Addition of an Anesthetic Agent to Enhance the Predictability of the Effects of Botulinum Toxin Type A

A Randomized Controlled Study


Objectives: To determine whether the paralyzing effect of botulinum toxin type A reconstituted in a solution of lidocaine with epinephrine is as effective as that of the same toxin reconstituted in saline and to determine whether the addition of lidocaine with epinephrine enhances the predictability of outcomes of botulinum toxin injections.

Subjects and Methods: This double-blind, within-sub­ject, randomized controlled study was conducted in 10 volunteer subjects. Lidocaine was added to botulinum toxin type A to achieve an immediate paralyzing effect on the injected muscle, and epinephrine was added to minimize diffusion of the injected toxin to adjacent mus­cles. This combination of agents was injected to tempo­rarily paralyze the frontalis, corrugator supercilii, and procerus muscles on 1 side of the forehead of the 10 volun­teers. The contralateral side was injected with the same dosage of the toxin, reconstituted in an equal volume of saline, to serve as control. Photographic and video

ince Scott' pioneered the clinical use of botulinum toxin in 1980, it has been used to treat a wide variety of disorders involving muscular dystonias. Applications have been extended more recently to the treatment of auriculotemporal syndrome (Frey syndrome), the reduction of age-related facial wrinkles, and the immobilization of cutaneous wounds to prevent the formation of hypertrophic scars. Botulinum toxins cause flaccid paralysis of striated muscle by irreversibly blocking acetylcholine exocytosis at the neuromuscular end plate. Various serotypes (A-F) of the toxin exist. Serotype A has found the most widespread clinical use. Botulinum toxin type B is expected to be available for clinical use in the near future. These toxins do not diffuse well through the skin and are typically applied by percutaneous injection into the target muscle. Adverse effects, even at dosages required for the treatment of larger muscles, have been reported as mild and transient.'' These adverse effects include diffusion to adjacent muscle groups with resultant reversible functional deficits. To maximize the precision of the intramuscular injections, electromy mentation of the drugs' effects was obtained before injec­tion and at 5 to 10 minutes, 1 week, and 3 months after the injections.

Results: Immediate paralysis ensued on the experi­mental side (botulinum toxin type A + lidocaine + epineph­rine) in all 10 volunteers. As assessed by 3 blinded evalua­tors, the extent of immediate paralysis resulting from the anesthetic agent was predictive of the extent of delayed paralysis resulting from the botulinum toxin. The botuli­num toxin - induced paralysis wore off symmetrically in all subjects.

Conclusion: The injection of botulinum toxin reconstituted in lidocaine with epinephrine provided the physician immediate feedback on the extent of paralysis to be expected from the chemodenervating action of the botuli­num toxin. This may enhance the safety and predictability of botulinum toxin injections in many applications.

Some authors feel that this improves the precision and predictability of the injections.' Because of the delayed onset of action of botulinum toxins, however, follow-up visits and reinjections are often necessary to achieve the desired treatment effect." Most patients do not demonstrate the full effect of the botulinum toxin - induced paraly­sis until 48 to 72 hours after injection. No method exists that gives the physician immediate feedback on the treatment effect.

Local anesthetic agents, such as lidocaine, have been used in combination with local vasoconstrictive agents, such as epinephrine, for the short-term relief of spasticity. The anesthetic agent acts by stabilizing the neuronal mem­brane and inhibiting the ionic fluxes required for the initia­tion and conduction of neuronal impulses. Through this mechanism efferent fibers are blocked, and paralysis of muscles and muscle groups ensues immediately after local injection. The vasoconstrictive agent achieves its effect through its sympathomimetic properties, acting on both a and B-adrenergic receptors. It thereby reduces local diffusion of the anesthetic agent and, as we hypothesize, the diffusion of other simultaneously injected agents as well."

The present study was designed to establish whether the paralyzing effect of botulinum toxin type A is preserved when it is reconstituted in anesthetic (lidocaine) and vasoconstrictive (epinephrine) agents. Additionally, we ana­lyzed whether lidocaine and epinephrine retained their pharmacologic effects in combination with botulinum toxin type A. Finally, we assessed whether the extent of paralysis resulting from the local anesthetic was predictive of the extent of paralysis eventually resulting from botuli­num toxin type A.


Ten volunteers were included in this double-blind, within-subject. randomized controlled study. To be included in the study each subject had to have symmetric mimetic fore-head muscle function, no history of a neuromuscular disor­der, and no allergy to botulinum toxin type A, lidocaine, or epinephrine. According to standard research policy, written informed consent was obtained from all subjects.

Two vials of botulinum toxin type A (Botox) were recon­stituted simultaneously. One vial was reconstituted in 5 mL of preservative-free 0.9% saline to serve as the control drug, and the other vial was reconstituted in 5 mL of 1% lidocaine with 1:100,000 epinephrine (Xylocaine 1% With Epineph­rine 1:100,000) to serve as the experimental drug. The at-tending nurse prepared 2 coded syringes, each containing 1.0 mL of the respective drug. and gave them to the injecting physician in a blinded fashion: ie, the physician was unaware of which substance each syringe contained. One side of the subject's forehead, divided from the contralateral side by the midline, was determined randomly by the nurse as the ex­perimental side. To ensure symmetry of the injections, a template was used to guide placement of the injections (Fig­ure I). This combination of drugs was injected to tempo­rarily paralyze the frontalis. corrugator supercilii. and procerus muscles. Eight predetermined sites were injected with 0.125 mL of the respective drug on each side of the forehead in the same manner used to treat age-related wrinkles of the forehead. This resulted in a total dose of 20 U of botulinum toxin type A to each half of the forehead.

To depict the functional status of the mimetic muscula­ture, photographic and video documentation was recorded using a standardized protocol, showing the patients' faces at rest and with repeated attempts at both furrowing and at raising their eyebrows. All visual documentation was ob­tained by the Mayo Clinic Department of Visual Informa­tion prior to injection and at 5 to 10 minutes. 1 week, and 3 months after the injection.

After all documentation was recorded, a panel of 3 experienced facial surgeons (one of us, D.A.S.. and those acknowledged) assessed the photographs in a blinded fash­ion. using standardized questionnaires. In addition, they assessed video documentation where they felt this was necessary. Random alphanumerical codes were used to label the photographs and videotapes at the time of the blinded assessment. The assessors judged each photo and video separately to answer the following:

  • Is there paralysis present on any side of the forehead? Yes /No
  • If Yes: Does the paralysis differ markedly in extent or intensity between the 2 sides of the forehead? Yes /No
  • If Yes: Which side of the forehead shows the more marked/ more extensive paralysis? Right / Left

Then they judged documentation obtained 5 minutes after the injection to answer the following:

  • Is there marked blanching on any side of the forehead? Yes / No
  • If Yes: Which side(s) of the forehead show(s) marked blanching? Right / Left

Finally the assessors judged documentation obtained 5 min­utes and I week after the injection to answer the following:

  • Does the extent of nntscular paralysis on the left side of this patient's forehead differ markedly between photo/video­tape 1 and 2? Yes /No
  • If Yes: Which photo/videotape shows more marked paraly­sis? 1/2

The last question was repeated for the contralateral side.

Statistical comparisons were evaluated based on the McNemar test for correlated proportions, with 2-sided P values based on exact theory. Comparisons between ex­perimental and control sides focused on comparing the discordant pairs (present on experimental side only vs present on control side only).


Paralysis ensued within 5 to 10 minutes after injection of the experimental drug combination (botulinum toxin type A + lidocaine + epinephrine) in all patients (Figure 2). At the same time, no paralysis was noted on the contralateral side of the forehead after the injection of the control drug (botulinum toxin type A + saline) in all patients. This difference was statistically significant (experimental side vs control side. P=.002).

At 1 week after the injection. symmetric paralysis was present on both the experimental and the control sides of the forehead in all patients (Figure 3). On the experimental side, the extent of the paralysis present at I week after the injection was rated as not markedly different from that present immedi­ately after the injection. On the control side, the paralysis present at I week after the injection was assessed as more marked than that seen immediately after the injection (experi­mental side vs control side. P=.002) (Figures 2 and 3).

The blanching effect of the injected epinephrine was noted in all patients on the experimental side 5 to 10 minutes after the injections (Figure 2). Symmetric return of muscle function (Figure 4) was noted in all patients 3 months after injection.

Injection of botulinum toxin type A
Figure 1. Injection of botulinum toxin type A reconstituted in saline at 1 of 8 points marked through the template onto subject's forehead. Note also midline.

Figure 2. Paralysis of the right side of subject's forehead 5 to 10 minutes after injection of botulinum toxin type A reconstituted in lidocaine with epinephrine. The left side, injected with botulinum toxin type A in saline, demonstrates no immediate paralysis. The subject is attempting maximal brow elevation.


Botulinum toxin injections for the treatment of various disorders, including torticollis, anal fissure, achalasia, tem­poromandibular joint dysfunction, and strabismus, have gained increasing popularity." In experienced hands these methods are reliable, and irreversible functional deficits are rare. The fact that the paralyzing effect of botulinum toxin takes days to occur is a considerable disadvantage, how-ever. The concept of simultaneously injecting botulinum toxin, a local anesthetic, and a vasoconstrictive agent is novel. We hypothesized that this drug formulation would have improved pharmacologic properties compared with those of the pure botulinum toxin. In the present study each component of the formulation maintained its function, and no adverse effects were observed. The anesthetic compo­nent, lidocaine, caused immediate paralysis of the injected muscle and thus gave the injecting physician immediate feedback on the eventual treatment effect. This avoids the need for reinjection days or weeks later because of inad­equate initial dosing. In some uses, for example, to treat spasmodic dysphonia, the immediate feedback may allow the injecting physician to know the injection went to the correct muscle because the patient's voice changed imme­diately. Hyperfunctional lines, which were treated in the present study, are not the result of dystonic muscle func­tion. Other disorders like cervicofacial dystonias are usu­ally associated with severe pain. We presume that the anes­thetic and paralyzing effect of the anesthetic agent would reduce the pain in these patients, as previously reported.

Injection of botulinum toxin type A
Figure 3. Symmetric paralysis I week after injection. The patient is attempting maximal brow elevation.

The vasoconstrictive effect of epinephrine was observed clinically through its blanching effect in all patients. Whether this markedly decreased the local diffusion rate of botulinum toxin was not measured in the present study. The extent and duration of delayed paralysis resulting from the action of botulinum toxin type A was equal for the estab­lished control drug and the experimental drug formulation. The botulinum toxin type A does not appear to be denatured immediately by the drug combinations used as described herein. Yet, refreezing of the botulinum toxin type A and lidocaine with epinephrine combination is not possible be-cause botulinum toxin in this new formulation does lose its efficacy when thawed again.

The clinical response to a certain dose of botulinum toxin type A in the previously untreated patient is difficult to predict, regardless of the application. Various authors. recommend starting with a conservative dose and reinjecting until the desired clinical effect is achieved. As the drug formulation described in this article causes immediate pa­ralysis, the physician receives immediate feedback on the treatment effect. This may decrease the need for titration of injections. As observed clinically, the addition of the vaso­constrictive agent reduced local hemoperfusion. This may decrease local adverse effects caused by diffusion of the toxin to adjacent areas. Reduced local hemoperfusion may also minimize local absorption and therefore reduce the dosage of botulinum toxin needed for the desired treatment effect. This may increase the threshold for systemic toxicity, as is the case for local anesthetic agents. For instance, the maximum dose of lidocaine for infiltration anesthesia is 3 mg/kg, while the maximum dose of lidocaine with epineph­rine for infiltration anesthesia is 7 mg/kg.''' With use of a 1% solution of lidocaine with epinephrine in a 70-kg adult, a total of 490 mg of lidocaine (or 49 mL) can be injected at 1 time. This would be enough to reconstitute 980 U of botuli­num toxin type A at the dose used in this study (5 mL of lidocaine with epinephrine per 100 U of botulinum toxin type A). Because 980 U is well beyond the recommended safe dose of botulinum toxin type A for use at I visit, the lidocaine with epinephrine would not be the limiting factor for patient treatment tolerance. It must be noted that epineph­rine-containing solutions must not be injected into tissues supplied by end arteries, such as fingers.

Further studies will be necessary to quantify the imme­diate and the delayed paralyzing and pain-relieving effects of this novel drug formulation at various concentrations of the separate components, especially when smaller dosages are used and smaller muscles are treated. The relative diffusion distances of lidocaine and botulinum toxin will also have to be analyzed closely so that the dilutions (both concentration and volume) of each substance will result in paralysis in the same size area of a specific muscle.


When reconstituting botulinum toxin type A in lidocaine with epinephrine, all components retain their function. All 3 components have relatively low adverse effect profiles, and no adverse effects were observed in the present study. The immediate paralysis caused by the anesthetic compo­nent was predictive of the delayed paralysis resulting from the botulinum toxin type A. Therefore, when compared with pure botulinum toxin type A injections, this novel formula­tion may be a safer alternative with superior pharmacologic properties. A wide variety of disorders ranging from spas­modic dysphonia to disorders of the lower back muscles could be treated better with such a medication.


We thank clinical photographers Carol J. Sparrow and James R. Hopfenspirger for their expert help, and Michael R. Shohet, MD, and Matthew J. Taylor, MD, for perform­ing blinded assessments.


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Dr. David A. Sherris

The Clinic of Facial Plastic Surgery

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