Relationship between sedation and pupillary function: comparison of diazepam and diphenhydramine

Abstract

Aims: To examine the relationship between sedation and pupillary function by comparing the effects of diazepam and diphenhydramine on arousal and pupillary activity.

Methods: Fifteen male volunteers participated in three weekly sessions in which they received (i) diazepam 10 mg, (ii) diphenhydramine 75 mg and (iii) placebo, according to a balanced, double-blind protocol. Pupil diameter was measured with infrared pupillometry under four luminance levels. Alertness was assessed by visual analogue scales (VAS) and by critical flicker fusion frequency (CFFF). Blood pressure, heart rate and skin conductance were recorded by conventional methods. Data were analysed with analysis of variance (anova) with multiple comparisons.

Results: There were significant effects of ambient luminance (F3,42 = 305.7, P < 0.001) and treatment condition (F2,28 = 9.0, P < 0.01) on pupil diameter; diphenhydramine caused miosis at all luminance levels (P < 0.05). The light reflex response was not affected. Both active drugs reduced the pre-post treatment changes compared with placebo [mean difference from placebo (95% confidence interval)]: in CFFF (Hz), diazepam -0.73 (-1.63, 0.17), diphenhydramine -1.46 (-2.40, -0.52); and VAS alertness (mm), diazepam -11.49 (-19.19, -3.79), diphenhydramine -19.83 (-27.46, -12.20). There were significant effects of both session (F2,26 = 145.1, P < 0.001) and treatment (F2,26 = 5.5, P < 0.01) on skin conductance; skin conductance was reduced by both drugs (P < 0.05).

Conclusions: The miosis by diphenhydramine and the reduction in skin conductance by both drugs may indicate central sympatholytic effects. A lack of a sympatholytic effect of diazepam on the pupil may be due to the masking of the miosis by mydriasis resulting from the inhibition of the parasympathetic output to the iris.

Figure 1

Critical flicker fusion frequency (CFFF) and visual analogue scales (VAS): post-treatment changes in CFFF (top) and VAS (bottom). Columns correspond to mean changes in the parameters in response to treatments, obtained in the group of 15 subjects. Treatments are indicated at the bottom of the graph (Pl, placebo; Dz, diazepam; Dph, diphenhydramine). Vertical bars are standard error of the mean (SEM). CFFF, Ordinate, change from pretreatment (Hz). Diphenhydramine reduced CFFF. *P < 0.05 (Dunnett’s test: comparison with placebo condition). VAS, Ordinate, change from pretreatment (mm). Both diazepam and diphenhydramine reduced alertness. Anxiety and contentedness were not affected. *P < 0.05 (Dunnett’s test: comparison with placebo condition)

Figure 2

Static pupil diameter: relationship between level of luminance and pupil diameter, pre- and post-treatment. The three treatment conditions are indicated by different symbols (see inset). Ordinate: absolute pupil diameter (mm); abscissa: level of luminance (cd m⁻²). Each point corresponds to the mean obtained in the group of 15 subjects; the vertical bars represent two standard errors of the difference (2 SED) obtained from the interaction term of the analysis of variance. Diphenhydramine reduced static pupil diameter at all luminance levels, whereas diazepam had no significant effect. *P < 0.05 (Dunnett’s test: comparison with placebo condition). Placebo (○), diazepam 10 mg (▴), diphenhydramine 75 mg (▪)

Figure 3

Light reflex response: initial diameter (left) and amplitude (right) evoked by a light stimulus of 2050 cd m⁻², under the three post-treatment conditions. Columns correspond to mean changes in the parameters in response to treatments, obtained in the group of 15 subjects. Treatments are indicated at the bottom of the graphs (as above). Vertical bars are SEM. Diphenhydramine reduced initial pupil diameter, whereas there was no treatment effect on amplitude after treatment. *P < 0.05 (Dunnett’s test: comparison with placebo condition)