Determination of highest no effect dose (HNED) for local anaesthetic responses to procaine, cocaine, bupivacaine and benzocaine.

The research article investigates the highest doses of four local anesthetics — procaine, cocaine, bupivacaine, and benzocaine — that can be administered without causing an effect, also known as the highest no effect doses (HNEDs). The study reveals procaine and bupivacaine to have remarkably low HNEDs, cocaine is less potent than anticipated, and 5% topical benzocaine doesn’t exhibit significant local anesthesia action.

Methods of Determining HNEDs

• The researchers used the heat lamp/hoof withdrawal model of Kamerling et al. (1985b) and the abaxial sesamoid block model of local anesthesia to determine the HNEDs.
• The heat lamp rapidly increased the temperature of the superficial skin layers of the pastern to approximately 90 degrees Celsius, which made the animal withdraw its hoof sharply. The absence of this response – thanks to effective local anesthesia – allowed the superficial skin temperatures to exceed 120 degrees Celsius.
• To prevent unnecessary tissue damage, thermal stimulus experiments were stopped after 10 seconds of exposure.

Highest No Effect Doses Results

• Bupivacaine: Following an abaxial sesamoid block with bupivacaine, the HNED for that drug was about 0.25 mg/site. A dose increase to 2 mg/site resulted in a complete and prolonged local anesthesia blockade.
• Procaine: The HNED for procaine was around 2.5 mg/site. Although its dose-response curve followed a similar pattern to bupivacaine, it was shifted 10-fold to the right, meaning higher doses were needed to achieve the same effect. Interestingly, the duration of the local anesthesia response after procaine injection was shorter than for bupivacaine.
• Cocaine: Cocaine was not as effective as procaine, with a HNED of less than 5 mg/site. Even at this dose, the duration of action was considerably short – less than 7.5 minutes.
• Benzocaine: A dose of 800 mg of benzocaine had no significant local anesthesia effect when applied topically at 5% concentration.

Key Insights and Implications

• The results show that the doses producing effective local anesthesia are remarkably low for both bupivacaine and procaine. This suggests that establishing plasma thresholds for these agents may be a challenge.
• Despite cocaine’s common association with potent effects, this study found it to be less effective as a LA than procaine.
• The study’s findings debunk the anesthetic effectiveness of 5% topical benzocaine suggesting that it doesn’t have significant pharmacological impact.