Theophylline Incidence study of behavioural changes in children: follow-up comments

In response to a recent article [Reactions 162: 11, 28 Feb 1987], the behavioural abnormalities recorded were assessed on unpublished check lists which therefore cannot be standardised. The check lists used by the parents and teachers did not appear to be the same, and 'school performance' was not defined by the authors. No behavioural effect was determined by psychological testing. DiTraglia J. Pediatrics 80: 122, 1 Jul 1987

In reply to the above, the check lists used were different because settings and behaviours being evaluated by parents and teachers were not the same. Further, the check lists have been published and standardised. Finally, the formal psychological testing may not have been sufficiently sensitive to detect some abnormalities, but 'school performance' (as defined by the parameters detailed in the table) as assessed by teachers detected . behavioural dysfunctions, Each child was evaluated by their own teacher, Rachelefsky GS. Pediatrics 80 122·123, 1 Jul

1987

In reference to the above·mentiond article, although there was a significant difference between the scores for the teachers' behavioural assessment for theophylline vs placebo, there was also a significant increase and decrease, respectively, for theophylline and placebo, in post­treatment compared to pre-treatment scores which was not accounted for,

Group comparability was established with no significant differences between the 2 groups in the pretreatment score while the post­treatment scores were significantly different; however, the difference in scores could also be explained by an initial subject bias, with more 'problem' children initially in the theophylline group and more 'normal' children in the placebo group,

Finally, of 53 statistical tests of significance performed for the teacher behavioural assessment score, 5 gave statistically significant results with theophylline vs placebo; 2 more than would be expected purely by chance. Schriver Re. Pediatrics 80: 123, 1 Ju11987

In reply to the above, a placebo effect in a double-blind controlled trial is not unusual, and the interpretation of the trial results must take this into account. Randomisation was performed by a computerised schedule and although the 2 highest

8 REACTIONS·' 8 Aug 1987

pretreatment scores were in the theophylline group there was extensive overlap between groups. The post-treatment difference in scores was detected by the teachers' observations and thus would seem to be clinically relevant. The evaluation of separate items was carried out to identify any particular aspects of behaviour to have been affected, but should be interpreted with caution, The claimed effect of theophylline was based on the total score difference between groups which was highly significant (p = 0.04). Rachelefsky GS. WO J, Aderson J, Mickey MR, Spector SL. et al. Pediatrics 80: 123-124, 1 Jul 1987

With reference to the above mentioned article, the double-blind status of the trial is contradicted by the different number of blood samples taken in the active drug group and the placebo group. The teachers' behavioural assessment findings were not supported by the parent ratings or psychological tests, and there was no direct assessment of school achievement, academic skills or learning.

The short term nature of the trial did not allow for the 'interaction of length of treatment and tolerance to drug'. This interaction has been proposed for caffeine and long term studies have revealed similar CNS effects from caffeine and theophylline. Weinburger M, Lindgren S, Joad J PediatriCS 80: 124·125, 1 Jul 1987

In reply to the above, the double­blind status of the trial remained intact; 20 teachers were evaluating children in 19 different schools and neither teachers, children, parents nor investigators had any way of knowing whether the child was receiving theophylline or placebo and the physician involved in medication administration was not involved in collecting the results.

No known published studies have prospectively evaluated the adverse effects of oral theophylline on school performance and the references cited did not address specific assessment of school behaviour.

Childhood asthma does not generally require chronic treatment; the study population was considered to be representative of asthmatic children.

Long term effects were not being assessed. The short term study performed demonstrated that serum theophylline concentrations > 10 II-g/ ml in children 'may affect how the child functions at school and the physician must ask the parents/child regarding this potentially adverse effect'.

Rachelefsky GS, WO J, Adelson J, Mickey MR, Spector SL. et at. Pediatrics 80: 125, 1 Jul 1987

With reference to the above­mentioned study, the positive findings in the study (teacher evaluations) were not clearly presented. The double-blind status of the study was contradicted by the different number of blood samples drawn in the theophylline­(once every 3 days) vs placebo (at the beginning and end of the study only) treated patients. The blood drawing itself may have adversely affected behaviour.

A positive placebo effect was observed, whereas the behaviour of the theophylline group significantly worsened; that of the placebo group significantly improved and this placebo effect was not accounted for. Most of the itemised significance tests, however, showed no difference between theophylline and placebo.

The correct identification of 7 of the children on theophylline and all on placebo by their teachers suggests that there may have been confounding variables in this trial. Further research is required to verify the findings of this study, Rappaport L, Fenton T, Twarog F. Pediatncs 80: 125-126, 1 Jul 1987

In reply to the above, the double­blind nature of the trial was maintained, The consent form did not give any information to change that status, and any adverse effect of blood drawing would have been seen in both groups; however, this was not likely to have any noticeable effect during the tria1.

The placebo effect observed is not unusual in a double-blind controlled trial, and the interpretation of the trial results must take this into account.

The evaluation of separate items was carried out to identify any particular aspects of behaviour to have been affected, but should be interpreted with caution. However, the overall teacher evaluation was statistically significant, and as this appears to be the first study to evaluate prospectively the effects of short-term theophylline on school behaviour, the results 'merit consideration' . Rachelefsky GS, Wo J, Adelson J, Mickey MR, Spector SL, et al. Pediatrics 80: 126-127, 1 Jul

1987

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