Botulinum Toxin for Post Abdominoplasty Pain Control

Pain Clinical Trial

Official title:

Intraoperative Botulinum Toxin for Post Abdominoplasty Pain Control

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02840838
• Other study ID #: HM20007433
• Status: Not yet recruiting
• Phase: Phase 4
• First received: July 19, 2016
• Last updated: July 31, 2017
• Start date: December 2018
• Est. completion date: December 2019

Study information

• Verified date: July 2017
• Source: Virginia Commonwealth University
• Contact: Lauren Nigro, MD
• Phone: (804) 828-3039
• Email: lauren.nigro[@]vcuhealth.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

We are investigating ways to reduce pain after abdominoplasty. We hypothesize that injection of Dysport (botulinum toxin A) into the rectus abdominis, abdominal wall musculature, during abdominoplasty will provide a more effective, longer lasting method for pain control than standard of care alone (use of Exparel (liposomal bupivacaine) intraoperatively followed by PRN narcotics. We will randomize patients to receive either Disport + standard of care or saline (placebo) + standard of care and compare post operative pain for the following 2-3 months.

Description:

Pain control after abdominoplasty is an important aspect of patients' post-operative experience. Several methods, including the use of pain pumps, regional blocks, and liposomal bupivacaine, to reduce post-abdominoplasty pain have been described (1-4). The use of these techniques has reduced reported postoperative pain, narcotic requirements, and time to ambulation / normal activity to varying degrees. Unfortunately, these techniques are not without potential complications or limitations (e.g. seroma, cost, inconvenience, or short effect).

Botulinum toxin A (BT) is a neuromuscular blocking agent derived from the bacterium Clostridium botulinum type A. It acts by inhibiting the release of acetylcholine at the neuromuscular junction. Botulinum toxin A is now not only used to mollify chronic pain (5-7), but has also been shown to reduce the pain associated with post-mastectomy breast reconstruction and breast augmentation when injected into the pectoralis muscle (8-10). Although the exact mechanism by which BT reduces pain is not clear, it may alter the sensitivity and response of muscle nociceptors and cholinergic signals (11). Injection of BT into the abdominal wall musculature (rectus abdominis, external and internal oblique, and transversus abdominis) under direction visualization may provide a safe, effective, longer lasting method for pain control than previously described techniques.

This is an exploratory, randomized pilot study with patients blinded to treatment for management of pain after abdominoplasty. There will be two study arms: (1) patients receiving intramuscular injections of intraoperative BT + standard of care and (2) patients receiving intraoperative saline placebo + standard of care (control). Microsoft Excel will be used to create a random list of 100 numbers with 50 of those numbers designating arm 1 treatment group and the other 50 designating arm 2 treatment group. These will be printed and placed in envelopes with treatment group on the inside and patient number on the outside.

Patients seen in the clinic preoperatively will be given informed consent and will then be assigned a treatment envelope by a nurse, which will be kept in the patient's chart. Both patient and nurse will be blinded to the treatment group.

Intraoperatively, the envelope will be opened and used to identify the patient's treatment by the OR nurse and surgeon, who will then administer treatment when clinically appropriate prior to wound closure, either botulinum toxin or equivalent dose of saline alone. Botulinum toxin A (Brand: Dysport), 300 U, will be diluted in 20 mL of normal saline. The treatment will be injected just under the rectus abdominis fascia along its length.

The treatment given will be recorded in the patient's chart. Immediately post-operatively prior to discharge, patients will be asked to complete a questionnaire (attached), which will assess their pain using a visual analog pain scale of 1-10.

After discharge, patients will be asked to record daily opioid use and will again be given the questionnaire assessing pain, time to return to ambulation, and time to return to "normal" activity. This will be completed at the initial post-operative visit and via phone call and recorded by a nurse who is blinded to the treatment group. Assessment will be attempted weekly for the first month in the office or by phone and bimonthly afterwards for the following two months. We will follow the patients for this duration as BT begins working within six hours after administration with a maximum effect between seven and 14 days.

Abdominoplasty will be performed by the same operative surgeon using the same technique throughout the duration of the study. There will be no additional costs to the patient.

All deidentified data will be stored in RedCap, a secure web application.

Study Population:

The study population will include non-pregnant, non-nursing patients over age 18 years with the ability to provide informed consent, undergoing abdominoplasty at the treating surgeon's outpatient surgical center. Exclusion criteria include a history of pre-existing neuromuscular disorders such as myasthenia gravis, Eaton-Lambert syndrome, or amyotrophic lateral sclerosis, hypersensitivity or allergy to Dysport, use of aminoglycosides at the time of surgery (as these antibiotics can potentiate the effect of BT), reported use of BT in the four months preceding surgery, daily pre-operative opioid use, skin infection at the planned surgical site.

Study drug / Interventions:

Dysport (abobotulinumtoxinA) for injection, for intramuscular use. Once reconstituted, it must be stored at 2-8°C, protected from light, and used within 24 hours. For Injection: 300 Units or 500 Units lyophilized powder in a single-use vial for reconstitution with preservative -free 0.9% Sodium Chloride.

Study Schedule/Timeline:

After IRB approval, approximately two patients will undergo abdominoplasty per month for the subsequent two years. After the follow-up period of three months, it is anticipated that this study will conclude after approximately 2-2.5 years.

Statistical Analysis Plan:

Randomization Eligible and consenting patients will be randomized to intervention and control groups using 1:1 allocation ratio. The surgical team will by randomly select a sealed envelopes contain treatment allocation and then administer the respective treatment. The data collector and data analyst will be blinded to group allocation.

Power and Sample size A power analysis based on the differences between the baseline and 8 week observations. If it is assumed that both treatment groups have a common standard deviation of 1.25, then 52 subjects would need to be recruited in order to observe a 1 difference in the change based on a two-sample t-test performed at the 0.05 level at 80% power. It is assumed that the dropout rate will be 10%, thus, 58 total subjects should be recruited. This sample size estimate is likely to be conservative, in that the intention-to-treat analysis that will be performed will have higher power then the analysis used to determine sample size since dropouts and longitudinal information will be used in the analysis.

Analysis plan All analyses will be performed in accordance to the CONSORT Statement. Patient demographics and outcomes variables will be summarized with means and standard deviations, median and interquartile ranges, or frequencies and percentages. The distribution of each of the demographic and outcome variables will be compared between the treatment groups using t-tests or Wilcoxon tests, chi-square tests, or log-rank tests (for time-to-event outcomes). We will analyze data following an intention-to-treat principle. The primary study aim will compare intervention and control group will be made using a repeated-measures ANOVA model which will contain the time, intervention group, and the interaction between the two variables. Estimates of the differences between the study groups will be accompanied by corresponding two-sided 95% confidence intervals, which will be adjusted for multiple comparison is the omnibus test for differences between the treatment groups at any time point indicate a difference. This analysis will be adjusted for covariates that are either not balanced by randomization or have significant relationship with each outcome. A similar model will be use to assess the relationship between opium daily dose and treatment group. A Cox proportional hazard model will be used to compare the time to return to work and activities between the intervention groups.

The aforementioned analyses require assumptions. In the event that the assumptions are not met, transformations and alternate analyses will be considered. All statistical tests will be performed using two-sided tests at the 0.05 significance level with SAS® 9.4 (2).

1. Statistical Solutions Ltd. nQuery + nTerim 3.0. 2014. 2. SAS institute Inc. SAS 9.4. Cary, NC, USA.; 2012.

1. According to the "Determination of IND Exemption for Marketed Drugs", this study meets all of the criteria for exemption.

(i) The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug; (ii) The investigation is not intended to support a significant change in the advertising for the product; (iii) The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product; (iv) The investigation is conducted in compliance with the requirements for review by an IRB (21CFR56) and the requirements for informed consent (21CFR 50); and

2. I changed this to Not Applicable as we are using FDA approved drugs

3. If not applicable for IDSP, there should not be a need for management form (v) The investigation is conducted in compliance with the requirements of 21CFR312.7 (Promotion and sale of investigational drugs).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: December 2019
• Est. primary completion date: December 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• non-pregnant, non-nursing patients over age 18 years with the ability to provide informed consent, undergoing abdominoplasty at the treating surgeon's outpatient surgical center

Exclusion Criteria:

• a history of pre-existing neuromuscular disorders such as myasthenia gravis, Eaton-Lambert syndrome, or amyotrophic lateral sclerosis, hypersensitivity or allergy to either Dysport, Exparel, or cow's milk protein, use of aminoglycosides at the time of surgery (as these antibiotics can potentiate the effect of Botulinum toxin or BT), reported use of BT in the four months preceding surgery, daily pre-operative opioid use, skin infection at the planned surgical site, BMI > 30

Related Conditions & MeSH terms

• Activity
• Pain

Intervention

Drug:
• Dysport
Dysport injection to rectus fascia/muscle
• Placebo
Placebo injection to rectus fascia/muscle

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Virginia Commonwealth University

References & Publications (11)

Arezzo JC. Possible mechanisms for the effects of botulinum toxin on pain. Clin J Pain. 2002 Nov-Dec;18(6 Suppl):S125-32. Review. — View Citation

Chavez-Abraham V, Barr JS, Zwiebel PC. The efficacy of a lidocaine-infused pain pump for postoperative analgesia following elective augmentation mammaplasty or abdominoplasty. Aesthetic Plast Surg. 2011 Aug;35(4):463-9. doi: 10.1007/s00266-010-9633-4. Epub 2010 Dec 7. — View Citation

Gabriel A, Champaneria MC, Maxwell GP. The efficacy of botulinum toxin A in post-mastectomy breast reconstruction: a pilot study. Aesthet Surg J. 2015 May;35(4):402-9. doi: 10.1093/asj/sjv040. Epub 2015 Mar 29. — View Citation

Göbel H, Heinze A, Reichel G, Hefter H, Benecke R; Dysport myofascial pain study group. Efficacy and safety of a single botulinum type A toxin complex treatment (Dysport) for the relief of upper back myofascial pain syndrome: results from a randomized double-blind placebo-controlled multicentre study. Pain. 2006 Nov;125(1-2):82-8. Epub 2006 Jun 5. — View Citation

Layeeque R, Hochberg J, Siegel E, Kunkel K, Kepple J, Henry-Tillman RS, Dunlap M, Seibert J, Klimberg VS. Botulinum toxin infiltration for pain control after mastectomy and expander reconstruction. Ann Surg. 2004 Oct;240(4):608-13; discussion 613-4. — View Citation

Lew MF. Review of the FDA-approved uses of botulinum toxins, including data suggesting efficacy in pain reduction. Clin J Pain. 2002 Nov-Dec;18(6 Suppl):S142-6. Review. — View Citation

Morales R Jr, Mentz H 3rd, Newall G, Patronella C, Masters O 3rd. Use of abdominal field block injections with liposomal bupivicaine to control postoperative pain after abdominoplasty. Aesthet Surg J. 2013 Nov 1;33(8):1148-53. doi: 10.1177/1090820X13510720. Epub 2013 Nov 8. — View Citation

Oppenheimer AJ, Fiala TG, Oppenheimer DC. Direct Transversus Abdominis Plane Blocks With Exparel During Abdominoplasty. Ann Plast Surg. 2015 Nov 5. [Epub ahead of print] — View Citation

Sforza M, Andjelkov K, Zaccheddu R, Nagi H, Colic M. Transversus abdominis plane block anesthesia in abdominoplasties. Plast Reconstr Surg. 2011 Aug;128(2):529-35. doi: 10.1097/PRS.0b013e31821e6f51. — View Citation

Sim WS. Application of botulinum toxin in pain management. Korean J Pain. 2011 Mar;24(1):1-6. doi: 10.3344/kjp.2011.24.1.1. Epub 2011 Feb 25. — View Citation

Zhibo X, Miaobo Z. Botulinum toxin type A infiltration for pain control after breast augmentation. Plast Reconstr Surg. 2009 Nov;124(5):263e-4e. doi: 10.1097/PRS.0b013e3181b98c34. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Post operative pain	Evaluation by Visual analog pain scale of post operative pain	2-3 months post operatively
Secondary	Return to activity	Evaluation by questionnaire of return to daily actvities	2-3 months post operatively