Section
1, Group 2 - November 11, 2014
Objective: Examine the effect of antihistamines
with varying anticholinergic properties on voluntary and involuntary movement
using a double blind, placebo-controlled, five-way crossover study design.
Source: Journal of Clinical Neurophysiology,
Impact Factor = 2.979, Ranked 60 out of 194 in Clinical Neurology journals.
Authors: Authors were affiliated with
Griffith University School of Pharmacy, the Centre for Musculoskeletal Research,
and the Griffith Health Institute in Gold Coast, Australia. Authors declared no conflicts of interest.
Funding: There were no external funding
sources.
Current Knowledge & Relevance: Research indicates that
antihistamines could affect reaction time and physiological tremors (Kavanagh et
al., 2012). The pathophysiology of tremors is complex and may be modulated by
cholinergic and histaminic
pathways. The current study provides
insight on select antihistamines and their effect on movement dysfunction.
Rationale: Antihistamines are one of the most
commonly used over-the-counter medications.
Antihistamines are known to cause varying degrees of sedation, but there
is relative lack of information on the anticholinergic properties of particular
antihistamines and their effect on movement.
Methods & Design
Design: Double-blind, placebo-controlled, five-way
crossover study in 11
subjects (7
female, 4 male, mean age: 24 ± 4 yrs).
Randomization: No randomization reported.
Inclusion Criteria: Healthy individuals from the
university community.
Exclusion Criteria: Individuals with epilepsy,
cardiopulmonary, metabolic, or neuromuscular disorders.
Intervention: Eleven subjects were administered
placebo, first generation antihistamines (promethazine 25mg), or second
generation antihistamines (loratadine 10mg, desloratadine 5mg, or fexofenadine 180mg). Blinding
was ensured using crushed drug in an opaque capsule. Six of the eleven subjects participated in an
additional experiment with hyoscine butylbromide 10mg to understand the
contribution of this peripheral antimuscarinic drug on neuromotor function. All testing sessions commenced at 12:30pm,
and participants avoided intense exercise, caffeine, and alcohol 5 hours prior
to each study with a one week washout period between experiments.
Main Outcomes: Assessments were performed
pre-ingestion and 1, 2, and 3 hours post-ingestion. Drowsiness was assessed
using a unipolar visual analogue scale (VAS), with end points being ‘not
drowsy’ and ‘very drowsy,’ as well as the Stanford Sleepiness scale (SSS). Voluntary movement was assessed using
reaction time tests and involuntary movement was assessed by examining
physiological tremor.
Statistical Analysis:
Calculations for power or sample size were
not reported. All statistical
analyses were performed using SAS version 9.2.
Level
of significance was set at 0.05. Wilcoxon
Mann-Whitney tests
and ANOVA were
performed.
Advantages: Outcome measures
for motor functioning and tremor magnitude were studied objectively. For each crushed drug, the dissolution
testing and elution rates were comparable to the tablet form.
Disadvantages: Drowsiness outcomes were based on
subjective data, the sample size was very low, and the study population was only young
healthy individuals.
Main Results
Primary Outcome: To determine if the
antihistaminergic or anticholinergic properties of antihistamines contribute to
deficits in neuromotor function.
Outcomes studied were effects on self-perceived drowsiness, reaction
time, and physiological tremor in response to the ingestion of promethazine,
loratadine, desloratadine, and fexofenadine.
There were no dropouts reported.
Per protocol analysis was conducted.
Self-perceived
drowsiness: Neither the VAS nor the SSS showed a significant change for
the testing sessions involving the placebo.
Visual analog scale showed that promethazine was the only drug to induce
drowsiness. VAS scores were
significantly greater than placebo at the intervals of 2 hours (z=2.27, p=0.023)
and 3 hours (z=2.15, p=0.031) after the ingestion of promethazine. The SSS indicated that promethazine,
desloratadine, and fexofenadine, induced drowsiness. Promethazine significantly increased SSS
scores at 1 hour (z=2.00, p=0.04), 2 hours (z=3.11, p=0.01), and 3 hours
(z=3.07, p=0.01) after ingestion. SSS
scores were significantly greater than placebo at the time point of 2 hours
post-ingestion of desloratadine (z=2.39, p=0.01) and fexofenadine (z=2.10, p=0.04).
Reaction
Time:
The
simple reaction time (SRT) and choice reaction time (CRT) post-ingestion of the
placebo did not change from pre-ingestion.
SRT was significantly slower than placebo at the time point of 3 hours
post-ingestion of loratadine (p=0.013) and promethazine (p=0.034). CRT was significantly slower than the placebo
condition at 2 hours post-ingestion of loratadine (p=0.0047), while
desloratadine increased CRT at 2 hours (p=0.007) and 3 hours (p=0.039) post-ingestion. CRT was slower than placebo at 1 hour
(P=0.007), 2 hours (p=0.001), and 3 hours (p=0.001) post-ingestion of
promethazine. The antimuscarinic
hyoscine butylbromide that was administered in the additional experiment had no
significant effect on SRT or CRT, indicating that the effects on movement were
centrally rather than peripherally mediated.
Physiological
tremor:
One
hour after ingesting desloratadine, acceleration root mean square (RMS)
(p=0.021) and total power (p=0.031) change scores were significantly lower than
placebo, indicating that tremor amplitude increased. Two hours after ingesting promethazine,
acceleration RMS (p=0.020), total power (p=0.029), and peak power (p=0.008)
change scores were significantly greater than placebo, indicating that tremor
amplitude and the neural component of tremor generation decreased. Hyoscine butylbromide had no significant
effect on any of the tremor-related variables.
F
values for all point estimates were large, between 4.00 and 16.11, and the
p-values were small, indicating statistically significant results. The absolute
values of the effect size estimates for each group mentioned above are between
1.22 and 2.11. The large effect size
indicates that there is a large magnitude of difference with treatment compared
to placebo.
Evaluation: Based on this study results, we can
conclude that different antihistamines have distinct effects on sedation as
well as voluntary and involuntary movements.
All antihistamines studied affected reaction time to some degree. The peripherally-acting antimuscarinic agent
hyoscine butylbromide did not affect reaction time, indicating that the effects
of antihistamines on involuntary and voluntary movement are likely
centrally-mediated.
Conclusion
Summary: The effects on voluntary and
involuntary movement between antihistamines with varying anticholinergic
properties differ between first and second generation. Promethazine had the
largest effects on drowsiness and some impairment on voluntary and involuntary
movement. While the second generation antihistamines, loratadine, fexofenadine,
and desloratadine, had a dissociation between their effects on drowsiness and
reaction times.
Evaluation: The authors argue
that the current study has merit because it supports their previous publication
by Kavanagh et al., 2012 showing that low dose promethazine and loratadine
negatively affect neuromotor function. This conclusion is not well defined because the antihistamine effects
are limited to the small population size and drugs dosages used in this trial.
Strengths: Double blind and
placebo-controlled study with a crossover design to examine differences between
similar treatments where the effects are small and reversible. The effects of antihistamines are immediate
and can be studied in a short time period.
A carryover effect is avoided due to short half-life of antihistamines
and a wash out period of 7 days.
Limitations: The younger study sample and the small
sample size limits the generalizability of the results.
Bottom Line: The results of this study show that some
second generation antihistamines such as fexofenadine provide a safe alternative to first generation
antihistamines in regards to movement. However, caution should be used because
the central anticholinergic and antihistaminergic properties of these
antihistamines differ.
Study Analysis and
Critique
Useful References/Practice
Guidelines:
1.
Baumann-Birkbeck L, Grant GD,
Anoopkumar-Dukie S, Kavanagh JJ. Drowsiness and motor responses to consecutive daily
doses of promethazine and loratadine. Clin. Neurophysiol. 2014 Apr;S1388-2457(14)00180-1.
PMID: 24791618.
2.
Stergiou N, Decker LM. Human movement variability, nonlinear
dynamics, and pathology: Is
there a connection? Hum Mov Sci.
2011 Oct;30(5):869-88. PMID: 21802756.
3.
Reich
MM, Volkmann J. Deep brain stimulation for hyperkinetic movement disorders. Nervenarzt. 2014 Feb;85(2):147-55. PMID:
24452308.
4.
Yoneda
H, et.al. Roles played by histamine in strenuous or prolonged masseter muscle activity in mice. Clin Exp Pharmacol Physiol. 2013
Dec;40(12):848-55. PMID: 24138758.
5.
Hindmarch
I, et.al. A double-blind, placebo-controlled investigation of the effects of fexofenadine, loratadine and promethazine on
cognitive and psychomotor function. Br J Clin Pharmacol. 1999 Aug;48(2):200-206.
PMID: 10417497.
6.
Kavanagh
JJ, Grant G, Anoopkumar-Dukie S. Low dosage promethazine and loratadine negatively affect neuromotor function.Clin
Neurophysiol. 2012 Apr;123(4):780-6. PMID: 21880544.
Future Research: Investigate voluntary
and involuntary movement effects of additional antihistamines and their dose-related
responses in a wider age range study population and a larger sample size.
