Infiltration analgesia with a local anesthetic is a frequently used technique for performing pain-free surgical procedures on the skin.1,2 The pharmacokinetic conditions during infiltration analgesia of the skin can be manipulated to optimize efficacy. The duration of effect and extent of effect are important. The measures to prolong the duration of effect are based essentially on the reduction of the vasodilatative effect of lidocaine by the addition of adrenergic substances. The resultant reduced hemovascular perfusion rate reduces the resorption and thus the elimination of the active substance.3 To increase the extent of effect, the structure of the extracellular matrix can be loosened by applying a hyaluronic acid–metabolizing enzyme, thus improving the diffusion conditions.4,5
This prospective, randomized, placebo-controlled study (EudraCT 2009-013865-25) investigated the hypothesis that the co-application of hyaluronidase as a diffusion promotor of lidocaine leads to an expanded effect in infiltration analgesia of the skin. The single-center study lasted a maximum 240 minutes for each of the 44 volunteers, of both sexes, aged between 18 and 40 years (Table 1). The effectiveness of 0.5 ml (75 IU) of bovine testicular hyaluronidase (Hylase Dessau 150 IU; Riemser Arzneimittel AG, Greifswald, Germany) was examined versus 0.5 ml placebo (0.9%iger sodium chloride solution) as an additive to 0.5 ml of aqueous 0.5% lidocaine hydrochloride solution (Lidocain Röwo 0.5%; Pharmakon Arzneimittel GmbH, Villmar, Germany). The size of the anesthetized area, the time elapsed to the onset of maximum effect, and the duration of analgesia were determined to validate the efficacy. For this, six points were marked at least 5 cm apart on the volar side of both forearms. The test preparation was applied subcutaneously in a depot under the markings by injection of approximately 1 cm to the side using a 30-gauge injection needle. The size of the anesthetized area was tested using a pinprick needle at 5, 10, 20, and 30 minutes and hourly until sensation returned. The border of the anesthetized area was determined by multiple pricks outward from the marking in a star-shaped pattern and marked with a skin marker. The points so determined were connected to form an outline that was then transferred to a transparent foil. The foil was digitalized using a scanner with a resolution of 600 × 600 dots per inch, and the number of pixels in the area was determined using digital image analysis (SigmaScan Pro, v.4.01.003; SPSS, Inc., Chicago, Ill.). Calculation of the number of pixels per square millimeter was enabled by calibration of the scanning process.
The data from the present study show that co-application of hyaluronidase with lidocaine in subcutaneous application results in bioavailability of analgesic efficacy in a greater tissue volume, especially in the first few minutes after application, by modification of the conditions of diffusion (Fig. 1). No influence on the temporal course of the analgesic effect with respect to either onset or duration of effect was observed (Fig. 2).
Johannes Wohlrab, M.D., Ph.D.
Department of Dermatology and Venereology and, Institute of Applied Dermatopharmacy
Rainer Finke, M.D., Ph.D.
Department of Paediatric Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany
Walter Gerd Franke, Ph.D.
Christian Müller Riemser Arzneimittel AG, Greifswald, Germany
Institute of Applied Dermatopharmacy and, Department of Paediatric Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany
The study was fully sponsored by Riemser Arzneimittel AG. The authors thank Claudia Richter, Claudia Bruhne, and Karin Hölsken for excellent technical assistance.
Dr. Wohlrab received lecture fees and was a cooperative partner in scientific projects and an investigator in clinical studies sponsored by Riemser Arzneimittel AG. Dr. Franke and Christan Müller are employees of the sponsor. The other authors have no conflicts of interest to declare.
1. Adams HA, Kochs E, Krier C. Heutige Anästhesieverfahren: Versuch einer Systematik. Anasthesiol Intensivmed Notfallmed Schmerzther. 2001;36:262–267.
2. Ganzberg S, Kramer KJ. The use of local anesthetic agents in medicine. Dent Clin North Am. 2010;54:601–610.
3. Thornton PC, Grant SA, Breslin DS. Adjuvants to local anesthetics in peripheral nerve blockade. Int Anesthesiol Clin. 2010;48:59–70.
4. Thorpe JN. Procaine with hyaluronidase as local anaesthetic. Lancet 1951;1:210–211.
5. Pettersson LO, Akerman B. Influence of hyaluronidase upon local infiltration anaesthesia by lidocaine: An experimental study in the guinea-pig. Scand J Plast Reconstr Surg. 1984;18:297–301.
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