% CBD .

Detailed Description
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The present study is designed to assess whether treatment with vaporized cannabis or dronabinol (oral Δ9-THC) reduces spontaneous and evoked pain more than placebo, and whether there are any differences between the two active treatments in terms of interference with activities of daily living. This study also aims to examine the effects of vaporized whole plant cannabis and dronabinol on mood, neuropsychological function, and psychomimetic side-effects (high, stoned, etc.) compared to placebo and to each other. In addition, we plan to examine the acute effects (after receiving stable treatment for 4 weeks) of vaporized cannabis and dronabinol compared to placebo and each other on driving skills.

Official Title
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A Randomized Controlled Trial of Dronabinol and Vaporized Cannabis in Chronic Low Back Pain

Conditions
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Cannabis, Low Back Pain, Neuropathic Pain

Intervention / Treatment
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* Drug: Placebos
* Drug: dronabinol
* Drug: Vaporized Cannabis 3.7% THC/5.6% CBD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than 18. Presence of chronic low back pain (CLBP) defined as the response to two questions 1) How long has back pain been an ongoing problem for you? 2) How often has low back pain been an ongoing problem for you over the past 6 months? A response of greater than 3 months to question 1 and a response of at least half the days in the past 6 months to question 2 will define CLBP according to the NIH Task Force on Research Standards for Chronic Low Back Pain. The numerical pain intensity must be greater than 3/10 each day during the one-week observation period. To avoid confounding by concurrent medications, participants will have had a stable analgesic regimen that they will continue throughout the study To obviate residual neuropsychological effects from cannabis exposure, participants will be abstinent from this herbal medicine for 7 days prior to study entry. Exclusion Criteria: Presence of another painful condition of greater severity than the neuropathic pain condition which is being studied. History of traumatic brain injury. Clinically significant or unstable medical condition. Individuals with significant cardiovascular, hepatic or renal disease, uncontrolled hypertension, and chronic pulmonary disease (eg, asthma, COPD), will be excluded. If warranted clinically, subjects will undergo laboratory evaluation (blood chemistry, electrocardiogram, urinalysis, toxicology screening for confirmation. Females of childbearing potential will undergo pregnancy testing. A positive result on toxicity screening will exclude individuals from participation. A urine drug test that screens for 5 categories of drugs: marijuana (Δ9-THC), cocaine, amphetamines/methamphetamines, opiates, benzodiazepines and phencyclidine (PCP) will be employed. A positive result for opioids and/or THC will not be exclusionary if the patient is receiving a prescription for an opioid and/or THC. Allergy to sesame oil, lactose, or gelatin Vascular disease, especially Raynauld's syndrome, systolic blood pressure > 170 mm, diastolic blood pressure > 100 mm Recent injuries to the upper extremity Cognitive impairment, such as Dementia or Alzheimer's Disease Substance Abuse History: The Substance Abuse Module of the Diagnostic Interview Schedule for the Diagnostic and Statistical Manual (DSM)-IV will be administered to exclude individuals with current substance use disorders. Pregnancy as ascertained by a mandatory commercial pregnancy test Past history of suicide attempt. Cannabis can exacerbate pre-existing schizophrenia, and has been linked to an increase in the risk of suicide in such patients. In patients with bipolar disorder, cannabis use has been associated with worsening of manic and psychotic symptoms. Such findings suggest that cannabis is contraindicated in individuals with serious mental health issues, a line of reasoning that will be observed in the present study by excluding patients in the bipolar/schizoaffective/schizophrenic spectrum. Suicidality. Exposure to cannabis does not lead to depression but it may be associated with suicidal thoughts and attempts. Therefore, the Beck Depression Inventory (BDI)-II will be used to measure suicidal ideation.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 70 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebos<br>The present study is designed to evaluate whether or not a medium dose of cannabis (3.7% delta-9-THC/5.6% CBD) can maintain an analgesic response over an eight week period compared to placebo. | Drug: Placebos<br>* Administration of vaporized cannabis plus either dronabinol or placebo pill<br>* Other names: sugar pill;|
| Active Comparator: Dronabinol<br>A direct comparison of cannabis and dronabinol has not been performed in a clinical population. The present study will fill this void by performing a randomized, controlled 8 week trial comparing the effectiveness of oral versus vaporized cannabis in patients with neuropathic low back pain. | Drug: dronabinol<br>* Administration of vaporized cannabis plus either dronabinol or placebo pill<br>* Other names: Marinol;|
| Experimental: Vaporized Cannabis 3.7% THC/5.6% CBD<br>The eight week outpatient study will compare the efficacy and side effect profile of cannabis (3.7%THC/5.6%CBD) and dronabinol. We will also perform a human laboratory experiment evaluating driving using the same study medications that subjects received during their 8 week outpatient treatment. | Drug: Vaporized Cannabis 3.7% THC/5.6% CBD<br>* Administration of vaporized cannabis plus either dronabinol or placebo pill<br>* Other names: marijuana;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numerical Pain Intensity | The primary outcome is self-reported daily average numerical pain intensity during the past 24 hours. The numerical pain intensity is an 11-point pain intensity numerical rating scale (PI-NRS), where 0 equals no pain and 10 equals worst possible pain. The time frame includes baseline and weeks 1, 3, 5, 7, 8. Baseline is the pain tensity reported at the first day in the daily diary, before the first dose. The follow-up pain intensities (weeks 1, 3, 5, 7, 8) are the daily diary average pain intensities since the previously reported timepoint. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Repeated Measures Recommended Minimal Dataset (NIH Task Force on Chronic Low Back Pain) | A Task Force was convened by the NIH Pain Consortium, with the goal of developing research standards for chronic low back pain. The results included recommendations for a repeated measures dataset in order to establish greater consistency in reporting in order to facilitate comparisons among studies. The repeated measure minimal dataset is based upon scores based upon the Patient-Reported Outcomes Measurement Information System ® (PROMIS). These items yield a classification of impacts on the lives of patients that range from 1 (least impact) to 42 (greatest impact). | 8 weeks | 
| Neuropathic Pain Scale | The Neuropathic Pain Scale (NPS) is an 11-point numerical scale consisting of 13 questions that ask ratings of various pain descriptors (including pain intensity, sharpness, burning, aching, cold, sensitivity, itching,unpleasantness, deep, and surface pain). The NPS is scored as the sum of these pain descriptors. Range of scores is from 0 to100. A higher score is a worse score. | 8 weeks | 
| Hopkins Verbal Learning Test | The Hopkins Verbal Learning Test provides information on the ability to learn and immediately recall verbal information across trials, as well at the ability to retain, reproduce, and recognize this information after a delay. A list of 12 words is presented to the subject over three trials. After each trial, the subject is to recall as many items as possible from the list in any desired order. A 20-minute delay follows the administration of the three trials, after which the subject is asked to recall the list. The ability to learn is represented by the number of correct words, with a score range of 0-36. A higher score indicates better performance. | 8 weeks | 
| Grooved Pegboard Test - Dominant Hand | The Grooved Pegboard Test is a test of fine motor coordination and speed. Subjects are required to place 25 small metal pegs into holes on a 3 x 3 metal board. All pegs are alike and have a ridge on one side, which corresponds to a notch in each hole on the board. First the dominant hand is tested, and subjects are asked to place the pegs in the holes as fast as they can. This is then repeated with the non-dominant hand, and the total time for each hand is recorded. A higher score indicates worse performance. | 8 weeks | 
| Wechsler Adult Intelligence Scale-III Digit Symbol Test | The Digit Symbol test measures concentration, psychomotor speed, and graphomotor abilities. This pen and paper test involves having subjects substitute a series of symbols with numbers as quickly and accurately as possible during a 120 second period. The results are expressed as the number of correct substitutions with a score range of 0-133. A higher number indicates better performance. | 8 weeks | 
| Profile of Mood States | This questionnaire contains 65 words/statements that describe feelings people have. The questionnaire requires the patient to indicate for each word or statement how he or she has been feeling in the past week. There are 6 subscales: tension-anxiety (9 items, score 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). The total mood disturbance (TMD) is calculated by adding the scores for tension-anxiety, depression, anger-hostility, fatigue and confusion-bewilderment and then subtracting the score for vigor-activity. The TMD is reported and has a score range of -32 to 200. A higher score indicates worse symptoms. | 8 weeks | 
| Beck Depression Inventory II | The Beck Depression Inventory is composed of items relating to symptoms of depression such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and lack of interest in sex. Range of scores is from 0 to 63. A higher score is a worse score. | 8 weeks | 
| Locally Developed Psychoactive Effect Scale - Good Drug Effect | Visual Analogue Scale (VAS) ratings will be presented as a 100-mm horizontal line, anchored on the left with 'not at all' and on the right with 'extremely'. Participants will pencil in a vertical line along the horizontal line that represents their current feeling (questions usually phrased, 'During the past week, did you feel ___after consuming the vaporized cannabis?'). Ratings will be: any drug effect, a good drug effect, a bad drug effect, high, drunk, impaired, stoned, as if you liked the drug effect, sedated, confused, nauseous, like you desired more of the drug, anxious, down, and very hungry. This is a substudy. A good drug effect is presented. Range of scores is from 0 to 100. A higher score is a worse score. | 6 hours | 
| Marijuana Subscale (M-scale) of the Addiction Research Center Inventory | The Marijuana subscale (M-scale) of the Addiction Research Center Inventory consists of 12 true or false questions corresponding to symptoms of cannabis intoxication; the minimum and maximum scores are 0 and 12 respectively. A higher score indicates a worse score. The questions were rephrased to evaluate the experience from the past week rather than an acute response to cannabis. | 8 weeks | 
| Cold Pressor Test - Pain Sensitivity | Each Cold Pressure Test will begin with an immersion of the left hand into a warm water bath for 3 min. During this time, blood pressure and heart rate will be measured. After removal of the hand from the warm water, skin temperature of the thumbpad will be recorded and participants will listen to a standardized script describing the procedures. Participants will then immerse the left hand into the cold water bath, and will be instructed to report the first painful sensation after immersion. They will then be asked to tolerate the stimulus as long as possible, but will be permitted to withdraw their hand from the cold water at any point. Maximum immersion time will be 2 min. Latency to first feel pain (pain sensitivity) and latency to withdraw the hand from the water (pain tolerance) will be recorded. Blood pressure and heart rate will be measured before and after each immersion using the arm that was not immersed in the water bath. | 8 weeks | 
| Cannabis Withdrawal Scale - Withdrawal Intensity | The Cannabis Withdrawal Scale is an assessment tool used to quantify the presence and intensity of various withdrawal symptoms (e.g., strange dreams, mood swings, depression, lack of appetite, and an inability to get to sleep). Range of scores for withdrawal intensity is from 0 to 190. A higher score is a worse score. | Week 8 and Week 10 | 
| Driving Simulation (Lane Tracking) | Lane Tracking: This task requires subjects to drive down a straight 2-lane road, maintain a constant speed of 55 mph, maintain appropriate lane position, and respond to divided attention tasks in the upper corners of the screen. The primary outcome is standard deviation of lateral deviation (swerving) with a score range of 0.51 - 3.24. A higher score indicates worse performance. The driving simulation assessments are conducted in a substudy, which only includes completers with a valid driver's license and who agreed to participate in the substudy. | 270 minutes | 
| Driving Simulation (Car Following) | Car Following: This simulation examines the participant's ability to closely match the speed of an automobile in front of them. Participants are to follow a lead vehicle at a safe and constant distance. The primary outcome is coherence between the participant and lead cars (a general correlation [0-1] of the participant's ability to accurately track the speed variations of the lead car. A higher score indicates worse performance. The driving simulation assessments are conducted in a substudy, which only includes completers with a valid driver's license and who agreed to participate in the substudy. | 270 minutes | 
| Locally Developed Psychoactive Effect Scale - High | A total of 15 separate VAS ratings will be presented as a 100-mm horizontal line, anchored on the left with 'not at all' and on the right with 'extremely'. Participants will pencil in a vertical line along the horizontal line that represents their current feeling (questions usually phrased, 'During the past week, did you feel ___after consuming the vaporized cannabis?'). Ratings will be: any drug effect, a good drug effect, a bad drug effect, high, drunk, impaired, stoned, as if you liked the drug effect, sedated, confused, nauseous, like you desired more of the drug, anxious, down, and very hungry. This is a substudy. Drug high will be presented. Range of scores is from 0 to 100. A higher score is a worse score. | 6 hours | 
| Cannabis Withdrawal Scale - Negative Impact of Withdrawal | The Cannabis Withdrawal Scale is an assessment tool used to quantify the presence and intensity of various withdrawal symptoms (e.g., strange dreams, mood swings, depression, lack of appetite, and an inability to get to sleep). The outcome is measured during the tapering period (weeks 8 and 10), at which patients slowly withdrew from medication over two weeks. Range of scores for the negative impact of withdrawal is from 0 to 190. A higher score is a worse score. | Week 8, Week 10 | 
| Cold Pressor Test - Pain Tolerance | Each Cold Pressure Test will begin with an immersion of the left hand into a warm water bath for 3 min. During this time, blood pressure and heart rate will be measured. After removal of the hand from the warm water, skin temperature of the thumbpad will be recorded and participants will listen to a standardized script describing the procedures. Participants will then immerse the left hand into the cold water bath, and will be instructed to report the first painful sensation after immersion. They will then be asked to tolerate the stimulus as long as possible, but will be permitted to withdraw their hand from the cold water at any point. Maximum immersion time will be 2 min. Latency to first feel pain (pain sensitivity) and latency to withdraw the hand from the water (pain tolerance) will be recorded. Blood pressure and heart rate will be measured before and after each immersion using the arm that was not immersed in the water bath. | 8 weeks |