Diphenhydramine for Local Anesthesia

Say you have any one of the following three scenarios in a patient who requires local anesthesia for repairing a minor wound laceration in the emergency department:
1 – Documented allergy to “-caine” agents (now, before you grumble…the patient assures you that this is a true allergy; yes, the whole nine yards with full-blown anaphylaxis that occurred years ago with some “-caine”).
2 – Shortage of all forms of parenteral lidocaine 1% and 2% (not a surprise, given the current climate of drug shortages that we routinely encounter in the emergency department).
3 – Close to nearing the toxic dose of your local anesthetic agent of choice…and in the rare circumstance, you have not yet achieved local anesthesia.

What is one to do to? You consult with one of your colleagues, who mentions that there has been some literature published related to the use of parenteral diphenhydramine as a local anesthetic.

Wait a minute…we’re talking Benadryl®? The same stuff that we prescribe to our patients here in the emergency department for all sorts of maladies on a daily basis?

Mind = blown.

Diphenhydramine (DPH) has been utilized as a local anesthetic for several decades. The earliest documentation of the evaluation of antihistamines in this capacity dates back to the 1940s, and with DPH specifically, its use as a local anesthetic in minor skin surgery was first described in 1956 (1). Other clinical applications of the use of DPH as a local anesthetic includes minor dental procedures and podiatric surgery. In terms of its mechanism of action in exertion of this effect, DPH and other H1 receptor antagonists will selectively bind to inactivated sodium channels, leading to stabilization of nerve cell membranes and inhibition of downstream depolarization. This has been hypothesized to be dependent upon the physical structure of DPH; for those readers interested in medicinal chemistry, the interaction of the compound with the inactivated sodium channel leading to the local anesthetic effect exhibited by DPH is attributed to the spatial configuration of the two phenyl moieties in close conjunction with the tertiary amine (2).

In terms of evidence of the use of DPH as a local anesthetic specific to emergency medicine, a number of case reports and clinical studies have been published evaluating its utility relative to other local anesthetics, including lidocaine and benzyl alcohol. In one validation study for its use as a dermal anesthetic, a prospective, randomized, double-blind, placebo-controlled study was conducted to assess both the degree of anesthesia (in square millimeters) and pain associated with injection in 24 subjects who received 0.5-mL injections of 1% DPH, 2% DPH, 1% lidocaine, and 0.9% sodium chloride placebo (3). Subjects who received 1% DPH achieved equivalent level of anesthesia relative to 1% lidocaine (p = 0.889); in addition, 1% DPH more effective in this outcome compared to 2% DPH. However, subjects did experience greater perception of pain at injection with both concentrations of DPH relative to 1% lidocaine (more pain perceived with 2% DPH), with some subjects experiencing persistent discomfort in the injected area for up to three days following injection. In another study evaluating other concentrations of DPH for local anesthesia, although a concentration of 0.5% DPH was deemed similar in perception of pain by patients upon injection compared to 1% lidocaine and a viable alternative to 1% lidocaine in maintaining local anesthesia, it was less effective than lidocaine when used for repairing minor skin lacerations in the face (4). In other head-to-head comparisons of 1% DPH and 1% lidocaine, similar levels and depths of local anesthesia were achieved (5-6).

With all of this mention of pain upon injection, it may be worth noting that the following statement can be found in the package insert for parenteral diphenhydramine (7):

“Use as a Local Anesthetic: Because of the risk of local necrosis, this drug should not be used as a local anesthetic.”

However, most of the data related to this cautionary warning arose as a result of its properties as an irritant to the skin, and reactions observed such as local tissue ischemia and hyperemia have been associated with parenteral administration of high concentrations of DPH. In one of the earliest studies evaluating the use of lower concentrations of antihistamines to determine properties associated with local anesthesia, 1% DPH was generally well tolerated and this was the very basis for utilizing the lower specific concentrations in several of the studies discussed above (8). In fact, in one study, the tolerance associated with injection of 1% DPH was demonstrated to be even more so compared to 2% procaine (1).

The following recipe can be utilized to create a 1% DPH (10 mg/mL) solution using commercially available vials of 50 mg/mL (5%) parenteral DPH (9):

One vial containing 50 mg/mL diphenhydramine for parenteral injection
0.9% sodium chloride
Needle and 10-mL syringe
Medication label


  1. Draw up entire contents of vial containing 50 mg/mL diphenhydramine into the syringe. This should measure to a volume of 1 mL.
  2. Dilute the contents of the syringe with 4 mL of 0.9% sodium chloride to yield a final volume of 5 mL.
  3. Clearly label the contents of the syringe with the medication label as “Diphenhydramine 1% (10 mg/mL).”

Depending on the location and depth of the wound, the amount of 1% DPH necessary to induce local anesthesia may vary, and can range from 1 mL to 10 mL (9). One adverse effect to monitor for with administration and dose escalation of 1% DPH is the potential for sedation, which has been noted to occur in some patients (3).
Going back to our case above, you follow the recipe and prepare a 1% DPH solution for your wound lac, and you administer via injection a total of 2 mL of 1% DPH to your patient for the procedure. Your patient appears to be comfortable and you are able to seamlessly (pun intended) repair the wound lac without any untoward issues.
Done and done.


More from EM PharmD related to Diphenhydramine for Local Anesthesia:

Smoke and Mirrors: Lidocaine Pre-RSI for ICP Reduction


  1. Steffen CG, Zimmerman M, Mihan R. Diphenhydramine hydrochloride as a local anesthetic agent. AMA Arch Derm 1956; 74:76-9.
  2. Kuo CC, Huang RC, Lou BS. Inhibition of Na(+) current by diphenhydramine and other diphenyl compounds: molecular determinants of selective binding to the inactivated channels. Mol Pharmacol 2000; 57:135-43.
  3. Green SM, Rothrock SG, Gorchynski J: Validation of diphenhydramine as a dermal local anesthetic. Ann Emerg Med 1994; 23:1284-1289.
  4. Ernst AA, Marvez-Valls E, Mall G, et al. 1% Lidocaine versus 0.5% diphenhydramine for local anesthesia in minor laceration repair. Ann Emerg Med 1994; 23:1328-1332.
  5. Dire DJ, Hogan DE. Double-blinded comparison of diphenhydramine versus lidocaine as a local anesthetic. Ann Emerg Med 1993; 22:1419-22.
  6. Ernst AA, Anand P, Nick T, et al. Lidocaine versus diphenhydramine for anesthesia in the repair of minor lacerations. J Trauma 1993; 34:354-7.
  7. Diphenhydramine hydrochloride injection. [package insert]. Franklin Lakes, NJ: BD Simplist; 2012.
  8. Steffen CG, Mihan R, Zimmerman M. The evaluation of various antihistamines as local anesthetic agents. J Invest Dermatol 1957; 29:7-8.
  9. Pollack CV, Swindle GM. Use of diphenhydramine for local anesthesia in “caine”-sensitive patients. J Emerg Med 1989; 7:611-4.