Analgesic Effects of Perioperative Propranolol Administration for Spine Surgery

NCT04421209 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: Pro00103364
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine if treatment with low-dose oral propranolol in the days before and after surgery decrease postoperative pain and improve pain scores.

Conditions

Lumbar Disc Disease; Spinal Fusion; Degenerative Disc Disease

Keywords

lumbar fusion; propranolol; beta-blockers; post-surgical pain; opioid-sparing

Outcome Measures

Primary Outcomes (1)

• Acute postoperative opioid use at 24 hours

  Total opioid use from 0 to 24 hours post-op will be quantified. Opioid doses administered via all routes will be converted to standard oral morphine equivalents (OME).

  24 hours postoperatively

Secondary Outcomes (9)

• Acute postoperative opioid use at 48 hours

  48 hours postoperatively

• Sub-acute postoperative opioid use at 1 week

  1 week postoperatively

• Sub-acute postoperative opioid use at 4 weeks

  4 weeks postoperatively

• Sub-acute postoperative opioid use at 12 weeks

  12 weeks postoperatively

• Acute postoperative pain scores at 24 hours

  24 hours post-op

Study Arms (2)

Propranolol treatment

EXPERIMENTAL

Subjects randomized to the propranolol treatment arm will be administered propranolol 40mg BID for three days prior to surgery, 40mg BID the day of surgery and on post-operative days 1 and 2. Subjects and researchers will be blinded and will not know if propranolol or placebo control is administered. Patients will be evaluated for opioid usend pain scores at 24 hrs, 48 hrs, 1 week, 4 weeks, and 12 weeks post-op. Blood will also be obtained pre-operatively, 8 hours and 24 hours post-operatively to measure the level of inflammatory markers. We will use these samples to evaluate if treatment with propranolol decreases the levels of inflammatory markers, and if this correlates to decreased opioid use and pain scores post-operatively. All other pre-, intra-, and post-operative interventions will be equivalent between the experimental and placebo groups, and this study's interventions will not affect surgical management.

Drug: Propranolol Hcl 40mg Tab

Placebo

PLACEBO COMPARATOR

Subjects randomized to the placebo treatment arm will be administered placebo tablets with the same schedule as propranolol in the experimental arm. Subjects and researchers will be blinded and will not know if propranolol or placebo control is administered. Patients will be evaluated for opioid use and pain scores at 24 hrs, 48 hrs, 1 week, 4 weeks, and 12 weeks post-op. Blood will also be obtained pre-operatively, 8 hours and 24 hours post-operatively to measure the level of inflammatory markers. We will use these samples to evaluate if treatment with propranolol decreases the levels of inflammatory markers compared to placebo, and if this correlates to decreased opioid use and pain scores post-operatively. All other pre-, intra-, and post-operative interventions will be equivalent between the experimental and placebo groups, and this study's interventions will not affect surgical management.

Drug: Placebo oral tablet

Interventions

Propranolol Hcl 40mg Tab DRUG

40mg PO BID for the three days prior to surgery, 40mg PO BID the day of surgery and on post-op days 1 and 2.

Also known as: CAS No 525-66-6, DIN: 00496499, Inderal

Propranolol treatment

Placebo oral tablet DRUG

Placebo tablets administered with the same schedule of Propranolol tablets

Also known as: Tablet containing microcrystalline dextrose, Sugar pill, dextrose pill

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients age \>18 undergoing elective spinal fusion surgery, with plans to remain inpatient for ≥ 48hrs and receive IV or oral opioids;
• Females of child bearing potential must test negative on a pregnancy test at Visit 1 and utilize acceptable means of birth control for the duration of the study;
• Patients must be judged by the study team to be likely to be reliable and to agree to keep all appointments for clinic visits, tests, and procedures required by the protocol;
• Patients must have the ability to fully participate in the informed consent process.

You may not qualify if:

• Disease-related: History of exercise- or exertion-induced asthma or current treatments for asthma; Unstable medical or neurological illness; Heart block greater than first degree (EKG); History of coronary artery disease, or history of congestive heart failure; Baseline heart rate or blood pressure that in the opinion of the investigator would constitute too great a risk when considered in the context of the patient's medical comorbidities and health history; Significant suicidal or homicidal ideation, or current DSM-IV diagnosis of bipolar disorder, schizophrenia or other psychotic disorder, or cognitive disorder due to a general medical condition; History of diabetes
• Exposure-related: History of β-blocker use within six months of enrollment in the trial; Total baseline preoperative opioid consumption greater than 50 oral milligram morphine equivalents (MME) per day; Current use or use within the past two weeks of methadone, levorphanol, buprenorphine, butorphanol, pentazocine, tramadol, nalbuphine, naloxone, or naltrexone.
• Patient characteristics: Female patients who are pregnant or breast-feeding; Known allergy to study medication; Alcohol/substance abuse within past six months; Ongoing or anticipated disability compensation or litigation issues, in the best judgement of the investigator; Presence of any factors/conditions, medical or other, that in the judgment of the investigator may interfere with performance of study outcome measures, such as treatment-refractory history; Non-ambulatory or require the use of crutches or a walker; No access to a telephone

Sponsors & Collaborators

• Duke University: lead
• Foundation for Anesthesia Education and Research: collaborator

Study Sites (1)

Duke University Hospital

Durham, North Carolina, 27710, United States

Location

Related Publications (13)

• Afify EA, Andijani NM. Potentiation of Morphine-Induced Antinociception by Propranolol: The Involvement of Dopamine and GABA Systems. Front Pharmacol. 2017 Nov 10;8:794. doi: 10.3389/fphar.2017.00794. eCollection 2017.

  PMID: 29209205 BACKGROUND

• Ciszek BP, O'Buckley SC, Nackley AG. Persistent Catechol-O-methyltransferase-dependent Pain Is Initiated by Peripheral beta-Adrenergic Receptors. Anesthesiology. 2016 May;124(5):1122-35. doi: 10.1097/ALN.0000000000001070.

  PMID: 26950706 BACKGROUND

• Gan TJ, Habib AS, Miller TE, White W, Apfelbaum JL. Incidence, patient satisfaction, and perceptions of post-surgical pain: results from a US national survey. Curr Med Res Opin. 2014 Jan;30(1):149-60. doi: 10.1185/03007995.2013.860019. Epub 2013 Nov 15.

  PMID: 24237004 BACKGROUND

• Hartung JE, Ciszek BP, Nackley AG. beta2- and beta3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines. Pain. 2014 Jul;155(7):1346-1355. doi: 10.1016/j.pain.2014.04.011. Epub 2014 Apr 13.

  PMID: 24727346 BACKGROUND

• Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006 May 13;367(9522):1618-25. doi: 10.1016/S0140-6736(06)68700-X.

  PMID: 16698416 BACKGROUND

• Krebs EE, Lorenz KA, Bair MJ, Damush TM, Wu J, Sutherland JM, Asch SM, Kroenke K. Development and initial validation of the PEG, a three-item scale assessing pain intensity and interference. J Gen Intern Med. 2009 Jun;24(6):733-8. doi: 10.1007/s11606-009-0981-1. Epub 2009 May 6.

  PMID: 19418100 BACKGROUND

• Light KC, Bragdon EE, Grewen KM, Brownley KA, Girdler SS, Maixner W. Adrenergic dysregulation and pain with and without acute beta-blockade in women with fibromyalgia and temporomandibular disorder. J Pain. 2009 May;10(5):542-52. doi: 10.1016/j.jpain.2008.12.006.

  PMID: 19411061 BACKGROUND

• Nackley AG, Tan KS, Fecho K, Flood P, Diatchenko L, Maixner W. Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3-adrenergic receptors. Pain. 2007 Apr;128(3):199-208. doi: 10.1016/j.pain.2006.09.022. Epub 2006 Nov 7.

  PMID: 17084978 BACKGROUND

• Page MG, Kudrina I, Zomahoun HTV, Ziegler D, Beaulieu P, Charbonneau C, Cogan J, Daoust R, Martel MO, Neron A, Richebe P, Clarke H. Relative frequency and risk factors for long-term opioid therapy following surgery and trauma among adults: a systematic review protocol. Syst Rev. 2018 Jul 18;7(1):97. doi: 10.1186/s13643-018-0760-3.

  PMID: 30021647 BACKGROUND

• Stanley TH, de Lange S, Boscoe MJ, de Bruijn N. The influence of chronic preoperative propranolol therapy on cardiovascular dynamics and narcotic requirements during operation in patients with coronary artery disease. Can Anaesth Soc J. 1982 Jul;29(4):319-24. doi: 10.1007/BF03007519.

  PMID: 6213289 BACKGROUND

• 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.

  PMID: 20216107 BACKGROUND

• Teimoori, B., Khoshfetrat, M., Beyrami, F., Sakhavar, N., Dehbashi, Z., Narouie, B., & Davarian, A. Propranolol decreases the post-operative pain and analgesic administration following abdominal hysterectomy. Life Sciences Journal 9: 1216-1220, 2012.

  BACKGROUND

• Zanelatto FB, Dias EV, Teixeira JM, Sartori CR, Parada CA, Tambeli CH. Anti-inflammatory effects of propranolol in the temporomandibular joint of female rats and its contribution to antinociceptive action. Eur J Pain. 2018 Mar;22(3):572-582. doi: 10.1002/ejp.1143. Epub 2017 Dec 11.

  PMID: 29226500 BACKGROUND

MeSH Terms

Conditions

Intervertebral disc disease; Intervertebral Disc Degeneration; Pain, Postoperative

Interventions

Propranolol; Glucose

Condition Hierarchy (Ancestors)

Spinal Diseases; Bone Diseases; Musculoskeletal Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Pain; Neurologic Manifestations; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Hexoses; Monosaccharides; Sugars; Carbohydrates

Study Officials

• Thomas Buchheit, MD

  Department of Anesthesiology, Duke University

  PRINCIPAL INVESTIGATOR

• Stephan Frangakis, MD/PhD

  Department of Anesthesiology, Duke University

  STUDY DIRECTOR

• William Maixner, DDS/PhD

  Department of Anesthesiology, Duke University

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 4, 2020
• First Posted: June 9, 2020
• Study Start: December 1, 2020
• Primary Completion: June 30, 2021
• Study Completion: September 30, 2021
• Last Updated: March 16, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)