Our blinded, randomized, placebo-controlled, crossover trial was designed to assess clinically-relevant (allergen induced) itch reduction by two modes of acupuncture stimulation as well a second generation antihistamine drug, cetirizine. The results demonstrated a specific effect of acupuncture as well as cetirizine on itch perception and skin reactions compared to placebo and no intervention controls. Moreover, the timing of acupuncture interventions played a significant role in itch reduction. While preventive acupuncture and cetirizine showed similar effect sizes, abortive acupuncture was superior to these and all other therapy arms. In fact, abortive acupuncture was the only intervention to reduce itch perception below the clinically meaningful scratch threshold
In order to control for placebo effects, we used a cross-over design with several placebo groups. All verum groups (VAa, VAp, VC) were significantly better at reducing itch compared to respective placebos. For acupuncture, placebo groups were designed with acupuncture-like stimulation at non-classical acupoints in the same dermatomes and with the same ritual as verum acupuncture groups. Moreover, PA was conducted in both a preventive and abortive manner to adequately control for placebo effects for both VAp and VAa, respectively. These results for acupuncture corroborate our previous studies, which demonstrated similar superiority of VA for reducing histamine-induced itch in healthy volunteers (9
) as well as allergen-itch in AD patients (11
). Importantly, our data confirmed successful blinding.
Several previous studies have also investigated acupuncture for itch reduction, using various methodological approaches. Our previous study evaluated continuous itch response following a skin prick application of allergen in AD patients (11
). Manual acupuncture, at the same acupoints stimulated with electro-acupuncture in our current study, was found to reduce itch and skin reaction compared to placebo acupuncture. In this study, itch reduction was also more effective during acupuncture compared to after the acupuncture procedure – suggesting that abortive exceed preventive effects (26
). Interestingly, both our previous study and current study found that preventive acupuncture was superior to placebo in suppressing flare skin reaction. Other groups have investigated acupuncture for histamine-induced itch and skin reactions in healthy volunteers. Belgrade et al.(7
) found that electroacupuncture reduced itch and flare following intradermal histamine injection. Lundeberg (8
) et al. observed reduced itch following intrasegmental electroacupuncture stimulation and subsequent intradermal histamine injection. Our group also investigated preventive acupuncture for histamine-induced itch in healthy adults and demonstrated reduced itch and wheal formation compared to placebo point acupuncture or no intervention (9
The mechanisms underlying acupuncture reduction of itch and skin response to allergen are currently not known. Our finding that abortive was superior to preventive acupuncture suggests that counter-irritation and/or distraction (26
), which have been better studied for analgesia, may also play a role in anti-pruritic effects. Also, in comparing preventive acupuncture and cetirizine (a “preventive” systemic therapy), VAp demonstrated a greater effect during peak itch intensity (cool blocks), while cetirizine had a stronger effect during lower itch intensity (warm blocks) pointing towards different mechanisms of action. Moreover, cetirizine produced a significant reduction of attention compared to both VAa and VAp. These differences hint at potential central mechanisms of action for both acupuncture and cetirizine therapy in reducing itch, which should be further explored with techniques such as neuroimaging.
Other potential mechanisms for anti-pruritic action of acupuncture include anti-inflammatory effects (27
). Inflammation is an important component of AD itch (28
). However, acupuncture anti-inflammatory effects probably apply to neurogenic inflammation and would not be specifically anti-pruritic. Other potential mechanisms might relate to mediators associated with itch, such as endogenous opioid peptides (e.g. beta-endorphin). These neuromodulators have been implicated in acupuncture analgesia (29
) and have been shown to influence itch sensation (28
). On a spinal level, acupuncture seems to have a counter-irritative effect and reduces prostaglandin E2 levels, a further mediator involved in itch, in both brain and serum in LPS-injected rats (31
). While long-term anti-pruritic acupuncture effects are not well known, our recent study demonstrated that reduced itch was associated with reduction of allergen-induced basophil activation in AD patients (32
Previous neuroimaging studies have demonstrated that acupuncture modulates some of the same limbic and paralimbic brain structures (33
) known to process itch sensation in both healthy adults (18
) and AD patients (20
), such as the amygdala, anterior cingulate and insular cortices. Further studies should apply neuroimaging methods to explore the possible pathways of acupuncture action in the pathophysiology of itch and allergic skin reactions.
Compared to placebo tablet (as well as all acupuncture procedures), cetirizine produced significant reduction of the D2-test of attention score. This result suggests that cetirizine may have affected cognitive function. While the common opinion is that second generation antihistamines cross the blood-brain barrier to a much lesser extent than first generation antihistamines, Tashiro et al. found that after a double therapeutic dose of 20mg, cetirizine occupied 20% to 50% of the H1
-receptors in the brain (35
). Whether the modulation of cognitive processes such as attention is specifically related to itch reduction should be explored in future studies.