What is the proper administration of penicillin (Penicillin) intramuscularly (IM) with lidocaine (Lidocaine)?

Administration of Intramuscular Penicillin with Lidocaine

Mixing lidocaine 1% (0.2-0.4 mg/kg or approximately 0.25 mL of 2% lidocaine) directly with benzathine penicillin G before injection significantly reduces injection pain and should be standard practice. 1, 2, 3

Evidence-Based Rationale

The FDA label for benzathine penicillin G explicitly states the medication is "painful" and recommends deep intramuscular injection only 4. However, the label does not prohibit mixing with lidocaine, and substantial clinical evidence supports this practice.

Pain Reduction Efficacy

Immediate pain reduction is clinically significant when lidocaine is mixed with benzathine penicillin G:

• Moderate-quality evidence demonstrates a mean pain reduction of -3.84 points on a 0-10 scale immediately post-injection when lidocaine is mixed with BPG compared to sterile water 2
• Pain reduction persists at 5 minutes (mean difference -2.85) and 20 minutes (mean difference -1.85) 2
• In pediatric rheumatic heart disease patients, pain scores at 5 minutes were significantly lower: median VAS score of 2 with lidocaine versus 5 with sterile water (P=0.001) 3
• A 71% uptake rate in clinical practice demonstrates real-world acceptability and effectiveness 5

Pharmacokinetic Safety

Mixing lidocaine with benzathine penicillin G does not alter penicillin pharmacokinetics or efficacy:

• Peak serum penicillin concentrations at 24 hours are identical whether diluted with lidocaine (0.102 μg/mL) or sterile water (0.100 μg/mL) 1
• Detectable penicillin concentrations at 28 days show no statistical difference between preparations 1
• No severe adverse reactions have been reported with this combination 2

Specific Administration Protocol

Preparation and Dosing

Use the following standardized approach:

• Mix 0.25 mL of lidocaine 2% (or 0.2-0.4 mg/kg for weight-based dosing) directly with the benzathine penicillin G in the same syringe before injection 1, 3, 5
• For pediatric patients <17 kg, calculate lidocaine dose at 0.175 mL/kg based on maximum safe lidocaine dosing 6
• Ensure total lidocaine dose does not exceed 5 mg/kg 6

Injection Technique

Follow these critical safety steps to minimize complications:

• Administer by deep intramuscular injection ONLY in the upper outer quadrant of the buttock (dorsogluteal) or ventrogluteal site 4
• Never inject into the anterolateral thigh due to risk of quadriceps femoris fibrosis and atrophy 4
• Use the shortest needle length possible to reach intramuscular tissue while applying concurrent manual pressure to the injection site 6
• Inject slowly to reduce pain 6
• Aspirate before injection to avoid intravascular administration, which can cause severe neurovascular damage including transverse myelitis, gangrene, and Nicolau syndrome 4

Critical Safety Warnings from FDA Label

The following complications have been reported and must be avoided:

• Injection into or near a nerve may result in permanent neurological damage 4
• Inadvertent intravascular administration has resulted in transverse myelitis with permanent paralysis, gangrene requiring amputation, and severe necrosis 4
• Immediate pallor, mottling, cyanosis, bleb formation, and severe edema requiring fasciotomy have occurred 4
• These severe effects occur most often in infants and small children 4
• Do not inject intravenously or admix with other intravenous solutions - cardiorespiratory arrest and death have been reported 4

Alternative Approaches (Less Effective)

Topical lidocaine cream applied to skin before injection is NOT effective:

• EMLA cream applied to intact skin showed no significant pain reduction (mean difference -0.54, P=0.13) 2
• This approach should not be used as it provides no benefit 2

Other local anesthetics may be considered if lidocaine is unavailable:

• Mepivacaine mixed with BPG showed significant immediate pain reduction (mean difference -2.19, P<0.0001) 2
• Procaine mixed with BPG demonstrated lower pain at 1 hour and 24 hours, though evidence quality is lower 2

Common Pitfalls to Avoid

• Do not apply topical lidocaine to skin - it is ineffective for deep IM injections 2
• Do not inject into the anterolateral thigh - this causes quadriceps fibrosis 4
• Do not fail to aspirate before injection - intravascular injection causes catastrophic complications 4
• Do not warm the medication to room temperature alone - while this reduces discomfort per the American Heart Association, it is far less effective than adding lidocaine 6
• Do not use multiple forms of lidocaine simultaneously without calculating total dose to avoid systemic toxicity 6