Liposomal Bupivacaine After Arthroscopic Rotator Cuff Repair

Arthroscopic rotator cuff repair is among the most painful of orthopedic surgeries (1-3).
Hundreds of thousands of these procedures are carried out in the U.S. each year. Many involve
the use of a brachial plexus nerve block, which serves to control pain for 12 to 14 hours.
However, when the block wears off, many patients are left with severe pain. (4-5) This severe
pain must then be managed at home with oral opioids, which have numerous undesirable side
effects, and may lead to chronic opioid dependence. Thus, any therapy which might reduce the
pain burden on these patients and therefore reduce opioid use and side effects, would be
advantageous.

Recently, a long-acting form of bupivacaine, prepared in liposomes, has been approved for use
by injection in the surgical field, though not for peripheral nerve blockade (6). The drug
has been used to improve postoperative pain after total knee arthroplasty and total hip
arthroplasty when injected in the peri-articular tissues by the orthopedist (7-12), as well
as in other surgeries, both orthopedic and non-orthopedic.(13-16) Unfortunately, preliminary
studies utilizing liposomal bupivacaine as the injectate in peripheral nerve blocks have been
disappointing, largely because the gradual release of the drug did not permit establishment
of effective nerve blockade; it appears to be more effective in the role of analgesic as
opposed to anesthetic (17).

In addition to lower extremity orthopedic procedures, liposomal bupivacaine has also been
demonstrated to reduce pain after shoulder arthroplasty (joint replacement), a similarly
painful shoulder procedure. Liposomal bupivacaine is FDA approved for administration into
surgical sites to produce postsurgical analgesia and mitigate pain, but it hasn't been
evaluated yet as an intervention to provide analgesia for rotator cuff surgery, though the
pain mechanisms for these two procedures, including joint capsule violation and boney
intervention are likely similar.

In this prospective, comparative, randomized, double blinded, placebo controlled trial, we
propose to provide standard therapy for both groups of patients, consisting of interscalene
block with 16 ml of standard 0.5% bupivacaine, as well as propofol infusion to provide
general anesthesia in the operating room and low doses of ketamine for analgesia. In
addition, half of the patients will receive an injection of 266 mg liposomal bupivacaine (FDA
approved dosage) into the subacromial space and peri-articular tissues at the end of surgery.
The other half of the patients will receive an injection of an inert solution of comparable
volume into the peri-articular tissues at the conclusion of surgery (control group).

The primary outcome measure is pain score at 24 hours, which will be obtained by phone follow
up. Secondary outcomes include maximal pain score on postoperative day 1, 2 and 3, total oral
opioid morphine equivalent after 3 days, and occurrence of typical opioid side effects
(nausea, vomiting, drowsiness). In addition to follow up phone call on postoperative day 1,
patients will keep a pain diary, documenting pain scores and opioid use for the first 72
hours, which will be collected by the surgeon in his office at the first postoperative visit.
Any adverse occurrences related to nerve blockade or prolonged bupivacaine effect will also
be recorded.

We expect to enroll 25 patients in each group (total of 50). Sample size is based upon the a
priori assumption that liposomal bupivacaine will result in reduced pain scores by 50% on
postoperative day 1. Inclusion criteria include adult patients, undergoing rotator cuff
repair as outpatients at our facility, ASA physical status category 1 through 3. Exclusion
criteria include inability to receive local anesthetic medications for any reason,
contraindications to peripheral nerve block (coagulopathy, patient refusal, local infection
and pre-existing nerve injury or dysfunction in the operative arm), chronic opioid
dependence, pregnancy and pediatric age group. This study will involve anesthesiology,
orthopedics, physical therapy, pain management and the center for translational science
institute at the University of Pittsburgh.

References:

1. Kim CW, Kim JH, Kim DG. The factors affecting pain pattern after arthroscopic rotator
cuff repair. Clin Orthop Surg. 2014;6:392-400.

2. Uquillas CA, Capogna BM, Rossy WH, Mahure SA, Rokito AS. Post operative pain control
after arthrosopic rotator cuff repair. Review JSES 2016.25(7): 1204-13.

3. Shin SJ, Do NH, Lee J, Ko YW. Efficacy of a subacromial corticosteroid injection for
persistent pain after arthroscopic rotator cuff repair. Am J Sports Med 2016.
44(9):2231-6.

4. Abdallah FW, Halpern SH, Aoyama K, Brull R. Will the real benefits of single-shot
interscalene block please stand up? A systematic review and meta-analysis. Anesth Analg.
2015. 120(5):1114-29.

5. Mifune Y, Inui A, Nagura I, Sakata R, Muto T, Harada Y, TAkase F, Kurosaka M, Kokubu T.
Application of pain quantitative analysis device for assessment of post operative pain
after arthroscopic rotator cuff repair. Open Orthoped J. 2015.9:89-93.

6. Ilfeld BM. Liposome bupivacaine in peripheral nerve blocks and epidural injections to
manage postoperative pain. Exp Opin Pharm. 2013. 14(17):2421-31.

7. Iorio R. The role of liposomal bupivacaine in vale-based care. Am J Ortho. 2016.
45(7):S13-S17.

8. Sporer SM, Rogers T. Postoperative pain management after primary total knee
arthroplasty: The value of liposomal bupivacaine. J Arthroplasty. 2016.
31(11):2603-2607.

9. Chugtai M, Cherian JJ, Mistry JB, Elmallah RD, Bennett A, Mont MA. Liposomal bpuivicaine
suspension can reduce lengths of stay and improve discharge status of patients
undergoing total knee arthroplasty. J Knee Surg. 2016. 29(5):e3

10. Yu SW, Szulc AL, Walton SL, Davidovitch RI, Bosco JA, Iorio R. Liposomal bupivacaine as
an adjunct to postoperative pain control in total hip arthroplasty. J Arthroplasty.
2016. 31(7):1510-5.

11. Cien AJ, Penny PC, Horn BJ, Popovich JM, Taunt CJ. Comparison between liposomal
bupivicane and femoral nerve block in patients undergoing primary total knee
arthroplasty. J Surg Orthop Adv. 2015. 24(4):225-9.

12. Barrington JW, Olugbode O, Lovald S, Ong K, Watson H, Emerson RJ. Liposomal bupivacaine:
A comparative study of more than 1000 total joint arthroplasty cases. Orthoped Clin Na.
2015. 46(4):469-77.

13. Robbins J. Green CL. Parekh SG. Liposomal bupivacaine in forefoot surgery. Foot Ankle
Int. 2015. 36(5):503-7.

14. Huh J, Parekh SG. Liposomal bupivacaine in hallux valgus surgery: a multimodal pain
management adjunct. J Surg Orthop Adv.2014. 23(4):198-202.

15. Hutchins JL, Kesha R, Blanco F, Dunn T, Hochhalter R. Ultrasound-guided subcostal
transversus abdominus plane blocks with liposomal bupivacaine vs. non-liposomal
bupivacaine for posteropative pain control after laparoscopic hand-assisted donor
nephrectomy: a prospective randomized observer-blinded study. Anaesthesia. 2016.
71(7):930-7.

16. Miranda SG, Liu Y, Morrison SD, Sood RF, Gallagher T, Gougoutas AJ, Colohan SM, Loui O,
Mathes DW, Neligan PC, Said HK. Improved health care economic outcomes after liposomal
bupivacaine administration in first-stage breast reconstruction. J Plast Reconstr
Aesthet Surg. 2016. 69(10):1456-7.

17. Ilfeld BM, Malhotra N single injection peripheral nerve block: a dose-response study. Anesth Analg.2013.
117(5):1248-56.

Inclusion Criteria:

- Adult patients up to age 75 years, undergoing elective, ambulatory, arthroscopic
rotator cuff repair.

Exclusion Criteria:

- Pregnancy, coagulopathy, allergy to bupivacaine, renal failure, hepatic insufficiency,
and/or inappropriate candidate for usual therapy (specifically, if unable to receive
the usual preoperative interscalene nerve block: preexisting nerve injury on side of
surgery, refusal of nerve block, infection at site of nerve block).