Inflammation can prevent local anesthetics from working optimally

Local anesthetics have the potential to create a strong foundation for pain management after surgery. However, most local anesthetics–including extended-release formulations–struggle to work beyond 12 to 24 hours, while severe postoperative pain often lasts through the first 72 hours.1-5

Ionized bupivacaine bouncing off the cell membrane with pain current traveling along cell membrane.

As the inflammatory process unfolds, the wound site becomes increasingly acidic.5

Influx of hydrogen molecules with bupivacaine and sodium at site of injury, pain current traveling along the cell membrane.

This acidity causes more local anesthetic molecules to become ionized outside the nerve cell.5

Hydrogen and bupivacaine molecules, sodium molecules breaching cell membrane, and pain current traveling along the cell membrane.

Ionized local anesthetic molecules cannot diffuse through the nerve cell membrane. Therefore, they are unable to block the sodium ion channels and cannot stop the pain signals from propagating at the surgical site and traveling to the brain.5

Inflammatory phase graph, maximal response over days after wounding. Postoperative inflammation is worst in the first 72 hours.

The Inflammatory Phase

Inflammation at the surgical site continues to increase until around 24 hours and then remains relatively high for 3 days.6 This means long-acting local anesthetics become increasingly ineffectual, regardless of administration injection technique.

Chart: duration of severe pain compared to duration of local anesthetic. Anesthetics last shorter than the pain they’re preventing, creating an efficacy gap.

*Defined as pain of >5 on 1-10 scale. ** ~50 of the top procedures requiring post-op pain management (selected for analysis based on real-world post-op pain management usage).

The efficacy gap

Following surgery, severe pain can often last 72 hours.4 Many products fall short against painful procedures. This creates an efficacy gap. Most often, this gap is filled with the use of opioids.7

Opioids are not an ideal solution

The central nervous system versus the site of injury

Opioids block pain centrally (at the brain), which can reduce the sensation of pain, but they do not block transmission of the pain signals from the site of injury.9

Silhouette of human head with diagram of human brain with dots, signifying opioid receptors

Human body with pointers to specific areas with opioid related adverse events: somnolence, vomiting, respiratory depression, nausea, urinary retention, constipation, pruritus.

Opioid-related adverse events

Opioids can be effective analgesics, but they are often associated with opioid-related adverse events that can make recovery more difficult for patients.8

Unintended consequences

Opioid addiction can begin in many ways. Some patients become dependent as a result of postoperative pain management.

Current WHO analgesic ladder suggests opioids for moderate to severe postoperative pain instead of longer-acting local anesthetics.

New proposed analgesic ladder suggests development of longer-acting local anesthetics to minimize the need of opioids after surgery.

Slide to see the impact a longer-acting local anesthetic could have

What if local anesthetics were capable of more?

Many experts agree it is time to update the existing WHO analgesic ladder to reflect advances in the understanding of the pathophysiology of pain as well as new therapeutic options.16-18

A local anesthetic that can consistently deliver beyond 24 hours of pain relief after surgery could impact the way we treat pain. Opioids could be pushed farther up the treatment algorithm.16,19

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References: 1. Berde CB, Strichartz GR. Local anesthetics. In: Miller RD, Cohen NH, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL, eds. Miller’s Anesthesia. Vol 2. 8th ed. Philadelphia, PA: Saunders; 2015:1012-1054.e4. 2. Carvalho B, Clark DJ, Yeomans DC, Angst MS. Continuous subcutaneous instillation of bupivacaine compared to saline reduces interleukin 10 and increases substance P in surgical wounds after cesarean delivery. Anesth Analg. 2010;111(6):1452-1459. doi:10.1213/ANE.0b013e3181f579de. 3. Kim J, Burke SM, Kryzanski JT, et al. The role of liposomal bupivacaine in reduction of postoperative pain after transforaminal lumbar interbody fusion: a clinical study. World Neurosurg. 2016;91:460-467. doi:10.1016/j.wneu.2016.04.058. 4. Svensson I, Sjöström B, Haljamäe H. Assessment of pain experiences after elective surgery. J Pain Symptom Manage. 2000;20(3):193-201. doi:10.1016/S0885-3924(00)00174-3. 5. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesthesia Progress. 2006;53(3):98-109. doi:10.2344/0003-3006(2006)53[98:EOLAP]2.0.CO;2. 6. Enoch S, Leaper DJ. Basic science of wound healing. Surgery (Oxford). 2007;26(2):31-37. doi:10.1016/j.mpsur.2007.11.005. 7. Data on file. DRG Physician Survey. Heron Therapeutics; 2016. 8. Kessler ER, Shah M, Gruschkus SK, Raju A. Cost and quality implications of opioid‐based postsurgical pain control using administrative claims data from a large health system: opioid‐related adverse events and their impact on clinical and economic outcomes. Pharmacotherapy. 2013;33(4):383-391. doi:10.1002/phar.1223. 9. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115(6):1363-1381. doi:10.1097/ALN.0b013e318238bba6. 10. Brummett CM, Waljee JF, Goesling J, et al. New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg. 2017;152(6):e170504. doi: 10.1001/jamasurg.2017.0504. 11. Hill MV, McMahon ML, Stucke RS, Barth RJ Jr. Wide variation and excessive dosage of opioid prescriptions for common general surgical procedures. Ann Surg. 2017;265(4):709-714. doi:10.1097/SLA.0000000000001993. 12. Banta-Green CJ, Merrill JO, Doyle SR, Boudreau DM, Calsyn DA. Opioid use behaviors, mental health and pain: development of a typology of chronic pain patients. Drug Alcohol Depend. 2009;104(1-2): 34–42. doi:10.1016/j.drugalcdep.2009.03.021. 13. Shah A, Hayes CJ, Martin BC. Characteristics of initial prescription episodes and likelihood of long-term opioid use – United States, 2006-2015. MMWR Morb Mortal Wkly Rep. 66(10):265-269. doi:10.15585/mmwr.mm6610a1. 14. Bates C, Laciak R, Southwick A, Bishoff J. Overprescription of postoperative narcotics: a look at postoperative pain medication delivery, consumption and disposal in urological practice. J Urol. 2011;185(2):551-555. doi:10.1016/j.juro.2010.09.088. 15. Canfield MC, Keller CE, Frydrych LM, Ashrafioun L, Purdy CH, Blondell RD. Prescription opioid use among patients seeking treatment for opioid dependence. J Addict Med. 2010;4(2):108-113. doi:10.1097/ADM.0b013e3181b5a713. 16. Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience. Can Fam Physician. 2010;56:514-517, e202-5. http://www.cfp.ca/content/56/6/514. Published June 14 2010. Accessed January 14, 2019. 17. Vargas-Schaffer G, Cogan J. Patient therapeutic education: placing the patient at the centre of the WHO analgesic ladder. Can Fam Physician. 2014;60:235-341. http://www.cfp.ca/content/60/3/235.long. Published March 13, 2014. Accessed January 14, 2019. 18. Pergolizzi JV, Paladini A, Varrassi G, Raffa R. Change pain: ever evolving—an update for 2016. Pain Ther. 2016;5:127-133. doi:10.1007/s40122-016-0058-x. 19. Crews JC. Multimodal pain management strategies for office-based and ambulatory procedures. JAMA. 2002;288(5):629-632. doi:10.1001/jama.288.5.629.