Home › Blog › Is Procaine the New Ropivacaine? Reviewing New PRP Data

How a physician uses local anesthetics with orthobiologics is a great way to spot a novice who may be destroying the positive effects of the treatment. For the past decade, Ropivacaine has been the king of this anesthetic hill among those few physicians who understand how to maximize patient outcomes. However, a colleague sent me some new research to digest about Procaine and PRP. So, let’s dive in.

Local Anesthetics

A local anesthetic is a drug that a doctor can inject to numb an area. These drugs have different set times and durations of action (1,2). For example, lidocaine sets up quickly and lasts a few hours at best. In contrast, bupivacaine sets up more slowly and lasts 2-4 times as long. These drugs also come in two main families: amnio amides and amnio esters. Of the commonly used drugs, lidocaine, bupivacaine, and ropivacaine are amides, whereas procaine is an ester.

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Cell Toxicity and Orthobiologics

While toxicity for local anesthetics is rarely discussed during residency or fellowship training outside of systemic effects, this is a much bigger deal when using orthobiologics. For example, what is the effect of the local anesthetic on the cells the doctor is injecting or the tissue where the doctor is trying to promote repair?

Let’s look at some practical situations to define the issues better. Using a local anesthetic that kills mesenchymal stem cells (MSCs) while injecting MSCs to promote tissue repair would be a pretty dumb move. Or using an anesthetic that kills tendon cells when injecting platelet-rich plasma to help repair tendon cells would be equally ignorant. Having said this, most physicians using orthobiologics haven’t gotten the memo on cell toxicity, so, on the one hand, they’re helping repair damage, and on the other, they are causing it. More on that below.

My Ancient History with Toxic Anesthetics

Remember, my experience in using stem cells to treat orthopedic problems goes back to 2005. In addition, since that experience was in the culture expansion of mesenchymal stem cells, we have always had the ability to see what impacts various drugs had on those cells in culture. Hence, more than 15 years ago, I asked the question of how the local anesthetics we were using impacted MSCs. The results that came back from our lab were disconcerting. Basically, bupivacaine, the world’s most commonly used long-acting anesthetic, was cell toxic down to very low concentrations, well below the commonly used dose. Lidocaine was better, but it still killed cells at its commonly used clinical dose.

What Does the Literature Say About Cell Toxicity and These Drugs?

In general, it’s considered that as far as negative effects on common cells that are present in joints and tendons (tenocytes and chondrocytes), ropivacaine is the least toxic, then lidocaine, with the most toxicity being shown for bupivacaine (4). These same effects in this order also exist for mesenchymal stem cells (5). These results confirm our early observations from the lab.

While there is a large volume of research on these three common local anesthetics, the cellular toxicity data is sparse on the less-used drug Procaine. Given that I have colleagues pinging me about the new PRP study, I performed a literature search on that drug. I found a nerve cell study where Procaine was found to be neurotoxic and is similar to bupivacaine in that effect (3). In addition, other research showed that procaine harmed the osteogenesis of mesenchymal stem cells (6).

Understanding How Platelets Work

A colleague reached out and asked my opinion on a new study (shown above) showing that procaine improved the secretion of exosomes and microvesicles from platelets (7). Sounds impressive, but is it? Nope. To understand that statement, we must learn how platelets release their growth factors over time.

Platelets are packed with alpha vesicles that, in turn, are packed with helpful growth factors (GFs). They also release exosomes. These are released over about a week in a timed fashion, with more GFs of one type released initially and of other types coming out of the platelet much later (8). For example, cell stimulators like TGF-b are released early, while growth factors involved in growing new blood vessels like VEGF are released later. Why? Platelet-based tissue repair is an orchestra where each instrument plays its role at a specific time. Hence, like an orchestra, amping up the horns early may help the music or produce incoherent noise.

Digging into the New Research on Procaine and PRP

The new research exposed the platelets in PRP to either ozone or procaine. Given that ozone is not approved for use in the US, we’ll focus on the effects of procaine, but the effects between the two were similar. The author noted that Procaine, “caused a decrease in surface protrusions and open canalicular system dilation but a remarkable increase in microvesicle release suggestive of high secretory activity.” In other words, they noted more secretions out of the platelets at 2 hours when they were exposed to Procaine.

As you now know, because the timing of what comes out of platelets is critical in the sequencing of the repair response, we can’t say with any certainty that more growth factors released sooner is a good thing. For example, VEGF is usually released late to promote neovasculogenesis (new blood vessels in the repaired tissue). Ozone increased this release at 2 hours, and procaine suppressed it. Is that good or bad? Your guess is as good as mine.

If the authors had wanted to try to determine if Procaine helped platelets repair tissues, they could have done simple in-vitro proliferation and functional testing of cell lines. For example, does this help MSCs proliferate? Or does it help tenocytes repair a gap in a scratch test? Or does it promote more blood vessels in an animal model or heal wounds more quickly? Without that data, it’s hard to know what to make of this paper’s results.

Spotting a Novice Hurting Patients

If you’re a patient, how do you use any of this information to ensure you get the best possible treatment? First, any physician who uses anything other than Ropivacaine that comes in contact with cells or any injured tissue is practicing below the standard of care for interventional orthobiologics. What should you look out for?

• A doctor numbs the inside of your knee joint with lidocaine and then injects PRP or stem cells.
• A doctor numbs your ligament, facet joint, or tendon with bupivacaine (Marcaine) before injecting bone marrow or PRP.

These procedures show no understanding of the basics and run from this provider.

There are times when using something like lidocaine to numb the skin or using it to numb the skin and soft tissues of a bone marrow aspiration is fine. In both cases, the cells or damaged areas to be treated are not coming in contact with the lidocaine.

The upshot? Is using Procaine with PRP a good idea based on this paper? Based on the toxicity data on Procaine, I would say the answer right now is a resounding NO. In addition, the new data published on more platelet secretions is hard to interpret as positive or negative.

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(1) Garmon EH, Huecker MR. Topical, Local, and Regional Anesthesia and Anesthetics. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430894/

(2) Becker DE, Reed KL. Local anesthetics: review of pharmacological considerations. Anesth Prog. 2012 Summer;59(2):90-101; quiz 102-3. doi: 10.2344/0003-3006-59.2.90. PMID: 22822998; PMCID: PMC3403589.

(3) Yu XJ, Zhao W, Li YJ, Li FX, Liu ZJ, Xu HL, Lai LY, Xu R, Xu SY. Neurotoxicity Comparison of Two Types of Local Anaesthetics: Amide-Bupivacaine versus Ester-Procaine. Sci Rep. 2017 Mar 24;7:45316. doi: 10.1038/srep45316. PMID: 28338089; PMCID: PMC5364425.

(4) Caballero M, Kobayashi Y, Gottschalk AW. Local Anesthetic Use in Musculoskeletal Injections. Ochsner J. 2022 Fall;22(3):200-203. doi: 10.31486/toj.22.0061. PMID: 36189094; PMCID: PMC9477137.

(5) Dregalla RC, Lyons NF, Reischling PD, Centeno CJ. Amide-type local anesthetics and human mesenchymal stem cells: clinical implications for stem cell therapy. Stem Cells Transl Med. 2014 Mar;3(3):365-74. doi: 10.5966/sctm.2013-0058. Epub 2014 Jan 16. PMID: 24436443; PMCID: PMC3952925.

(6) Herencia, C., Diaz-Tocados, J. M., Jurado, L., Rodríguez-Ortiz, M. E., Martín-Alonso, C., Martínez-Moreno, J. M., Vergara, N., Rodríguez, M., Almadén, Y., & Muñoz-Castañeda, J. R. (2016). Procaine Inhibits Osteo/Odontogenesis through Wnt/β-Catenin Inactivation. PLOS ONE, 11(6), e0156788. https://doi.org/10.1371/journal.pone.0156788

(7) Inguscio CR, Cisterna B, Lacavalla MA, Donati F, Angelini O, Tabaracci G, Malatesta M. Ozone and procaine increase secretion of platelet-derived factors in platelet-rich plasma. Eur J Histochem. 2023 Oct 10;67(4):3879. doi: 10.4081/ejh.2023.3839. PMID: 37817677; PMCID: PMC10644046.

(8) Lacoste E, Martineau I, Gagnon G. Platelet concentrates: effects of calcium and thrombin on endothelial cell proliferation and growth factor release. J Periodontol. 2003 Oct;74(10):1498-507. doi: 10.1902/jop.2003.74.10.1498. PMID: 14653397.

Chris Centeno, MD is a specialist in regenerative medicine and the new field of Interventional Orthopedics. Centeno pioneered orthopedic stem cell procedures in 2005 and is responsible for a large amount of the published research on stem cell use for orthopedic applications. View Profile