controlled trial involving 26 patients with chronic neck complaints after whiplash injury a signiﬁcant improvement on total pain was suggested [7, 8].This study however has some methodological problems, such as a relatively short follow-up period of 4 weeks and a small sample size [7, 8]. Based upon the present evidence botulinum toxin cannot be recommended as standard treatment for chronic neck pain after whi- plash injury. We therefore conducted a double blind placebo- controlled randomized trial to conﬁrm if botulinum toxin in treatment of neck pain is indeed effective in chronic whiplash syndrome. Methods j Patients Patients were eligible if they had a whiplash type neck distortion deﬁned as a soft tissue injury of the neck following a vehicle colli- sion, with symptoms lasting longer than 6 months. They also met criteria of the Quebec Task Force grade 1 or 2 whiplash-associated disorders (WAD). WAD grade 1 means only neck pain and stiffness and grade 2 requires also musculoskeletal signs, e.g. a decreased range of motion [24]. Exclusion criteria were: age < 18; pregnancy; neuromuscular disorders; previous use of other investigational new drugs in the past 30 days prior to the screening visit; previous use of botulinum toxin; traumatic abnormalities on radiological ex- aminations. The institutional ethics committee approved the study protocol, and patients gave informed consent before inclusion. j Study design The trial had a double-blind, placebo-controlled parallel design. After patient’s consent was obtained, we recorded demographics (age, gender). During a baseline-period of 4 weeks, patients used a diary to record the presence of neck pain, number of neck pain hours per day, number of days on which medication was taken, and number of tablets taken per day. At the end of this baseline- period (week 0) patients recorded their mean neck pain intensity scored on 100 mm Visual Analogue Scale of the previous 4 weeks (week –4 to 0, VAS-pre-treatment). At week 0, patients were randomly assigned to receive 100 units botulinum toxin (Botox ) or placebo (saline) in 2 cc syringes. At 12 weeks follow-up they recorded again their mean neck pain intensity of the previous 12 weeks (week 0 to 12, VAS-post-treatment). The local trial pharmacist prepared the drug, coded the syringes, and kept treatment codes. The pharmacist had no further participation in the trial. An experienced clinical neurophysiologist (D.T.) per- formed all injections. Injection sites were selected individually (i.e. follow the pain’ approach) in muscles with clinically increased muscle tone or muscle tenderness, and included m. occipito- frontalis, m.temporalis, m. masseter, m. sternocleidomastoideus, m. splenius capitis, m. trapezius and m. semispinalis. j Outcomes After patients were injected at week 0 in one single treatment- session, clinical characteristics were recorded using diaries during the 12 weeks post-treatment. The primary outcome measure was the intensity of the neck pain of the total study period, week 0–12, scored on the VAS at week 12 (one single measurement) compared 291 with baseline (VAS week –4 to 0). Patients were asked to rate (in a single value) severity of neck pain which at times may be mild and perhaps at others severe, by ‘‘integrating severity over time’’. Secondary outcome measures were average number of neck pain days, average number of neck pain hours per day, average number of days on which symptomatic treatment was taken, mean number of symptomatic tablets per day at 12 weeks compared with baseline. Additionally, a blinded investigator asked patients whe- ther there was any improvement in their condition after 4, 8 and 12 weeks in the two treatment groups (ﬁve-point scale: great wor- sening, any worsening, no improvement, any improvement and great improvement). Range of cervical motion was measured with a cervical range of motion (CROM) device to measure the six con- ventional movements of the spine at week 12 compared with baseline. For measurements of CROM, the patients were seated in a chair with their shoulders supported on a backrest. Patients were instructed to assume a comfortable position and then to perform each required movement and return to the start position. The movements were assessed in this order: right rotation, left rotation, right ﬂexion, left ﬂexion, extension, ﬂexion and then summated to determine the mean total range of motion. We also divided all patients in responders and non-responders at week 12. We considered at least 45% reduction in the VAS compared with baseline to be clinically relevant (e.g. responder). All adverse events during the 3 months follow-up were recorded by the investigators. j Sample size determination At baseline we expected mean neck pain intensity on the VAS of 40/ 100 mm. The estimated placebo effect was a 8 mm reduction to a VAS intensity of 32/100 at 12 weeks. We hypothesized a 18 mm reduction in the treatment group to a VAS intensity of 22/100, although there are no earlier data on treatment effect of BTX in these patients. To detect this clinically relevant effect (8 versus 18 mm improvement) at a 5% level of statistical signiﬁcance (two- tailed), with a power of 80%, a total of 40 patients was needed. j Statistical analysis We calculated mean differences between baseline VAS data and VAS data after 12 weeks, using the t-test; statistical uncertainty was expressed in 95% conﬁdence intervals. The responders at week 12 in each treatment group and the differences in improvement scores were compared by use of the Chi-square test. All these analysis were done with SPSS (version 10.0). Results Between November 1999 and March 2003 40 patients were included at Leyenburg hospital The Hague. Of the 59 patients assessed for eligibility, 19 patients were excluded. Four patients did not meet the inclu- sion criteria, eight patients refused to participate and seven patients withdrew in the baseline period. No patient was lost to follow-up. In 1 patient the neck pain diary was incomplete during the whole study period (missing data on neck pain duration, days on which medication was taken and mean number of tablets per day). In 7 patients the neck pain diary for the post-treatment period was