What evidence is available regarding the off-label use of spinal mepivacaine versus bupivacaine for total hip and total knee arthroplasty?

Introduction

Total knee arthroplasty (TKA) and total hip arthroplasty (THA) procedures are increasingly being performed as outpatient or early-discharge procedures.1-3 The use of spinal anesthesia for these procedures has gained popularity due to a variety of factors, including reduced operating time, improved hemodynamic and cardiopulmonary factors, and decreased bleeding.1,2 However, spinal anesthesia may result in adverse events such as urinary retention and transient neurologic symptoms (TNS), and delayed ambulation, which may postpone discharge.

Spinal anesthesia is performed with injection of a local anesthetic into the cerebrospinal fluid (CSF).4 Bupivacaine, a long-acting amide, is commonly used in the United States and many experts consider it the drug of choice for lower extremity total joint arthroplasties.2,4-6 However, some experts have cited the potentially long duration of spinal anesthesia with bupivacaine (3 to 9 hours) as a reason to investigate the use of mepivacaine, an intermediate-acting agent, for spinal anesthesia.2,5,6

Mepivacaine for spinal anesthesia

Mepivacaine was Food and Drug Administration (FDA)-approved in 1960.7 Mepivacaine is available in 1%, 1.5%, and 2% formulations (the 3% solution is only for dental use) for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks.8-10 Although mepivacaine package inserts state that the mepivacaine is not intended for spinal anesthesia, it has been administered off-label in this manner.4,11 Importantly, only preservative-free formulations should be administered intrathecally.4 According to the prescribing information, the single-dose vials are preservative-free, while the multiple-dose vials contain methylparaben.8,9

As stated above, bupivacaine is a longer-acting amide local anesthetic compared to mepivacaine, which is an intermediate-acting agent.4,12 Bupivacaine is commercially available in hyperbaric (0.75% in 8.25% dextrose) and isobaric formulations (0.5%), while mepivacaine is available in isobaric formulations (1%, 1.5%, and 2%).4 The typical dose for spinal anesthesia for bupivacaine is 6 to 15 mg (12.5 to 15 mg for lower extremity joint arthroplasty), while the dose of mepivacaine is 50 to 70 mg. The typical duration of surgical anesthesia is 1.5 to 2.5 hours for bupivacaine versus 45 to 75 minutes for mepivacaine.

Mepivacaine and risk of transient neurologic symptoms

Mepivacaine was previously used for spinal anesthesia; however, it lost popularity in the late 1990s due to concern for high rates of TNS.5,12 Transient neurologic symptoms include pain or abnormal sensations in the lower back, buttocks, and lower extremities several hours (eg, 2 to 24 hours) after spinal anesthesia is completed.13 Typically these symptoms resolve after several days. However, the exact rate of TNS with mepivacaine is debated, and has reportedly ranged from 0 to 37%.13-17 Of note, studies with higher incidence of TNS used hyperbaric 4% mepivacaine; this formulation is not commercially available in the United States.11,14,15 It has been proposed that the high rates of TNS observed with previous mepivacaine use were due to higher and non-standardized concentrations used, former preservatives, and outdated purification methods.5,6 A 2019 Cochrane review found that risk of TNS was not higher than the risk with lidocaine (based on uncertain evidence), although several other local anesthetics had a lower risk than lidocaine.18 Of note, the included mepivacaine studies were performed in 1998 and 2000.

Literature review

Recently, studies have been published investigating the use of mepivacaine for THA and TKA. The purpose of this FAQ is to discuss recent data comparing mepivacaine to bupivacaine for spinal anesthesia in patients undergoing THA or TKA. Three randomized controlled trials (RCTs) and 1 retrospective review are summarized in the Table.1,2,5,6 One RCT evaluated patients undergoing THA,1 one RCT and one retrospective review examined patients undergoing TKA,5,6 and one RCT evaluated both THA and TKA.2 Of note, the retrospective review and the 2019 RCT were both conducted by the same group (Mahan et al).5,6 All studies were conducted in the United States.

All 4 studies found a benefit for use of mepivacaine versus bupivacaine for the outcomes related to motor or sensory function,1,2,6 ambulation,1 or length of stay.1,5 Schwenk et al (2020) found that a higher percentage of patients could ambulate between 3 to 3.5 hours with mepivacaine compared to hyperbaric or isobaric bupivacaine.1 Wyles et al (2020) found a shorter time to return of lower extremity motor function and more predictable return of motor function with mepivacaine versus bupivacaine.2 The authors demonstrated predictable return of motor function by measuring the proportion of patients requiring >300 minutes to experience return of function. Mahan et al (2019) found faster return of sensory and motor function with mepivacaine, while the retrospective study by Mahan et al (2018) found that use of mepivacaine was associated with a shorter length of stay.5,6 Multiple studies found higher pain scores and/or opioid consumption in the post-anesthesia care unit (PACU) with use of mepivacaine compared to bupivacaine; however, these outcomes did not differ during the remainder of the hospital stay.1,5,6 Transient neurologic symptoms were reported in only 1 of the 4 studies. In the study by Schwenk et al (2020), the rate of TNS was 10% with mepivacaine compared to 11.3% with hyperbaric bupivacaine and 3.9% with isobaric bupivacaine.1 The other 3 studies did not find any reports of TNS.2,5,6

Table. Overview of studies comparing spinal mepivacaine to bupivacaine in THA/TKA.1,2,5,6
Citation/
Design		SubjectsInterventionsResultsLimitations
Randomized controlled trials
Schwenk et al. 20201
 
DB, 2-center, RCT
N=154 patients with ASA I-III, <85 years old, undergoing primary elective THA, and the ability to walk 10 feet without assistance

Exclusion: contraindications to spinal anesthesia, neuropathy in buttocks or posterior thighs, >30 mg daily oxycodone (or equivalent)

Mepivacaine 52.5 mg (3.5 mL of 1.5%) (n=50)
 
Hyperbaric bupivacaine 11.25 mg (1.5 mL of 0.75%) (n=53)
 
Isobaric bupivacaine 12.5 mg (2.5 mL of 0.5%) (n=51)
 
Extra 0.5 mL LA was given for ≥74 inches or BMI ≥35 kg/m2

Patients received a standard pain and anesthesia regimen
 
Percentage of patients who could ambulate 3 to 3.5 h after spinal placement: 70% mepivacaine, 37.7% hyperbaric bupivacaine, 17.6% isobaric bupivacaine (p<0.001)
 
Return of motor function was earlier and LOS was shorter with mepivacaine vs. hyperbaric or isobaric bupivacaine (p=0.001; p=0.049)
 
Patients who received mepivacaine consumed more opioids in the PACU vs. hyperbaric or isobaric bupivacaine, but there was no difference during the remainder of the hospital stay
 
TNS: 10% mepivacaine, 11.3% hyperbaric bupivacaine, 3.9% isobaric bupivacaine (p=NS)
 
Urinary retention, dizziness, and patient satisfaction did not differ between groups
 
One patient assigned to mepivacaine was readmitted 26 days postoperatively for a UTI, possibly related to a difficult attempted Foley catheter placement postoperatively
The mepivacaine group had a slightly shorter surgery duration
 
Sedation adjustment and blood pressure treatment were not standardized
Wyles et al. 20202
 
DB, SC, RCT
N=154 patients undergoing unilateral primary THA or TKA
 
Exclusion criteria: BMI > 45 kg/m2, preexistent substantial lower-extremity sensorimotor deficit, impaired cognition, standard spinal anesthesia contraindications*
 
At baseline, 52% underwent TKA and 48% underwent THA
 
Mepivacaine 70 mg (3.5 mL of 2%) (n=74)
 
Low-dose isobaric bupivacaine 10 mg (2 mL of 0.5%) (n=80)
 
Additional medications not described
Return of motor function was >250 minutes: 9% (7 of 74) mepivacaine vs. 20% (16 of 80) bupivacaine (p=NR)
 
Return of motor function was >300 minutes: 1% (1 of 74) mepivacaine vs. 11% (9 of 80) bupivacaine (p=0.013)
 
Mean time to return of lower-extremity motor function: 185 min mepivacaine vs. 210 min bupivacaine (p=0.016) (TKA, 203 vs. 237 min [p=0.020]; THA, 165 vs. 182 min [p=NS])
 
Median pain scores, orthostatic hypotension, and urinary retention did not differ between groups
 
TNS was not reported while inpatient or at 1-week follow-up
SC study
 
A lower dose of bupivacaine and higher dose of mepivacaine were used compared to other studies
 
Mahan et al. 20196
 
DB, SC, RCT
N=31 patients undergoing TKA
 
Exclusion: contraindications to spinal anesthesia, previous neurologic conditions, chronic back pain or radiculopathy, history of urinary retention/ incontinence, history of PONV
 
 
Mepivacaine 60 to 68 mg (2%; based on height) (n=15)
 
Hyperbaric bupivacaine 10.5 to 12 mg (0.75%; based on height) (n=16)
 
Height between 4’10” and 5’7”: mepivacaine 3 mL (60 mg), bupivacaine 1.4 mL (10.5 mg)
 
Height greater than 5’7”: mepivacaine 3.4 mL (68 mg), bupivacaine 1.6 mL (12 mg)
 
Patients received a standard pain and anesthesia regimen
Use of mepivacaine vs. bupivacaine resulted in a faster return of sensory function (164 min vs. 212 min; p=0.015), motor function (153 vs. 200 min; p=0.025), and straight leg raise (148 vs. 194 min; p=0.023)
 
LOS was not different between groups
 
Time to unintentional urination was shorter with mepivacaine (344 vs. 416 min; p=0.039)
 
Failure to void within 6 h was higher with bupivacaine vs. mepivacaine (13/16 vs. 6/15; p=0.029)
 
Mean PACU VAS scores were greater with mepivacaine vs. bupivacaine (2.7 vs. 1.0; p=0.046), but there was no difference during the remainder of the hospital stay
 
There were no TNS cases in either group
Small sample-size, SC study
 
Sedation during the procedure was not standardized
Retrospective analysis
Mahan et al. 20185
 
Retrospective SC study
N=156 patients undergoing unilateral TKA and received either mepivacaine or bupivacaine
 
Exclusion: history of PONV, urinary retention, chronic narcotic use, BPH
 
Mepivacaine 60 to 68 mg (2%; based on height) (n=53)
 
Hyperbaric bupivacaine 10.5 to 12 mg (0.75%; based on height) (n=103)
 
Height between 4’10” and 5’7”: mepivacaine 3 mL (60 mg), bupivacaine 1.4 mL (10.5 mg)
 
Height greater than 5’7”: mepivacaine 3.4 mL (68 mg), bupivacaine 1.6 mL (12 mg)
 
 
Mean LOS was 28.1 h with mepivacaine vs. 33.6 h with bupivacaine (p=0.002)
 
Mean PACU VAS pain scores (1.3 vs. 0.5; p=0.002) and rate of morphine consumption (2.2 vs. 0.8 morphine equivalents; p=0.002) were higher with mepivacaine vs bupivacaine, but there was no difference for the remainder of the hospital stay
 
Time to ambulation was not different between groups
 
Use of mepivacaine resulted in ability to walk numerically longer distances (82 feet vs. 53 feet on day 0; p=NS; 187.5 feet vs. 163.3 feet on day 1; p=NS)
 
Straight catheterization occurred more frequently with bupivacaine (17 of 103) vs. mepivacaine (2 of 51) (p=0.021)
 
Foley on discharge occurred in 2 of 103 patients with bupivacaine vs. 0 of 53 patients with mepivacaine (p=NS)
 
No cases of TNS were observed
Retrospective review
 
SC study
 
Documentation of urinary incontinence may have been missing
*Standard contraindications defined as: known spinal stenosis, coagulopathy, sepsis, infection at the injection site, patient refusal, or anticoagulation medications not stopped at the appropriate time frame.
Abbreviations: ASA=American Society of Anesthesiologists Status Scale; BMI=body mass index; BPH=benign prostatic hyperplasia; DB=double-blind; LA=local anesthetic; LOS=length of stay; PACU= post-anesthesia care unit; PONV=postoperative nausea and vomiting; NR=not reported; NS=not significant; RCT=randomized controlled trial; SC=single-center; THA=total hip arthroplasty; TKA=total knee arthroplasty; TNS=transient neurologic symptoms; UTI=urinary tract infection; VAS=visual analogue scale.

Conclusion

Mepivacaine was previously used for spinal anesthesia but fell out of favor due to relatively high rates of TNS. Recently, use of spinal mepivacaine for THA and TKA has increased, in part due to reduced time to motor function recovery and patient discharge. Recent RCTs have found that mepivacaine reduced time to ambulation or sensory and motor function compared to bupivacaine. Pain and/or opioid consumption in the PACU were higher with mepivacaine in multiple studies; however, there was no differences between groups for the rest of the hospitalization. Indeed, Mahan et al (2018) observed that rebound pain is a risk with shorter anesthetics. One of the 4 studies found the rate of TNS with mepivacaine was 10.6%, while the other 3 studies did not observe TNS. Overall, preservative-free mepivacaine may be an appropriate option for spinal anesthesia for THA and TKA; however, additional studies are important to further evaluate the safety and efficacy.

References

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  2. Wyles CC, Pagnano MW, Trousdale RT, et al. More predictable return of motor function with mepivacaine versus bupivacaine spinal anesthetic in total hip and total knee arthroplasty: a double-blinded, randomized clinical trial. J Bone Joint Surg Am. 2020;102(18):1609-1615. doi: 10.2106/JBJS.20.00231
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Prepared by:

Patricia Hartke, PharmD, BCPS
Clinical Associate Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2021

The information presented is current as of March 18, 2021.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.