Effect of topical capsaicin on the cutaneous reactions and itching to histamine in atopic eczema compared to healthy skin

Abstract Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is thought to produce analgesic and possibly also antipruritic effects when applied topically. Capsaicin 0.05% was applied three times daily over a 5-day period to the same infrascapular region. The effects of the pretreatment upon the pruritogenic and wheal and flare reactions to subsequent histamine iontophoresis (20 mC) were evaluated on the following day. The antipruritic effects of the pretreatment were compared with the effects of placebo pretreatment and no pretreatment. Wheal and flare areas were evaluated planimetrically. Itch or pain were rated every minute over a 24-min period. The areas of alloknesis, i.e. the induction of perifocal itch sensation by usually nonitching (e.g. mechanical) stimuli, were also evaluated. In control subjects, but not in atopic eczema (AE) patients, capsaicin pretreatment significantly reduced the flare area. Compared with control subjects, AE patients showed a lack of alloknesis or significantly smaller areas of alloknesis in pretreated and nonpretreated skin. In control subjects, capsaicin pretreatment significantly reduced itch sensations compared with nonpretreated skin, whereas in AE patients no differences were seen. Itch sensations in capsaicin-pretreated skin were significantly lower in control subjects than in AE patients. We conclude that capsaicin does effectively suppress histamine-induced itching in healthy skin but has less effect in AE. The diminished itch sensations and the absence of alloknesis in atopic individuals indicate that histamine is not the key factor in itching in AE. Received: 24 July 1997     

Efficacy of naltrexone on acetylcholine-induced alloknesis in atopic eczema

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.     

Acetylcholine Is an Inducer of Itching in Patients with Atopic Eczema

As previous experimental studies disproved histamine as the main mediator of eliciting pruritus in atopic eczema (AE), we examined the neurocutaneous sensations in 15 patients with AE and in 15 age- and sex-matched non-atopic controls after i.c. injection of acetylcholine (Ach, 0.5 M, 20 μl) or buffered saline. The sensory perceptions were rated by the participants of the study with regard to their quality and intensity using a visual analogue scale. Simultaneously, the vascular reactions to Ach were recorded by the examinators via laser Doppler fluxmetry as well as flare and wheal planimetry. In contrast to the approximately equal flare and wheal extensions in either group, the cutaneous sensations differed significantly. The patients complained of ‘pure’ itching that developed shortly after Ach injection, whereas the control subjects reported only burning pain. Moreover, the patients perceived their sensations significantly earlier and significantly longer than did the controls. The study provides evidence that Ach plays an important role in the pathogeny of pruritus in patients with AE. Further investigations of the neuronal mechanisms involved in this atopy-related effect of Ach have to be performed.     

A quantitative comparison of the effect of local analgesics on argon laser induced cutaneous pain and on histamine induced wheal, flare and itch

A quantitative comparison was made of the effect of infiltration of local analgesics and topical analgesic cream (EMLA) on laser-induced pain and histamine-induced wheal, flare and itch. Wheal and flare were quantified by planimetry and analgesia was quantified by the pricking pain threshold to argon laser stimulation. The intensity of histamine-induced itch was scored on a 4-point scale. Local analgesics had no effect on the wheal area. The flare reaction was abolished by infiltrating lignocaine, and gradually inhibited by increased application times of EMLA. Itch was abolished after local lignocaine infiltration, but not significantly reduced after EMLA cream applied for less than 120 min, although the skin was anaesthetized to laser-induced pain. The reduction of flare area correlated to the level of analgesia, which may therefore reflect the cutaneous responsiveness to neurogenic inflammation. It is suggested that itch and pricking pain are mediated by different populations of nerve fibres, as itch can be evoked even when the sensation of pricking pain is abolished. Surgery, skin prick tests and other traumatic procedures should therefore be performed under local anaesthesia to reduce neurogenic inflammation.     

Correlations between histamine-induced wheal,flare and itch

Correlations between the skin reactions wheal and flare and the subjectively reported degree of itch were investigated in response to 1% histamine, intradermally applied by standardized skin prick and by iontophoresis. Experiments were performed with 15 male volunteers using a threefold repeated measures design (skin prick, and iontophoresis with 0.13 mA for 10 s and with 2.0 mA for 10 s). Skin reactions (perpendicular diameters) were determined at the time of their maximum (10 min). Itch was rated on a computerized visual analogue scale which was anchored upon the individual scratch threshold. Most effective in producing itch was the skin prick which caused strong sensations markedly above the scratch threshold during the entire period of measurement (30 min), whereas iontophoresis induced only transient itch sensations. On the other hand, the largest wheals were generated by iontophoresis of both intensities (mean 10 or 14 mm vs 6 mm with skin prick). The higher current induced higher itch, wheal and flare responses, but after eliminating this effect of stimulus intensity, no correlations were found. In contrast, skin prick-induced flare reactions varied with the degree of itch above the scratch threshold ( r = 0.56; P < 0.01). Repeated measurements showed a higher stability for the itch reaction with skin prick compared with iontophoresis. It is hypothesized that in iontophoresis the brief (10-s) histamine bolus passed the most superficial pruritoceptive C fibres too quickly to induce long-lasting itch sensations, whereas the skin prick caused a deposit at the dermal-epidermal junction releasing histamine during the entire time of measurement. Consequently, both the C fibre-mediated itch and the axon reflex flare were more pronounced with the skin prick, and the wheal resulting from a permeability increase in the postcapillary venule walls was an independent phenomenon. Received: 21 June 1995     

Reactions to intradermally injected substance P and topically applied mustard oil in atopic dermatitis patients.

Skin reactions and itch or burning pain sensations following intradermal injection of the neuropeptide substance P and topical application of the substance P releasing agent mustard oil were studied in 20 atopic dermatitis patients and 20 healthy controls. Changes in skin blood flow were measured with a Laser Doppler flowmeter. Areas of wheal and flare reactions were evaluated planimetrically. Simultaneous with Laser Doppler flowmeter measurements, subjective itch and burning pain ratings were verbally reported on a category partitioning scale at 10-second intervals. Substance P evoked dose-dependent wheal, flare, and itch reactions in both patients and controls. However, substance P doses of 10(-9) -10(-11) mol elicited smaller flares in patients than in the controls whereas the wheal sizes were similar in both groups. Substance P-induced itch ratings were lower in patients at a dose of 10(-10) mol, and the onset of itching was delayed at all substance P levels applied. Mustard oil elicited similar neurogenic inflammatory reactions in both groups, although pain sensations were significantly delayed in atopic dermatitis patients at two mustard oil concentrations, which is further indication of a desensitization of afferent nerve endings contributing to the neurogenic inflammatory reactions in the skin of these patients.     

Recent studies of cutaneous nociception in atopic and non-atopic subjects

Itching reflects a distinct quality of cutaneous nociception elicited by chemical or other stimuli to neuronal receptors at the superficial layers of the skin and muco-cutaneous orifices. Although recent experimental studies of the conduction and perception of itch have yielded deeper insight into the physiology of this sensory quality, little is known about the neuromechanisms involved in pruritus accompanying many inflammatory skin diseases, in particular, in atopic eczema. Previous case-control studies of our research group with patients suffering from atopic eczema (AE) revealed significantly diminished itch perception after iontophoretic application of different doses of histamine as well as substance P (i.c. injected). Further experiments using acetylcholine (ACh, i.c.) clearly demonstrated that ACh elicits pruritus instead of pain in patients with AE. The first part of the present review deals with the results of our most recent case-control studies on histamine-induced itch perception in atopics devoid of eczema as well as in patients with urticaria or psoriasis compared to atopics with or without manifest eczema. We demonstrated that both focal itch and perifocal alloknesis (i.e., itch elicited by a slight mechanical, otherwise non-itching stimulus) were significantly reduced in eczema-free atopics yet were normal in non-atopics suffering from urticaria or psoriasis. In further studies using ACh i.c. injected into the uninvolved skin of patients with AE, lichen ruber, psoriasis, type IV contact eczema, or non-specific nummular eczema (n = 10/each group), all the atopics and 6/10 psoriatics felt itch instead of burning pain, but none of the others did. Different doses of vasoactive intestinal peptide (VIP) i.c. applied to the controls and the atopics with or without eczema did not markedly increase the intensity of nociceptive sensations. However, ACh induced pain in the controls, pure pruritus in the atopics with acute eczema, and a 'mixture' of pain and itch in the atopics just free from eczema. Obviously, the quality of sensations evoked by ACh and VIP depends on the inflammatory or non-inflammatory state of the atopic skin. In a placebo-controlled, double blind study on histamine-induced focal itch and alloknesis with healthy subjects (n = 15) using naltrexone (opioid receptor antagonist) and cetirizine (H1-blocking agent), naltrexone was found to significantly reduce both itching and alloknesis. Cetirizine reduced focal itch but failed to influence the alloknesis phenomenon. The wheal and flare reaction was suppressed only by cetirizine. These different effects point to a mainly CNS-based activity of naltrexone but a peripheral level effect of cetirizine. Due to long-lasting experience with group sport as a supporting adjuvant for inpatients with AE, we evaluated, by clinical, psychometric, and physiological studies, the therapeutic efficacy of controlled physical exercise in addition to otherwise equal anti-eczematous therapy for both voluntary participants and non-participants in sports by performing several case-control studies, one followed-up to 6 months after the patients' discharge from the hospital. Regular moderate exercises neither deteriorated nor impeded the recovery from AE, ameliorated the participants' scratch controlling ability and significantly their depressed emotional mood. The non-participants failed to achieve these aims. Sweating-induced itch was inhibited in almost all participants if simple skin care (clearing by warm shower, ointment) and short-term rest were used by informed patients. In conclusion, there are several indications that itching is elicited in individuals inclined to cutaneous atopy, regardless of their eczematous or just eczema-free state, by a different physiological pathway from that in non-atopic individuals. Therefore, antipruritic agents influencing the centrally altered nociception of atopics are needed and may be expected in near future. (ABSTRACT TRUNCATED)     

Topically applied aspirin decreases histamine-induced wheal and flare reactions in normal and SLS-inflamed skin,but does not decrease itch. A randomized,double-blind and placebo-controlled human study

Topically applied aspirin has recently been reported to decrease histamine-induced itch in human volunteers. Our aim is to confirm this and to study the antipruritic ability of topical aspirin in inflamed skin. In 24 non-atopic volunteers, an inflammatory skin reaction was induced in forearm skin at 5 different sites by sodium lauryl sulphate contained in Finn Chambers. Aspirin 10%, aspirin 1%, mepyramine 5% and vehicle were applied to the inflamed and corresponding non-inflamed areas 20 min before itch induction with intradermal histamine injection. Itch and pain were scored on a visual analogue scale at regular intervals. Wheal and flare areas were measured. No difference in itch intensities was found after application of aspirin, mepyramine and vehicle, but more itch was induced in aspirin and mepyramine pretreated sites in inflamed skin compared to normal skin (p<0.05). In normal skin, flare areas were smaller after pretreatment with aspirin 10% (p<0.05) and mepyramine (p<0.001), as were wheal areas after mepyramine (p<0.01), compared to vehicle pretreatments. In inflamed skin, flare areas were smaller after pretreatment with aspirin 10% (p<0.01) and mepyramine (p<0.001), as were wheal areas after aspirin 10% (p<0.01), aspirin 1% (p<0.05) and mepyramine (p<0.001). We conclude that despite a significant skin penetration as measured by the influence on wheal and flare reactions, topically applied aspirin did not decrease histamine-induced itch in the model used.     

Skin reactions and itch sensation induced by epicutaneous histamine application in atopic dermatitis and controls

Itch sensations and skin reactions induced by histamine iontophoresis at six different current intensities were studied in 27 atopic dermatitis (AD) patients and 20 healthy controls. Subjective itch ratings were assessed on a visual analogue scale (VAS) for 8-min periods after 10-sec histamine application, while changes of skin blood flow were simultaneously measured using two Laser Doppler flowmeters. Ten minutes after each histamine application, the areas of wheal and flare reactions were planimetrically evaluated. When no or weak current was applied, AD patients revealed stronger wheal and flare reactions than controls, possibly due to disturbed skin barrier function. Higher histamine doses, however, produced weaker subjective and vascular reactions in AD patients. In contrast to the controls, AD patients were unable to distinguish between weak and strong histamine stimulation, as shown by their VAS ratings. These results imply that AD patients have an altered histamine response. In particular, their afferent cutaneous nerve fibers show a decreased ability to signal itching to the central nervous system and to release vasoactive neuropeptides upon histamine stimulation.     

The influence of the opiate antagonist naloxone on experimental pruritus

The antipruritic effect of naloxone hydrochloride was evaluated in a double-blind, cross-over design. Systemic pretreatment with the opiate antagonist did not interfere with the cutaneous itch and flare responses evoked by morphine or histamine, nor did it inhibit the morphine-produced potentiation of the histamine-elicited skin reactions.     

Inhibition of histamine-induced pruritus by topical tricyclic antidepressants

Frequent antihistaminic side effects noted during treatment of depression by tricyclic drugs, as well as the high affinity of tricyclic antidepressants for H₁ receptors in mouse neuroblastoma cells, suggest possibly useful antihistaminic properties. We investigated the antipruritic activity of topically applied 5% solutions of doxepin hydrochloride (Adapin; Sinequan) and amitriptyline hydrochloride (Elavil) and compared such activity to that of a 5% solution of diphenhydramine and vehicle alone. Test solutions were applied to 25-cm² areas on the flexor forearms of forty subjects, and the development of itch to single drops of eight dilutions of histamine phosphate instilled in each area was reported over a 3-minute period. The lowest concentration of histamine able to elicit unequivocal itching in each treated area was the histamine itch threshold (HIT). Doxepin, amitriptyline, and diphenhydramine all produced significantly higher mean and median HITs (p < 0.01) than did vehicle control. Sixty-eight percent of subjects had a HIT ≥2 × 10^?4 mg/ml in doxepin-treated areas versus 58% for amitriptyline, 53% for diphenhydramine, and 25% for vehicle. Our data suggest that tricyclic antidepressants are effective topical antipruritic agents.     

Processing of histamine-induced itch in the human cerebral cortex: a correlation analysis with dermal reactions

The subjective sensation of itch is a complex emotional experience depending on a variety of factors. In this study, the central nervous processing of pruritus was investigated in a human model. Activation of involved cerebral areas was correlated to scales of nociception and skin reactions. Six healthy male right-handed subjects participated in a standardized epidermal stimulus model with nine increasing doses of histamine dihydrochloride (0.03%-8%) on their right forearms. Controls consisted of three NaCl stimuli. Cerebral activation patterns were determined by H(2)(15)O positron emission tomography 120 s after stimulation. Dermal reactions to the stimulus (wheal, flare, temperature) were coregistered during the procedure. Itch sensation was determined by visual analog scale rating. Pain was not reported during the study; all volunteers had localized itch from 0.03% histamine on. Subtraction analysis versus control revealed significant activation of the left primary sensory cortex and motor-associated areas (mainly primary motor cortex, supplementary motor area, premotor cortex). Predominantly left-sided activations of frontal, orbitofrontal, and superior temporal cortex and anterior cingulate were also observed. Correlation analysis revealed coactivation of dermal reactions and cerebral response to itch in the following Brodmann areas with a Z score greater than 5: wheal, areas 5 (bilateral) and 19 (right); flare, areas 2-5 (left); temperature, area 10 (left) and left insula. Itch intensity ratings were mainly correlated with activation of the left sensory and motor areas. Functional covariates of the itch sensation in the central nervous system were identified. The intention to pruritofensive movements is probably mirrored by the activation of motor areas in the cortex. Other areas may be involved in emotional processing of sensations. Skin reactions wheal and flare also had significantly activated covariate areas in the central nervous system.J Invest Dermatol 115:1029-1033 2000     

The effects of topical doxepin on responses to histamine, substance P and prostaglandin E2 in human skin

The tricyclic antidepressant, doxepin, is known to have H₁ and H₂ antihistaminic effects. Recently, 5% doxepin cream has been marketed in the U.S.A. for treatment of eczematous dermatoses. We investigated the effects of topical doxepin treatment on histamine-, substance P-and prostaglandin E₂-(PGE₂) induced responses in the skin of normal and atopic subjects. We compared the effects of topical doxepin with those of the oral antihistamine terfenadine. The weal volume and flare area responses to histamine were significantly reduced by treatment with topical doxepin or oral terfenadine in both normal and atopic subjects (P<0·05). The mean ±SEM percentage reduction in flare area for 10μ/site of histamine in non-atopics and atopics was 48±8% and 60±17% with terfenadine, and 54 ± 12% and 81 ± 4% with topical doxepin, respectively. The mean percentage reduction in weal volume for the same dose of histamine in non-atopics and atopics was 70 ± 9% and 63 ± 16% with terfenadine, and 96 ± 2% and 89 ± 6% with topical doxepin, respectively. The flare but not the weal response to substance P was inhibited by both treatments in all subjects (P<0·05). The mean ±SEM percentage reduction in flare area for 200 pmol/site of substance P in non-atopics and atopics was 53 ± 10% and 73 ±4% with terfenadine, and 74 ± 7% and 75 ± 4% with topical doxepin, respectively. The cutaneous responses to PGE₂ were not affected by either drug. The inhibitory effects of doxepin were as great as those of terfenadine, and doxepin had a significantly greater effect than terfenadine in inhibiting the weal response to histamine and flare response to substance P in normal volunteers (P<0·05). There was no significant difference between atopics and non-atopics in the percentage reduction of cutaneous responses by oral terfenadine or topical doxepin. Marked sedation occurred in three of the first 10 subjects treated with topical doxepin, necessitating a reduction in dosage for the remaining six subjects. In summary, topical doxepin was as effective as, and sometimes more effective than, a standard dose of oral terfenadine in the inhibition of histamine-induced and axon-reflex-mediated cutaneous responses. The marked sedative effect may limit its clinical use in some patients.     

Video-optical monitoring of wheal and flare reactions

Background/aims: In order to monitor the dynamics of experimentally-induced cutaneous inflammation in humans, we developed an objective, computerized video-optical method for wheal and flare area determination.
Methods: The method was used for evaluation of PAF-acether-induced experimental inflammations on the volar aspect of the forearms of human volunteers. The study design was double-blind, randomized, placebo-controlled. Repeated measurements can be performed, e.g., with intervals of 1 min to reveal the time-course of the inflammatory reaction. In the present study, the effect of topical application of creams containing 3 different concentrations of the putative anti-inflammatory drug sodium sucrose-sulphate (SoS) on cutaneous inflammation was investigated.
Results: 30 min after intracutaneous PAF-acether injection, a statistically significantly increased (p<0.05) wheal area was found in skin sites treated by either 1%, 3% and 9% SoS cream, whereas no influence of sucrose-sulphate could be demonstrated on the flare area. The reduction of the wheal area was significantly faster in the SoS-treated areas than in the placebo (p<0.05).
Conclusions: Computerized video-optical quantification of acute skin inflammatory reactions may be a suitable experimental tool for objective dynamic monitoring of both wheal and flare reactions and hence for quantification of the effect of anti-inflammatory drugs in humans. Topical application of SoS surprisingly increased PAF-acether-induced skin oedema (wheal), significantly whereas no effect was found on the flare reaction. No concentration-related effect of SoS could be shown.     

Anti pruritic effects of topical crotamiton, capsaicin, and a corticosteroid on pruritogen-induced scratching behavior

Itch accompanies various skin diseases. As a number of mediators other than histamine can be involved in the itch sensation, H1 receptor antagonists are not necessarily effective in treating itch. External application of antipruritic drugs is occasionally used as an alternative therapy for pruritic skin conditions, such as pruritus on primary non-diseased, non-inflamed skin. Even so, the actual effects of these drugs on the itch sensation have yet to be studied in detail. To verify the antipruritic effects of crotamiton, capsaicin, and a corticosteroid on the itch sensation, we examined the inhibitory effects of these drugs on various pruritogen-induced scratching behaviors in mice. Topical application of 10% crotamiton moderately inhibited histamine-, serotonin-, and PAR-2 agonist-induced scratching behaviors. Topical capsaicin (0.025%) also exerted a moderate suppressive effect on histamine-, substance P-, and PAR-2 agonist-induced itch responses. Notably, topical corticosteroid (0.05% clobetasol propionate) remarkably inhibited the scratching behaviors induced by all of the pruritogenic agents tested. Therapeutic effects of capsaicin on substance P-induced pruritus did not seem to be mediated by desensitization of the TRPV1 (+) C fibers and/or by altered responsiveness of the mast cells. In addition, the antipruritic effects of crotamiton and corticosteroid appear to be, at least partly, associated with a TRPV1-independent pathway. This study examined the itch responses to pruritogens and demonstrated the mode of action of the externally applied antipruritic drugs.     

Neurophysiology of pruritus: cutaneous elicitation of itch

Itching is defined as an unpleasant cutaneous sensation leading to the desire to scratch. It serves as a physiological self-protective mechanism as do other cutaneous sensations like pain, touch, vibration, cold, and heat to help defend the skin against harmful external agents. Pruritus can be evoked in the skin directly by mechanical and thermal stimuli or indirectly through chemical mediators. It may also be generated in the central nervous system independently of peripheral stimulation. Single-nerve-fiber recordings have shown that histamine-evoked itch is transmitted by selective slow-conducting subpopulations of unmyelinated C-polymodal neurons. Recent experimental studies using improved methods have demonstrated which of the suspected chemical itch mediators such as histamine, neuropeptides, prostaglandins, serotonin, acetylcholine, or bradykinin act pruritogenically on C-fibers. Moreover, investigations have revealed new receptor systems such as vanilloid, opioid, and cannabinoid receptors on cutaneous sensory nerve fibers that may modulate itch and thereby represent targets for antipruritic therapy. This review focuses on the peripheral generation of itch, including neurotransmitters, neuropeptides, and inflammatory mediators.     

The addition of topical doxepin to corticosteroid therapy: an improved treatment regimen for atopic dermatitis

Three hundred and forty-nine (349) patients with pruritic atopic dermatitis who provided written informed consent participated in this study. To enter, patients had to have experienced moderate to severe pruritis accompanying their eczematous lesions daily for at least 1 week prior to enrollment, a family history of atopy and/or a personal history of atopic dermatitis, 25% or less body surface area affected by atopic dermatitis, and good general health. After enrollment, patients were required to discontinue systemic corticosteroids at least 4 weeks prior to study entry as well as antipruritic and central nervous system-active medications at least 1 week before entry. In addition, no topical medications were permitted to be applied to treatment sites for at least 2 days before entry. Patients who had infected treatment sites, other concurrent cutaneous conditions, or who were pregnant or lactating were excluded from the study. This was an 8-day multicenter double-blind parallel-design study assessing the effects of adding topical doxepin to topical corticosteroid treatment vs. the topical corticosteroid treatment itself. All test products were incorporated in an identical cream base to that for doxepin hydrochloride cream. Using a computer-generated randomization schedule, patients were assigned to treatment groups receiving creams containing: (1) 2.5% hydrocortisone; (2) 0.1% triamcinolone acetonide; (3) 2.5% hydrocortisone and 5% doxepin hydrochloride; (4) 0.1% severity acetonide and 5% doxepin hydrochloride. Patients were instructed to apply the study cream four times daily for 8 days of treatment. The physician initially rated the patients’ pruritis as mild, moderate, or severe, and their atopic dermatitis as mild, moderate, marked, or severe. A baseline visual analog scale (VAS) for pruritis severity, consisting of a 100-mm horizontal line labeled “no itch” and “worst itch imaginable” at opposite ends, was completed by the patients to quantify the intensity of pruritis experienced during the week before study entry and daily during the study. Additionally, daily during the study, each patient completed a VAS for pruritis relief by marking a 100-mm vertical line labeled “no relief from itching” and “complete relief from itching” at opposite ends. After the baseline evaluation, subsequent visits were scheduled for days 2, 3, 4, and 8. At each visit, the physician reviewed the patient’s daily VASs to record a global evaluation of pruritis relief and rated the overall change in dermatitis on a five-point scale ranging from much worse to much better. Any reports of adverse effects were also recorded. Analysis of covariance was used to assess the VAS for pruritis severity. With the use of the row mean score with ridit assigned scores, Cochran–Mantel–Haenszel (CMH) analysis for ordered response categories was performed in the analysis of the physicians’ global evaluations (pruritis and dermatitis). Intent-to-treat analysis was used for all efficacy variables. Statistical significance was defined as p < 0.05 (two-tailed).     

Skin testing of the pruritogenic activity of histamine and cytokines (interleukin-2 and tumour necrosis factor-α) at the dermal–epidermal junction

Cytokines have been proposed as histamine-independent itch mediators. To investigate this hypothesis, single doses of interleukin-2 (IL-2, 10MU/mL) and tumour necrosis factor α (TNF-α, 10 μg/mL) were delivered to the epidermis of 10 healthy volunteers with a controlled skin-prick model; 1% histamine and solvent controls were included in a double-blind, randomized crossover design. Itch ratings (computerized visual analogue scale) were obtained every 20s for 15 min and cutaneous reactions (weal, flare and temperature) were measured. Reactions were also recorded after 2, 24 and 48 h. The mean itch ratings were: histamine 35·5, IL-2 3·3 (both P<0·01 compared with control), TNF-α 1.6 and solvent control 1.75 (not significant). Weal and flare occurred only with histamine. In two volunteers, an inflammatory papule with transient pruritus developed 12–18 h after applying IL-2. In conclusion, IL-2 showed a rapid, low pruritogenic effect, which may be followed by an inflammatory response. TNF-α induced no itching in this setting. Skin-prick testing with appropriate doses of potential pruritogens provides a safe and sensitive model for further chemoreceptor studies.     

Neuronal sensitization for histamine-induced itch in lesional skin of patients with atopic dermatitis

OBJECTIVE: Lowered threshold of neurons (ie, neuronal sensitization) in atopic dermatitis was investigated by testing sensitivity to histamine. DESIGN: Comparative study. SETTING: A dermatological clinic and a research laboratory. PARTICIPANTS: Eighteen patients with atopic dermatitis (AD) and 6 patients with chronic plaque-type psoriasis as well as 14 healthy control subjects. INTERVENTIONS: Histamine prick was performed in lesional and nonlesional skin of patients and in control subjects. MAIN OUTCOME MEASURES: Axon reflex flare and wheal were measured planimetrically, and the itch intensity was rated on a numerical scale (0-10). RESULTS: In nonlesional skin of patients with AD, itch intensity and axon reflex flare were both significantly smaller compared with controls (mean +/- SEM maximum itch, 1.5 +/- 0.3 vs 3.1 +/- 0.2 [P<.05]; mean +/- SEM diameter, 12.3 +/- 2.0 vs 25.3 +/- 2.5 mm [P<.01]). In lesional skin of patients with AD, on the contrary, massive itch was provoked (maximum itch, 4.4 +/- 0.3), although flare was relatively small (diameter, 16.1 +/- 3.4 mm). Itch ratings in patients with psoriasis were low both in lesional and nonlesional skin (maximum itch, 1.3 +/- 0.6 and 1.0 +/- 0.4, respectively). CONCLUSION: As the area of axon reflex flare is an indirect measure of activity in primary afferent neurons, our results suggest a decreased activation of peripheral pruriceptors in patients with AD. The massively increased itch in lesional skin of patients with AD might therefore be based on sensitization for itch in the spinal cord rather than in primary afferent neurons. This sensitization does not appear to be simply based on skin inflammation because histamine-induced itch was not augmented in lesional skin of psoriasis.     

Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus

Pruritus (itch) can be defined as an unpleasant cutaneous sensation associated with the immediate desire to scratch. Recent findings have identified potential classes of endogenous "itch mediators" and establish a modern concept for the pathophysiology of pruritus. First, there in no universal peripheral itch mediator, but disease-specific sets of involved mediators. Second, numerous mediators of skin cells can activate and sensitize pruritic nerve endings, and even modulate their growth. Our knowledge of itch processing in the spinal cord and the involved centers in the central nervous system is rapidly growing. This review summarizes the current information about the significance of neuron-skin interactions, ion channels, neuropeptides, proteases, cannabinoids, opioids, kinins, cytokines, biogenic amines, neurotransmitters, and their receptors in the pathobiology of pruritus. A deeper understanding of these circuits is required for the development of novel antipruritic strategies.