Genetic Variants Associated With Low Back Pain and Their Response to Treatment With Duloxetine or Propranolol
NCT ID: NCT03364075
Last Updated: 2018-08-28
Study Results
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Basic Information
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TERMINATED
PHASE2
10 participants
INTERVENTIONAL
2017-09-01
2018-05-31
Brief Summary
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Detailed Description
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Within the population of CLBP patients, two broad subgroups can easily be identified in the clinical setting: the patients who present with CLBP as their only pain symptom, and patients that present with CLBP and also associate widespread painful symptoms. The presence of widespread painful symptoms in the setting of low back pain has been recognized as a strong predictor of chronicity, apart from this, patients in this subgroup are more commonly middle aged females, report higher intensity of pain, more emotional problems and sleep disorders amongst others.
A recent publication by Slate et al has described genetic differences in patients with Temporal Mandibular Disorder (TMD) that present with either localized or widespread painful symptoms. This study established a link between Single Nucleotide Polymorphisms (SNPs) associated to the Serotonin Receptor and patients with localized TDM, and the presence of SNPs associated to the T cell receptor with patients with TMD and widespread symptoms. CLBP and TMD are two chronic pain conditions that are commonly present together. Given the connection between these two chronic pain disorders, it is highly likely that the genetic association findings from Slate et al could also be present in the CLPB population.
The main purpose of this study is to determine if CLBP patients presenting with either localized or widespread painful symptoms respond differently to treatment with Duloxetine, a Serotonin and Norepinephrine Reuptake Inhibitor (SNRI), and if the effectiveness of treatment with this drug can determined by the presence or absence of SNPs associated with the Serotonin receptor.
Another novel treatment alternative for patients with CLBP is Propranolol. This drug is a non-selective beta blocker that has also been shown to have analgesic effects on TMD. These effects though, are only present in patients carrying haplotypes associated with low activity of catechol-O-methyltransferase (COMT). The effect of beta blockers as analgesics has not yet been fully characterized, in animal models, catecholamine stimulation of beta 2 and beta 3 adrenoreceptors has shown to produce hyperalgesia and allodynia, on the other hand, in the clinical setting, the beta 1 selective blocker Esmolol has also been shown to have an analgesic effect in postoperative acute pain management. The inclusion of Propranolol as one of the treatment arms of this study will help elucidate Propranolol's possible role in chronic pain management; the expectation being that a more prominent analgesic effect will be found in patients displaying low activity COMT haplotypes.
Patients will be recruited from the Montreal General Hospital (MGH) Pain Centre and from the Quebec Pain Registry.
This study is a randomized, double-blind, placebo controlled, three period crossover clinical study. Each treatment period will be of two weeks duration with a 1 week washout phase between treatment periods. Following a Latin square design, patients will be randomly assigned to one of six different treatment groups, starting their first treatment cycle with either Duloxetine, Propranolol or Placebo and rotating through the other treatments in the subsequent cycles. The trial has a duration of 56 days total, and involves 6 clinic visits per participant, one at the beginning and at the end of each treatment cycle.
Randomization will be performed by a member of our research group that is not involved in the study using the online software (http//:www.randomization.com). The software's first generator will be used which randomizes each subject to a single treatment group by using the method of randomly permuted blocks. The randomization log will be provided to the pharmacy which will be in charge of dispensing the treatment.
All clinicians and researchers involved in the study data collection and experimental procedures will remain blinded to study group allocation for the duration of the study. Blinding will be maintained until the end for statistical analysis.
In case of serious adverse effects interfering with the patient safety, the blind responsible (pharmacy) will disclose the treatment to the MD of the MGH Pain Centre and that subject will be dropped out of the study.
Conditions
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Study Design
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RANDOMIZED
CROSSOVER
TREATMENT
TRIPLE
Study Groups
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Duloxetine Treatment
patients treated with Duloxetine
Duloxetine
30 mg for seven days, then increased to 60 mg for seven days
Genotype for SNPs associated to Serotonin and COMT
DNA and RNA extraction from blood samples to identify genetic variants associated to pain pathways
Placebo Treatment
1 capsule BID for two weeks
Propranolol Treatment
patients treated with Propranolol
Propranolol
40 mg for seven days, then increase to 60 mg for seven days
Genotype for SNPs associated to Serotonin and COMT
DNA and RNA extraction from blood samples to identify genetic variants associated to pain pathways
Placebo Treatment
1 capsule BID for two weeks
Placebo Treatment
patients treated with placebo
Duloxetine
30 mg for seven days, then increased to 60 mg for seven days
Propranolol
40 mg for seven days, then increase to 60 mg for seven days
Interventions
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Duloxetine
30 mg for seven days, then increased to 60 mg for seven days
Propranolol
40 mg for seven days, then increase to 60 mg for seven days
Genotype for SNPs associated to Serotonin and COMT
DNA and RNA extraction from blood samples to identify genetic variants associated to pain pathways
Placebo Treatment
1 capsule BID for two weeks
Other Intervention Names
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Eligibility Criteria
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Exclusion Criteria
2. History of major depressive disorder, psychotic disorder or schizophrenia, and/or manic episodes within the past year.
3. Pregnancy and/or breast-feeding. Patients who are unsure of their status will also be excluded from participating
4. Pain due to cancer.
5. Disability compensation or litigation.
6. Neurologic signs of lumbosacral radiculopathy within the past 6 months: lower extremity muscle weakness/sensory loss in a dermatomal distribution, abnormal deep tendon reflexes.
7. Radiographic and/or electrophysiology evidence of radicular compression in the past 6 months.
8. Clinical signs of lumbar stenosis within the past 6 months: numbness, weakness, and/or discomfort radiating from the spine down to the buttocks and legs while walking or in prolonged standing and relieved with sitting or lying.
9. Clinical signs of back pain that requires an urgent/alternative intervention: new onset bowel/bladder incontinence, saddle anaesthesia, foot drop, unexplained weight loss, fever.
10. Radiographic evidence of spinal stenosis, high-grade spondylolisthesis (grade 3 or 4), acute spinal fracture, tumour, abscess or acute pathology in the low back/abdominal area in the past 6 months.
11. Low back surgery (lumbosacral spine) within the past 12 months, or history of more than 1 low back surgery.
12. Minimally invasive procedures aimed to reduce pain in the lumbosacral area within the past month (Medial Branch Blocks/Ablations, Epidural Steroid Injections, Trigger point injections, Sacroiliac Joint Injections, Greater Trochanteric/Acetabulofemoral Joint Injections).
13. Known hypersensitivity to Beta Blockers or SNRIs.
14. Currently taking SNRIs, Beta Blockers, Opioids at a daily dose superior to 30mg of Morphine Oral Equivalent, Tricyclic Antidepressants, Methylene Blue, Linezolid, Monoamine Oxidase Inhibitors (such as Selegiline, Isoniazid, Procarbazine), Thioridazine, CYP1A2 inhibitors (Fluvoxamine, Verapamil, Cimetidine, Fluoroquinolone antibiotics such as Ciprofloxacin).
15. Active alcoholism within the past 6 months.
16. Psychoactive recreational drug abuse within the past 6 months including MDMA, Ketamine, hallucinogens such as LSD and/or sympathomimetics such as Cocaine.
17. Patients with asthma, cardiac arrhythmias such as Wolff-Parkinson-White syndrome, coronary artery disease, congestive heart failure, renal failure or dialysis, liver insufficiency, diabetes mellitus, hyperthyroidism.
18. Heart rate less than 60 bpm or systolic/diastolic blood pressure less than 105/60 mmHg during the initial visit.
18 Years
ALL
No
Sponsors
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Mark Ware
OTHER
Responsible Party
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Mark Ware
BA, MBBS, MRCP, MSc
Principal Investigators
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Mark Ware, MBBS MRCP
Role: PRINCIPAL_INVESTIGATOR
Director of Clinical Research Alan Edwards Pain Management Unit
Locations
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Centre for Innovative Medicine - McGill University Health Centre
Montreal, Quebec, Canada
Countries
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References
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Lim KL, Jacobs P, Klarenbach S. A population-based analysis of healthcare utilization of persons with back disorders: results from the Canadian Community Health Survey 2000-2001. Spine (Phila Pa 1976). 2006 Jan 15;31(2):212-8. doi: 10.1097/01.brs.0000194773.10461.9f.
Von Korff M, Crane P, Lane M, Miglioretti DL, Simon G, Saunders K, Stang P, Brandenburg N, Kessler R. Chronic spinal pain and physical-mental comorbidity in the United States: results from the national comorbidity survey replication. Pain. 2005 Feb;113(3):331-339. doi: 10.1016/j.pain.2004.11.010.
Coyte PC, Asche CV, Croxford R, Chan B. The economic cost of musculoskeletal disorders in Canada. Arthritis Care Res. 1998 Oct;11(5):315-25. doi: 10.1002/art.1790110503.
Koes BW, van Tulder M, Lin CW, Macedo LG, McAuley J, Maher C. An updated overview of clinical guidelines for the management of non-specific low back pain in primary care. Eur Spine J. 2010 Dec;19(12):2075-94. doi: 10.1007/s00586-010-1502-y. Epub 2010 Jul 3.
Fairbank J, Gwilym SE, France JC, Daffner SD, Dettori J, Hermsmeyer J, Andersson G. The role of classification of chronic low back pain. Spine (Phila Pa 1976). 2011 Oct 1;36(21 Suppl):S19-42. doi: 10.1097/BRS.0b013e31822ef72c.
Thomas E, Silman AJ, Croft PR, Papageorgiou AC, Jayson MI, Macfarlane GJ. Predicting who develops chronic low back pain in primary care: a prospective study. BMJ. 1999 Jun 19;318(7199):1662-7. doi: 10.1136/bmj.318.7199.1662.
Natvig B, Bruusgaard D, Eriksen W. Localized low back pain and low back pain as part of widespread musculoskeletal pain: two different disorders? A cross-sectional population study. J Rehabil Med. 2001 Jan;33(1):21-5. doi: 10.1080/165019701300006498.
Slade GD, Smith SB, Zaykin DV, Tchivileva IE, Gibson DG, Yuryev A, Mazo I, Bair E, Fillingim R, Ohrbach R, Greenspan J, Maixner W, Diatchenko L. Facial pain with localized and widespread manifestations: separate pathways of vulnerability. Pain. 2013 Nov;154(11):2335-2343. doi: 10.1016/j.pain.2013.07.009. Epub 2013 Jul 16.
Wiesinger B, Malker H, Englund E, Wanman A. Back pain in relation to musculoskeletal disorders in the jaw-face: a matched case-control study. Pain. 2007 Oct;131(3):311-319. doi: 10.1016/j.pain.2007.03.018. Epub 2007 Apr 24.
Millan MJ. Descending control of pain. Prog Neurobiol. 2002 Apr;66(6):355-474. doi: 10.1016/s0301-0082(02)00009-6.
Tchivileva IE, Lim PF, Smith SB, Slade GD, Diatchenko L, McLean SA, Maixner W. Effect of catechol-O-methyltransferase polymorphism on response to propranolol therapy in chronic musculoskeletal pain: a randomized, double-blind, placebo-controlled, crossover pilot study. Pharmacogenet Genomics. 2010 Apr;20(4):239-48. doi: 10.1097/FPC.0b013e328337f9ab.
Other Identifiers
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MUHC15046
Identifier Type: -
Identifier Source: org_study_id
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