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Local pain during REBIF injection is not due to acidic pH
  1. M Buttmann,
  2. M Goebeler,
  3. P Rieckmann
  1. Clinical Research Unit for Multiple Sclerosis and Neuroimmunology, Department of Neurology and Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany
  1. Correspondence to:
 Dr M Buttmann;

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In our clinical experience, local pain at the injection site is a common adverse event for persons with MS receiving subcutaneous REBIF (interferon-β1a) injections. Most of our patients experiencing this describe a moderate burning or stabbing pain during injection, that may persist for a few minutes. These reactions vary among individuals and also for the same individual on different occasions. The acidic pH of REBIF, which is necessary to ensure stability of the IFN-β1a solution, is considered a possible cause of pain. We provide data suggesting that the pH of 3.8 cannot be the sole reason for the local pain during REBIF injection.

Seven unselected subjects with MS, all having received REBIF 22 (22 µg IFN-β1a) for at least three months before our study, also participated in a skin biopsy study (reported separately). As part of the present investigation, we assessed events related to the injections. Our study was approved by the local ethics committee of the Medical Faculty at the University of Würzburg, and all patients gave written informed consent before participation.

All the recipients were asked before injection to describe their sensations during and after the procedure, to which they were all blinded. The unblinded clinical investigator made no comments until the skin biopsies had been completed the next day, nor were the participants asked any additional questions. They received 0.5 ml REBIF 22 over 10 seconds in one buttock and directly afterwards 0.5 ml placebo, or vice versa, over 10 seconds in the other buttock, by subcutaneous injection. None of the patients had previously received REBIF in the buttock. All solutions were warmed to hand temperature before injection. Injection sites were not cooled before or after injection. Steps were taken to ensure that there were no drops at the needle tips. The placebo, as provided by our local pharmacy, was of similar composition to the commercial REBIF preparation apart from IFN-β1a and consisted, as did the placebo used in the clinical REBIF trials, of 8.0 mg/ml human serum albumin and 54.6 mg/ml mannitol, osmolality 362 mOsm/kg, pH 3.8 (adjusted with acetic acid).1–3 Sterility of the preparation was extensively tested before use by a specialised commercial laboratory (Labor L+S AG, Bad Bocklet, Germany). The placebo was administered with a Sterican needle (Braun, Kronberg, Germany) of the same diameter as the REBIF needle (27 gauge).

All seven subjects reported a moderate burning pain at the REBIF site during injection. The pain was described as similar to what they had previously experienced in all cases. At the site of placebo injection, only a slight feeling of pressure during the injection was reported and almost no pain. Without specifically being asked, all seven individuals correctly identified the REBIF injection site. Our findings provide evidence that the pain of REBIF injection cannot be solely due to the acidic pH of REBIF, because no pain was perceived with placebo injections at a similar pH. Rather, the pain may be due to IFN-β in combination with the acidic pH, to other aspects of the IFN-β formulation, or to the needle tip used for injection. Although pain can be overcome to some extent by cooling of injection site before and after the procedure, the true cause of the pain remains to be elucidated.


We thank Professor K V Toyka for critical reading of the manuscript.



  • The study was supported by an unrestricted educational grant from Serono, the manufacturer of REBIF (, and by local funds from the state of Bavaria.

  • PR has received speaker’s fees from Serono.

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