Nanotechnology for pain management in orthopedic surgery

Table 1 Benefits of multivesicular particles (DepoFoam bupivacaine^®) based medications

Benefits
High drug-loading capacity combined with controlled release, resulting in enhanced analgesic efficacy
Uniform and lengthy medication liberation
Increased encapsulation yield
Structural stability
Inferior exposure and toxicity in another location
Negligible negative complications
Greater medication half-life
Biocompatibility for medication liberation into frail zones (e.g. epidural, intrathecal)

Table 2 Contraindications to the use of Zynrelef^®

Contraindications
Individuals with proven hypersensitivity to local anesthetics and NSAIDs
Individuals with a history of asthma, urticaria, or allergic reaction related to aspirin or other NSAIDs
Individuals receiving obstetric paracervical block anesthesia
Individuals experiencing coronary bypass surgery

NSAIDs: Non-steroidal anti-inflammatory drugs.

Table 3 Main studies performed on liposome-based formulations (DepoFoam bupivacaine^®, DepoDur^®, Exparel^®, Zynrelef^®) in postoperative pain management in orthopedic surgery

Study	Ref.	Number of patients (n), type of study	Treatment vs comparison	Results
DepoFoam bupivacaine® (a slow-release liposomal bupivacaine-based analgesic)
Bunionectomy	Golf et al[9]	n = 216. Randomized, multicenter, double-blind phase 3 clinical study	Individuals received placebo (n = 96) or DepoFoam bupivacaine® 120 mg (n = 97) via wound infiltration before wound closure	The area under the curve for NRS scores was substantially less in individuals treated with DepoFoam bupivacaine® vs individuals receiving placebo at 24 h and 36 h. More individuals treated with DepoFoam bupivacaine® avoided the use of opioid ‘rescue’ medication during the first 24 h and were pain-free (NRS ≤ 1) at 2 h, 4 h, 8 h, and 48 h
DepoDur® (DepoFoam mixed with morphine)
THA	Viscusi et al[10]	n = 200. Patients scheduled to undergo THA were randomized to receive a single dose of 15 mg, 20 mg, or 25 mg EREM or placebo	15 mg, 20 mg, or 25 mg DepoDur® (single dose, epidural injection) vs saline	All EREM dosages diminished the mean fentanyl usage vs placebo (510 µg vs 2091 µg) and delayed the median time to first dose of fentanyl (21.3 h vs 3.6 h). All EREM cohorts had substantially improved pain control at rest for up to 48 h post-surgery compared with placebo. More EREM-treated individuals rated their pain control as good or very good compared with placebo (at 24 h: 90% vs 65%; at 48 h: 83% vs 67%). No supplementary analgesia was required in 25% of EREM-treated individuals and 2% of placebo-treated individuals at 48 h
Exparel® (bupivacaine liposome injectable suspension)
TKA	Malige et al[11]	n = 100. Prospective, double-blind randomized controlled trial. Each patient received an iPACK block utilizing ropivacaine and was additionally randomized to receive an ACB with Exparel® or ropivacaine	Liposomal bupivacaine 20 mL with 5 mL of 0.5% bupivacaine in ACB and 20 mL of 0.2% ropivacaine in iPACK (local anesthetic infiltration of the interspace between the popliteal artery and the posterior knee capsule) block vs 25 mL of 0.2% ropivacaine in ACB and 20 mL of 0.2% ropivacaine in iPACK block prior to TKA	The Exparel® cohort had a lower hospital length of stay compared to the control cohort (36.3 h vs 49.7 h). Individuals in the Exparel® cohort experienced an improvement in NRS pain score at all postsurgical time points. These individuals also utilized a lower level of inpatient opioids (40.9 MME/day vs 47.3 MME/day) but a similar amount of outpatient opioids (33.4 MME/day vs 32.1 MME/day). Additionally, the Exparel® group showed increased improvements in all Western Ontario and McMaster Universities Osteoarthritis Index sub scores and total scores at most timepoints compared with the control cohort
Zynrelef® (liposome preparation of bupivacaine/meloxicam)
Bunionectomy	Viscusi et al[12]	n = 412. EPOCH 1 was a randomized, double-blind, placebo-controlled and active-controlled phase III study in subjects undergoing a primary unilateral, distal, first metatarsal bunionectomy in which subjects received either a single intraoperative dose of HTX-011, immediate-release bupivacaine HCl or saline placebo	Zynrelef® PR 60/1.8 mg vs bupivacaine HCl by 0.5%. 50 mg via wound infiltration before wound closure	Zynrelef® PR diminished pain intensity by 18% compared to bupivacaine HCl. Opioid consumption was reduced by 37% in the bupivacaine/meloxicam cohort vs 25% in the bupivacaine HCl cohort

ACB: Adductor canal block; EREM: Extended-release epidural morphine; MME: Morphine milligram equivalents; NRS: Numeric rating scale; PR: Prolonged release; THA: Total hip arthroplasty; TKA: Total knee arthroplasty.