Clinical trial NCT02437383: Study of Orofacial Pain and PropRANOlol
Official title: Effect of COMT (Catecholamine-O-methyltransferase) Genetic Polymorphisms on Response to Propranolol Therapy in Temporomandibular Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Temporomandibular Disorders
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: University of Florida
name: Rho, Inc.
name: National Institutes of Health (NIH)
name: National Institute of Dental and Craniofacial Research (NIDCR)
name: State University of New York at Buffalo
First posted: 2015-05-07
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Purpose:

Primary: To evaluate the efficacy of extended-release (ER) propranolol compared to placebo in the reduction of a pain index in patients with temporomandibular disorder (TMD).

Secondary: To determine if extended-release propranolol efficacy varies according to participants' catechol-O-methyltransferase (COMT) genetic polymorphisms and to investigate the efficacy of extended-release propranolol compared with placebo using secondary endpoints.

Exploratory: To investigate whether the efficacy of extended-release propranolol in the reduction of the pain index varies according to participants' polymorphisms in 3 other genetic regions and according to various phenotypic characteristics.

Participants:

200 patients with chronic TMD will be randomly assigned, in a 1:1 parallel, double-blind fashion, to receive either extended-release propranolol or placebo at one of three study sites: University of North Carolina-Chapel Hill School of Dentistry; University of Florida-Gainesville College of Dentistry; and the State University of New York at Buffalo School of Dental Medicine.

Procedures (methods):

Randomization will be to either propranolol or placebo. The 10-week study treatment period is divided into: 1 week of drug titration, 8 weeks of drug maintenance, and 1 week of drug tapering. The titration and tapering doses are 60 mg (capsules) once per day orally; the maintenance dose is 60 mg twice per day orally. Participants will attend 6 clinic visits over 12-15 weeks as follows: screening and baseline visit (Visit \[V\] 0, 7-21 days prior to V1); randomization and start of treatment (titration) (V1, study day 0); maintenance visit 2 (V2, 1 week post-randomization, study day 7+3); maintenance visit 3 (V3, 5 weeks post-randomization, study day 35 +/- 7); tapering visit (V4, 9 weeks post-randomization, study day 63 +/- 7); and tapering visit 5 (V5, 11 weeks post-randomization and 1 week after drug tapering ends, study day 77 +/- 7). Depending on the visit, procedures will include: reviews of medical history, weekly alcohol consumption, concomitant therapies and medications, adverse events, compliance, and eligibility; administration/review of questionnaires; blood draw; pregnancy test in women of childbearing potential; and dispensing of study drug.

Detailed description: "Temporomandibular disorder" (TMD) encompasses all musculoskeletal disorders of the masticatory system and includes myalgia, arthralgia, temporomandibular joint (TMJ) disc displacements, and TMJ degenerative joint diseases. The prevalence of TMD ranges from 6% to 12% in the general population, with muscle dysfunction the most prevalent TMD diagnostic group. TMD is associated with substantial disability and suffering and negatively impacts quality of life. Jaw pain is the most common symptom that compels treatment seeking. In addition to facial pain, TMD patients frequently report comorbid pain conditions such as headache, low back pain, and fibromyalgia. New approaches to TMD therapy are urgently needed to improve clinical outcomes and reduce economic impact of this disorder.

There is currently no FDA-approved product labeled specifically to manage/treat TMD; however, classes of drugs are used to relieve TMD-associated pain, such as non-steroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory drugs, corticosteroids, benzodiazepines, sedative hypnotics, muscle relaxants, opioids, antidepressants, and anticonvulsants - although evidence to establish their efficacy and safety in this population is scarce. Practitioners' justification for their use may be based on poorly controlled clinical trials or clinical trials in other pain disorders such as acute postsurgical dental pain, arthritic pain, chronic lower back pain, and neuropathic pain. Thus, there is a need for controlled clinical trials to better understand the physiological mechanisms responsible for TMD symptoms.

Evidence suggests that enhanced β-adrenergic drive contributes to the pathogenesis of TMD and other complex persistent pain conditions. For example, individuals with myofascial pain conditions have elevated catecholamine levels and augmented sympathetic responses to stressors. While increased β-adrenergic drive appears to heighten pain, β-adrenergic antagonists can reduce clinical pain and/or nociceptive sensitivity. A recent study of a single infusion of propranolol in TMD and fibromyalgia patients revealed short-term improvement in clinical pain ratings. The antagonist pindolol was similarly efficacious in alleviating cardinal symptoms of fibromyalgia pain. In addition, intramuscular injections of low-dose propranolol in rats reduced inflammatory pain associated with carrageen-induced inflammation of the gastrocnemius muscle.

The study hypothesis is that therapy with the nonselective β-adrenergic receptor antagonist propranolol extended-release capsules (FDA approved to treat many cardiac conditions, tremor, migraine, and pheochromocytoma) will provide efficacious and safe treatment for painful TMD. It has well-studied pharmacodynamic, pharmacokinetic, and side-effect profiles. Peak blood level occurs at approximately 6 hrs, and the plasma half-life is approximately 10 hrs. The primary objective is to investigate the efficacy of propranolol compared with placebo over 9 weeks to reduce pain in patients with TMD. Secondary objectives are to: investigate by treatment group whether reduction in pain varies according to polymorphisms in the COMT gene coding region; and investigate the effect of propranolol compared with placebo to affect pain sensitivity, physical and emotional function, adverse effects, and use of rescue medications. Exploratory objectives are to: investigate gene-by-treatment group interaction to determine the effect of propranolol on reduction in the pain index according to polymorphisms in the COMT, beta-2 adrenergic receptor (ADRβ2), and beta-3 adrenergic receptor (ADRβ3) genetic coding regions.

Eligibility criteria: Inclusion:

* Diagnostic criteria for TMD: Group II, Masticatory Muscle Disorders, Myalgia
* Facial pain for at least 3 months (and at least 10 of the last 30 days at Visit 0)
* Average pain intensity rating ≥30 (0-100 numeric rating scale) over the past week or average daily pain intensity rating ≥30 on the same scale on at least 3 days over the past week
* Agrees to terms for continuing/discontinuing certain prescription/over-the-counter pain medications throughout participation
* Agrees to not commence new prescription medication, injection therapy, occlusal splint therapy or certain other pain management techniques throughout participation
* Agrees to limit consumption of alcohol to no more than 7 drinks/week (females) and no more than 14 drinks/week (males) throughout participation
* If a female of childbearing potential, agrees to use of contraception (licensed hormonal method, intrauterine device, condoms with contraceptive foam, abstinence, or partner vasectomy) throughout participation
* Able to understand and comply with study procedures and provide written informed consent

Exclusion:

* History of congestive heart failure or certain cardiac conditions including coronary artery disease, uncontrolled hypertension, or hypotension
* Bronchial asthma, nonallergic bronchospasm, renal failure or dialysis, diabetes mellitus, hyperthyroidism, fibromyalgia, or uncontrolled seizures
* Currently taking a β-blocker or certain other medications including haloperidol, intravenous verapamil, or reserpine
* Currently taking an opioid medication
* Daily prescription medication, occlusal splint therapy, or an investigational drug or treatment for pain management within past 30 days
* Injection therapy or certain other pain management techniques within last 2 weeks
* Facial trauma or orofacial surgery within past 6 weeks
* Active orthodontic treatment
* History of major depression or other psychiatric disorder requiring hospitalization within past 6 months
* Treatment for drug or alcohol abuse within the last year
* Smokes 25 or more cigarettes/day
* Currently receiving chemotherapy or radiation therapy
* Pregnant or breastfeeding

Primary outcomes:
measure: Change in the Weekly Mean Pain Index After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Secondary outcomes:
measure: Change in the Weekly Mean Pain Intensity After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the Weekly Mean Pain Duration After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the SF-McGill Pain Questionnaire Affective Component After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the SF-McGill Pain Questionnaire Sensory Component After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the SF-McGill Pain Questionnaire Present Facial Pain Intensity After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the SF-McGill Pain Questionnaire Weekly Average Facial Pain Intensity After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the SF-McGill Pain Questionnaire Weekly Average Facial Pain Duration After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the SF-McGill Pain Questionnaire Weekly Fatigue After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Number of Participants Stratified Per Graded Chronic Pain Scale (GCPS) Grade After 9 Weeks of Treatment
timeFrame: Visit 4 (study day 63 +/-7)
measure: Change in the Jaw Functional Limitation Scale (JFLS) Global Score After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the Headache Impact Test (HIT-6) Global Score After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the Pittsburgh Sleep Quality Index (PSQI) Global Score After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Number of Participants Stratified Per Dichotomized Score From the Patient Global Impression of Change (PGIC) Scale After 9 Weeks of Treatment
timeFrame: Visit 4 (study day 63 +/-7)
measure: Change in the Perceived Stress Scale (PSS) Global Score After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the Hospital Anxiety and Depression Scale (HADS) Depression Score After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the Hospital Anxiety and Depression Scale (HADS) Anxiety Score After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the Symptom Checklist 90-Revised (SCL-90R) Somatization Scale Score After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the SF-12 Health Survey v2 (SF-12v2) Physical Component Summary (PCS) After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the SF-12 Health Survey v2 (SF-12v2) Mental Component Summary (MCS) After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Thermal Pain Threshold After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Thermal Pain Tolerance After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Pressure Pain Threshold at Temporalis Muscle After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Pressure Pain Threshold at Masseter Muscle After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/- 7)
measure: Change in Pressure Pain Threshold at Temporomandibular Joint After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Pressure Pain Threshold at Trapezius Muscle After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Pressure Pain Threshold at Lateral Epicondyle After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Pain-free Jaw Opening After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Maximum Unassisted Jaw Opening After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Maximum Assisted Jaw Opening After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Systolic Blood Pressure After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Diastolic Blood Pressure After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in Heart Rate After 9 Weeks of Treatment
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Other outcomes:
measure: Change in the Weekly Mean Pain Index After 9 Weeks of Treatment Stratified Per Number of COMT LPS Haplotypes
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
measure: Change in the Weekly Mean Pain Index After 9 Weeks of Treatment Stratified Per Number of COMT Valine Alleles at rs4680
timeFrame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Locations:
city: Gainesville
country: United States
facility: University of Florida-Gainesville College of Dentistry
state: Florida
city: Buffalo
country: United States
facility: University at Buffalo School of Dental Medicine
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill School of Dentistry
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Inna E. Tchivileva, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida-Gainesville College of Dentistry
name: Roger B. Fillingim, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University at Buffalo School of Dental Medicine
name: Richard Ohrbach, DDS, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Gursoy S, Erdal E, Herken H, Madenci E, Alasehirli B, Erdal N. Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatol Int. 2003 May;23(3):104-7. doi: 10.1007/s00296-002-0260-5. Epub 2002 Oct 22.
citation: Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005 Jan 1;14(1):135-43. doi: 10.1093/hmg/ddi013. Epub 2004 Nov 10.
citation: Tchivileva IE, Ohrbach R, Fillingim RB, Lin FC, Lim PF, Arbes SJ Jr, Slade GD. Clinical, psychological, and sensory characteristics associated with headache attributed to temporomandibular disorder in people with chronic myogenous temporomandibular disorder and primary headaches. J Headache Pain. 2021 May 22;22(1):42. doi: 10.1186/s10194-021-01255-1.
citation: Tchivileva IE, Ohrbach R, Fillingim RB, Lim PF, Giosia MD, Ribeiro-Dasilva M, Campbell JH, Hadgraft H, Willis J, Arbes SJ Jr, Slade GD. Effect of comorbid migraine on propranolol efficacy for painful TMD in a randomized controlled trial. Cephalalgia. 2021 Jun;41(7):839-850. doi: 10.1177/0333102421989268. Epub 2021 Feb 9.
citation: Slade GD, Fillingim RB, Ohrbach R, Hadgraft H, Willis J, Arbes SJ Jr, Tchivileva IE. COMT Genotype and Efficacy of Propranolol for TMD Pain: A Randomized Trial. J Dent Res. 2021 Feb;100(2):163-170. doi: 10.1177/0022034520962733. Epub 2020 Oct 8.
citation: Tchivileva IE, Hadgraft H, Lim PF, Di Giosia M, Ribeiro-Dasilva M, Campbell JH, Willis J, James R, Herman-Giddens M, Fillingim RB, Ohrbach R, Arbes SJ Jr, Slade GD. Efficacy and safety of propranolol for treatment of temporomandibular disorder pain: a randomized, placebo-controlled clinical trial. Pain. 2020 Aug;161(8):1755-1767. doi: 10.1097/j.pain.0000000000001882.
citation: Sanders AE, Slade GD, Fillingim RB, Ohrbach R, Arbes SJ Jr, Tchivileva IE. Effect of Treatment Expectation on Placebo Response and Analgesic Efficacy: A Secondary Aim in a Randomized Clinical Trial. JAMA Netw Open. 2020 Apr 1;3(4):e202907. doi: 10.1001/jamanetworkopen.2020.2907.