Bupivacaine is a local and central nervous system anesthetic drug originally discovered in 1957 along with mepivacaine. German chemical engineers isolated bupivacaine from a compound called cinchocaine. Bupivacaine, which has a unique structural design, produces nerve blocks for up to eight hours and is considered a second-line drug for the treatment of pain by the Polyanalgesic Consensus Conference. This drug is often combined with opioid analgesics and, in some cases, is administered as the sole agent for the relief of neuropathic pain. When combined with other drugs such as hydromorphone, morphine, fentanyl or sufentanil there was no drug induced toxicity or complications observed.
Key Studies Establish Stability
Many long-term studies have been performed regarding intrathecal administration of bupivacaine with clonidine or analgesics for the relief of pain. One particular study, again by Lawrence Trissel[1], showed stability of low and high-dose concentrations of morphine sulfate with bupivacaine when packaged in plastic syringes. The study looked at morphine, 5 mg/ml in combination with bupivacaine hydrochloride, 2.5 mg/ml in sodium chloride 0.9%. The findings indicated that there was no loss of morphine or bupivacaine concentrations in the samples that were stored at 4ºC and 23ºC for 60 days.
Additionally, Trissel studied the stability of morphine sulfate, 50 mg/ml and bupivacaine, 25 mg/ml also stored at 4ºC and 23ºC. This study also concluded that there was no loss of potency for up to 60 days. In another study by K.R.Hildebrand[2] et. al., the objective was to show that the drug was effective for relief of pain when administered through an implantable drug delivery device. In this particular study, commercially available bupivacaine at 7.5 mg/ml was incubated at 37°C for 12 weeks within an implantable infusion device. It was revealed that concentrations remained greater than 96 percent in the implantable drug delivery systems. Stability of bupivacaine is well documented in many other publications.
A December 2004 article in the Journal of Pain and Symptom Management showed bupivacaine hydrochloride, 20 mg/ml, morphine sulfate, 50mg/ml and clonidine, 2mg/ml to be stable within an implantable infusion device for 90 days.
Recommended Dosing
At Hartley Medical, we recommend that the starting dose of bupivacaine be maxed out at approximately 1 to 5 milligrams per day. The upper doses of bupivacaine should not exceed 15 milligrams per day. However, various pain physicians in the western United States have utilized bupivacaine for the treatment of both cancer and non-cancer pain, with doses ranging from 30 to 40 mg/day.
Pivotal Role as Anti-Microbial
A very significant study of bupivacaine was published by Per H. Rosenberg, M.D., and Olli V. Renkonen[3]. The authors examined the anti-microbial activity of bupivacaine and morphine against 10 strains of bacteria. Bupivacaine was studied with various microorganisms, in particular E. coli, Pseudomonas aeruginosa, and Staphylococcus aureus and epidermis. The concentrations of bupivacaine examined were 0.5 mg/ml and 1.25, 2.5, and 5 mg/ml. Bupivacaine in concentrations of 2.5 mg/ml inhibited growth of Staph. epidermis strain and Staph. pyogenes as well as Streptococcus pneumonia. Morphine showed no growth-inhibiting activity against bacteria.
The study’s bottom line is that bupivacaine spurs anti-bacterial activity against common pathogens. More significantly, bupivacaine has specific inhibitory effects on Staphylococcus aureus and Staphylococcus epidermis commonly found on human skin. Bupivacaine has a maximum solubility at 40 mg/ml at room temperature. However, bupivacaine’s solubility increases with temperature; therefore, bupivacaine in concentrations exceeding 40 mg/ml can be stable in an implantable infusion device at 37ºC. However, bupivacaine 40mg/ml stability may be compromised when combined with other drugs within an implantable infusion device.