Traumeel S ® for Pain Relief following Hallux Valgus Surgery: A Randomized Controlled Trial

Shepherd R Singer; Michal Amit-Kohn; Samuel Weiss; Jonathan Rosenblum; Guy Maoz; Noah Samuels; Esther Lukasiewicz; Laurence Freedman; Ora Paltiel; Menachem Itzchaki; Meir Niska; Menachem Oberbaum

Disclosures

BMC Clin Pharmacol. 2010;10:1-23. 

In This Article

Methods

Study Design

The study was designed, conducted, and reported according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines,[21] and approved by the ethics committees of the Shaare Zedek Medical Center (SZMC) and the Meir Medical Centers (MMC). All patients scheduled for ambulatory hallus valgus surgery at the Shaare Zedek Medical Center department of orthopedics between 12 September 2006 and 19 November 2007, and at Meir Medical Center between 1 August 2007 and 19 November 2007 were screened for inclusion in the trial. The exclusion criteria were as follows: age under 18 years, bilateral surgery, previous hallus valgus surgery on the ipsilateral foot, diseases possibly effecting wound healing or pain sensation (uncontrolled diabetes mellitus, Berger's disease, deep vein thrombosis, peripheral vascular disease), sensitivity to any of the study medications and technical or cognitive inability to comply with the study protocol. Eighty consecutive patients who fulfilled all inclusion and no exclusion criteria and who signed informed consent were enrolled in the trial.

Study design was randomized and double-blind. Randomization blocks of four subjects were created, and then selected using random number sequence. The HEEL Company (Baden- Baden, Germany) prepared and supplied the study medication or an indistinguishable placebo in 100 consecutively numbered, sealed boxes, according to the randomization list. Sealed copies of the randomization list were held by the manufacturer and a hospital physician not otherwise involved in the trial. These were to be opened only in the event of a medical emergency necessitating knowledge of the treatment allocation of a given patient. Otherwise, patient and all study personnel remained unaware of treatment allocation until the trail was completed and the database sealed, at which point the allocation envelopes were to be opened and the randomization code unveiled. Each eligible patient was assigned the lowest numbered box available. Surgery was performed as orthopedically indicated, with all patients anesthetized using an ankle block of 20 cc Lidocaine 1% and Marcaine 0.5%. Upon completion of surgery, patients were instructed to take two tablets of the study medication five times daily for the first three days, and three times daily afterwards. The composition of Traumeel tablets is displayed in Table 1. Patients also received tablets of paracetamol 325mg with codeine 15mg (Cod-Acamol Forte, Teva Pharmaceutical Industries, Israel) as primary analgesic, to be taken in a two-tablet dose up to six times daily, as needed. Patients additionally received a prescription for Tramadol tablets 100mg (Tramadex, Dexcel Pharma, Israel) as rescue analgesic to be taken as needed, up to a maximum of four tablets a day. The choice of a primary analgesic including a mild opiate was based upon the necessity for standardized primary analgesia while offering patients adequate pain relief over the course of the trial. Previous experience had indicated that non-opiate analgesics were insufficient for this purpose. Patients were instructed to record maximal daily pain scores at rest using a selfadministered, horizontal 11-point numerical rating score (NRS-11), graded from 0 (no pain) to 10 (worst imaginable pain). Patients were further requested to record in the patient diary the number of primary and rescue analgesic tablets taken, and the maximum level of pain at rest they had experienced during that day.

Patients were contacted by telephone every evening by a study nurse, who recorded the reported NSR and analgesic consumption values in the case report form. The nurse also encouraged study compliance. Patients were instructed to withhold study medication if the NRS score was three or less and no other analgesics had been consumed for two consecutive days. Patients were examined by a surgeon on days 6 and 13 days after surgery, and any adverse events, related or unrelated to treatment, were registered. On post-operative day 13, all study materials were collected from the patient.

Efficacy Measures

The primary outcome measure was maximum daily pain at rest, as measured by a horizontal, 11-point numerical rating scale (NRS-11) filled out on the day of surgery (day 0) and for 13 post-operative days. Secondary outcomes were total consumption of primary analgesics and number of days requiring rescue analgesics. Adverse events were monitored throughout the study.

Statistical Analysis

Statistical analysis was performed following the intention-to-treat principle. To compare the post-operative pain between the study groups, the area-under-the-curve (AUC) of the NRS pain scores recorded daily over the 2 weeks post-operative was used. We chose the AUC for both clinical and statistical reasons. Clinically, it summarizes the strength of pain and the number of days the patient experienced pain. Statistically, it is a summary measure which allows one to deal with repeated measurements with no need to adjust for the type 1 error rate. For each patient, an AUC was obtained by graphing the NRS pain scores recorded every day during follow-up, linking time-adjacent points by a straight line and calculating the area under the resulting polygon. When all 14 pain scores are available, this is equivalent to the sum of the 14 scores. Linear interpolation was performed to estimate the NRS score on those days that were missing. The mean AUCs were compared between study groups using the Mann-Whitney test. The repeated measures mixed model was used to test for an interaction between time and treatment allocation. Mann-Whitney tests were used to compare the total amount of primary analgesics consumed and the total number of days taking rescue analgesics. Post-hoc subgroup analysis was performed to assess the influence of type of surgery on post-operative pain scores. Surgical procedures were characterized as 'Chevron only', 'Additional osteotomy', or 'Triple or proximal osteotomy', and Mann-Whitney tests were performed in each subgroup to compare the area-under-the-curve of the NRS pain scores between treatment arms. Frequency of the main adverse events was compared using Fisher's exact test. Sample size was calculated using a conservative interpretation of the data obtained in our previous pilot study,[20] a type I error of 0.05, a power of 90% and a 15% loss to follow-up.

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