Efficacy of naltrexone on acetylcholine‐induced alloknesis in atopic eczema

Abstract

Atopic eczema (AE) is a chronically pruritic inflammatory skin disease. Although the mediators and exact mechanisms eliciting and sustaining pruritus are not completely known, AE patients in clinical trials have been shown to benefit under treatment with morphine antagonists. Naltrexone (NAL) is a relatively pure morphine antagonist that blocks the effects of opioids twice as much as naloxone. NAL exhibits minimal pharmacological activity and displaces endorphines at mu- and kappa-receptors without its own intrinsic activity. NAL's excellent oral bioavailability and linear increases in the area under plasma concentration-time curve make it ideal for use in experimental studies. We designed our present experiments similar to former experiments evaluating both peripheral cutaneous sensations and central itch procession in order to gain more information about the possible distribution of opioid receptors and their involvement in the pathophysiology of pruritus. Eleven AE patients participated in our double-blind study. Either 25 mg of NAL (Nemexin) or a placebo (PLA) was given to the participants 60 min prior to the acetylcholine (ACH) injection [intracutaneous (i.c.) injection of 0.02 ml of 0.55 M]. A PLA stimulus with buffered saline served as control on the opposite forearm. We used laser Doppler flowmetry to measure the vasomotoric changes after ACH injection and recorded the duration and intensity of itch with a visual analogue scale (VAS). Following the evaluation of wheal and flare sensation, we obtained the area of itchy skin around the injection site (alloknesis) by gently stroking the surrounding skin with a brush in the centripetal direction towards the injection site. The results were planimetrically evaluated. Oral NAL reduced the perifocal itch significantly (P < 0.009). In four of our observations the area of alloknesis completely disappeared. Itch duration was reduced by 20 s and the intensity of itch was diminished, yet not significantly. NAL had no significant effects on cholinergic vasoreactions measured by the laser Doppler (P > 0.50) and especially failed to decrease the initial flux response, which is a typical sign of an altered vascular reaction (P > 0.25). The decrease of wheal (P = 0.008) and flare (P = 0.01) extension indicates an appropriate dosage of our treatment for this experiment. The most significant effects of NAL were observed in parameters of itch processing such as alloknesis (P = 0.009) and flare extension (P = 0.01). Therefore we favour the concept that NAL might have a stronger impact on central nervous mechanisms than on peripheral nociceptive structures.

Chloroquine-induced Pruritus

“…Due to the complex mechanism of pruritus irrespective of the pathogenesis some opioid antagonists have been identified to have antipruritic effect examples of such are µ-opioid antagonists (naloxone and naltrexone) that have been observed in experimentally evoked histamine-induced itch as well as pruritus in different dermatoses[2930]. Interestingly, µ-opioid receptor antagonists significantly diminish itch, in animal experiments, κ-opioid antagonists enhanced itch[31].…”

Itch and Analgesia Resulting from Intrathecal Application of Morphine: Contrasting Effects on Different Populations of Trigeminothalamic Tract Neurons

“…Itch can be accompanied by debilitating phenomena such as hyperknesis, increased itch caused by pruritogens, and alloknesis, itch caused by innocuous mechanical stimuli that normally do not cause itch. Opioids likely play a role in producing both; morphine administration causes hyperknesis (Fjellner and Hägermark, 1982; Onigbogi et al, 2000), and opioid receptor antagonists reduce alloknesis (Heyer et al, 2002). Endogenous opioids are likely involved in producing pruritus associated with atopic dermatitis, chronic urticaria, or cholestasis, as itch accompanying these conditions is treated with opioid receptor antagonists (Phan et al, 2010).…”

Itch elicited by intradermal injection of serotonin, intracisternal injection of morphine, and their synergistic interactions in rats

“…This finding suggests that μ-opioid receptor activation has opposite effects on processing of itchy versus painful stimuli applied to the cheek. Opioids such as morphine likely also play a role in producing other itch-related sensory phenomena such as hyperknesis (increased itch caused by pruritogens) (Fjellner and Hägermark, 1982; Onigbogi et al, 2000) and alloknesis (itch caused by innocuous mechanical stimuli that normally do not cause itch) (Koenigstein, 1948; Heyer et al, 2002). …”