Psychotropics in different causes of itch: systematic review with controlled studies*

Among the wide range of symptoms neglected or resistant to conventional treatments in clinical practice, itch is emerging gradually as a theme to be studied. Itch complaints and the negative effects in the quality of life are observed in several medical fields. Although the partially obscure pathophysiology, some researchers decided to check and test the use of psychotropic drugs in resistant itch to conventional topical treatments and antihistamines. The objective of this study was to evaluate scientific evidence in psychotropic use in the treatment of itch of various causes. This is a systematic review of scientific literature. The following databases were used: PubMed, Web of Science, Scopus and Scielo. Randomized controlled trials that should focus on treatment with psychotropic drugs of pruritus of various causes were the inclusion criteria. All articles were analyzed by the authors, and the consensus was reached in cases of disagreement. Fifteen articles were included after analysis and selection in databases, with the majority of clinical trials focusing on psychopharmacological treatment of itch on account of chronic kidney disease. Clinical trials with psychotropic drugs mostly indicated significant improvement in the itching. In most trials of chronic kidney disease as basal disease for itch, greater effectiveness was observed with the use of psychotropic drugs compared with placebo or other antipruritic. However, the small amount of controlled trials conducted precludes the generalization that psychiatric drugs are effective for itch of various causes.


INTRODUCTION
Itch was defined for a long time as an unpleasant cutaneous sensation that provokes the desire to scratch. 1 The chronicity of itch involves multidimensional phenomenon that includes physiological (as the central neurons and nerve pathways), cognitive and emotional aspects. 1,2 Itch can be classified into four dimensional categories, according to the neurophysiologic considerations: pruritoceptive, with peripheral origin; neuropathic; neurogenic; and psychogenic, with central origin. [3][4][5] The diagnosis of psychogenic itch has the need to discard skin causes or underlying systemic disease, representing a diagnostic challenge. 6,7 When the itch is related to chronic diseases or diseases that cause major limitation for life, such as chronic kidney disease and liver or skin diseases, it can cause considerable influence on the behavior and, just like pain, it can cause loss of quality of life. [8][9][10] The itch sensation originates in free nerve endings in the skin and is transmitted by C fibers to the dorsal horn of the spinal cord and then to the cerebral cortex via the spinothalamic tract. 11,12 There are no itch specialized receptors at the end of the peripheral nerves, but the specificity of the neurons that transmit the itch is in connection with the spinal cord tracts. 9 As a consequence of chronic itch, a person may have skin lesions caused by excessive scratching, pinching (ulcers, secondary infections, bleeding, permanent discoloration or scarring), just as it can cause sleep disturbance, depression, overall stress or anxiety, among other psychiatric disorders. 9,10,13 The treatment of itch often include antihistamines, antidepressants, opioid antagonists and 5HT 3 receptors, since endogenous pruritogenic mediators (serotonin, histamine, neuropeptides, prostaglandins, endogenous opioids) have been implicated in triggering pruritic stimulus. 15,8,14 Often, chronic itch is refractory to conventional therapies, which leads to the search for medications initially underused as psychotropics, reason why clinical trials are being conducted in this area.
It is worth mentioning that pharmacological therapy that has been used in clinical practice is based on small studies, and that there are few controlled clinical trials.
This paper is a systematic review, which aims to observe the published studies that demonstrate the effectiveness of psychotropic drugs in different primary causes of itch.

MATERIAL AND METHODS
This review was conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guideline.
The preparation of the systematic review was initiated in The first step consisted of reading the titles and abstracts, and selecting articles that contained the keywords previously explained or derived words (MeSH terms). Based on selected articles, the second step consisted of thorough and independent analysis of each article by the authors, assessing the consistency with the proposed theme and methodological rigor. The authors met before the collection to ensure uniform understanding of the eligibility criteria.
In cases of disagreement, the authors tried to reach a consensus.
Finally, in order to find useful items that were not contained in the initial search, the reference lists of articles originally included were used.

RESULTS
Based on the terms used for the search and specifiers, 134 articles were found in PubMed; 12 articles in Web of Science; 97 in Scopus; and 0 in Scielo database. All items found were in English.
Among these, 15 articles fulfilling the inclusion criteria were included in this systematic review. From PubMed database, 114 articles were excluded because they were not related to the keywords and 06 for not being controlled clinical trials; 01 article was included from a reference list ( Figure 1). In the other databases, all items were excluded because none was a controlled trial.
We observed significant heterogeneity in clinical trials as the primary types that led to itch as well as to the psychotropic and methodologies used.
The articles included in this review presented as the origin of itch: chronic kidney disease or dialysis (6); itch after burn (2); mustard gas lesions and itch for other dermatological causes (2); chronic liver disease or cholestasis (2); chronic idiopathic urticaria (2); and one for not dermatologic causes (with a predominance of cancer).
It should also be evidenced that there has been no controlled study addressing the psychogenic or somatoform as an origin of itch.
The psychotropic drugs used in these clinical trials for the various causes of itch were: pregabalin, gabapentin, doxepin, paroxetine and sertraline. It was decided that clinical trials comprised in this review would be presented grouped by the cause of itch to allow some inferences on the observed heterogeneity of etiologies.
Where it was not feasible a more homogeneous grouping, we performed the methodological, results and other possible outcomes descriptions of each study. Table 1 shows the six clinical trials included in the study on itch due to chronic kidney disease.

Itch secondary to chronic kidney disease or dialysis
In the six studies of patients with chronic kidney disease (CKD) at advanced stage, and therefore performing hemodialysis (HD), there was the participation of a total of 179 individuals with a mean age of 56 years (± 11.8).
In most of the six studies, the characteristics of patients was similar as well as the criteria that led to the selection of the participating subjects. As inclusion criteria, the subjects should be at least  improvement: complete improvement, relative improvement and no effect, respectively. 16 We found that, of the six trials on CKD as underlying disease for itch, five used gabapentin 100-300 mg following dialysis sessions as medication to be compared and/or tested. Doxepin was used in one study on the grounds that, until then, it had not been tested in patients with CKD in controlled trials. 16 The rationale for the use of such tricyclic antidepressant would be because it presents strong anti-histaminergic action, acting in one of the neurotransmitters of itch mechanism. 16 Among these six studies, we observed that in five of them there was a significant improvement of itch with use of psychotropic, although Solak et al. study compared gabapentin 300 mg, 3 times a week, with pregabalin 75 mg daily, two anticonvulsants. 15 Interestingly, in one of the trials, the outcome was different. Marquez et al. compared a group using desloratadine 5 mg/day (3 weeks) with other group using gabapentin 300 mg after hemodialysis sessions (3 weeks), with cross over and a week washout. The study showed that desloratadine presented significant improvement in itch, while gabapentin, although it also improved the symptom, was not statistically significant. 17 Furthermore, three of the six studies presented very similar methodologies, but one of the differences observed in these studies was the dosage of gabapentin 300 mg 3 times a week, 400 mg 2 times a week and 100 mg 3 times a week. [18][19][20] These three trials demonstrate the effectiveness of gabapentin over the placebo group. [18][19][20] As for secondary endpoints, all six trials demonstrated greater adverse events in the groups using psychotropics, especially dizziness, drowsiness and fatigue, more intense after the first dose and with gradual tolerance. However, some subjects could not continue in the trial due to the intensity and persistence of adverse events. This occurred in the study of Marquez et al., in which four subjects discontinued the study due to gabapentin (fatigue and drowsiness) and one abandoned it when used desloratadine due to "nervousness". 17 In Razeghi et al., there was a loss caused by adverse events of gabapentin. 20

Itch with dermatological cause
Two articles included in this review addressed different skin impairment (in sequence, lesion resulting from sulfuric gas and atopic eczema), so it was not possible to unify methods or actions to be taken, although the tested medication was the same, doxepin cream 5% (Table 2).
Panahi's clinical trial aimed to check whether doxepin could be an effective alternative to relieve the itching caused by mustard gas. The study included 75 men who were exposed to mustard gas decades ago and who presented itch. Subjects were excluded if they presented itch secondary to systemic or cutaneous disease, not triggered by mustard gas. Patients were divided into two groups: in one group (40 men), doxepin 5% was applied in lesions two times a day; in the other group (35 males), betamethasone 0.1% was applied for 6 weeks. 21 It was found a significant improvement in almost all affected parts of the body in both groups, with no significant difference between groups, according to VAS and DLQI (Dermatology Life Quality Index). Doxepin cream 5% resulted in fewer adverse events compared with betamethasone topical. Topical presentation of doxepin compared with oral presentation presented advantages because it did not cause adverse events typical of tricyclic antidepressants. 21 Groene et al.  Despite this improvement, methodological flaws limited incisively the conclusions from these observations. For example, the symptoms were grouped into categories, resulting in ordinal variables, which were compared using paired t-tests, which are applied to mean of interval variables, beacuse it does not make sense to calculate mean of ordinal of categorical variables. Thus, the data presented as statistically significant actually were not calculated properly. 24

Itch for chronic liver disease (CLD) or cholestasis
Two clinical trials were conducted in 2006, randomized, placebo-controlled, totaling 28 subjects with chronic liver disease (the leading cause of both studies was the primary biliary cirrho-sis) and presence of itch (Table 3). The factors necessary to enter in both studies were: evidence of cholestatic liver disease and itch over three months. The exclusion criteria in common were: patients could not have dermatologic disease associated with itch or make use of antipruritic agents. These, if used, should be suspended until two weeks before starting the study; also, patients could not be taking antidepressant, opioid, corticosteroids, phenothiazines and antiviral for hepatitis or they should be suspended five days before the start of the trial. 26   weeks, and a higher effectiveness was verified, with significance in the group using sertraline 75 mg to 100 mg daily compared with placebo. 26 It was also observed that doses higher than 100 mg/day does not necessarily caused benefits related to itch, but increased adverse events like insomnia, fatigue and increased bowel habits.

Itch after burning
Two articles related to burning as a primary cause of itch were included, both with methodological design of randomized, double-blind, and only the first described below held control with placebo group (Table 3).
Inclusion criteria were nearly identical between the two clinical trials as well as the exclusion criteria. To enter these studies, patients should be aged between 18-60 years (in the second study, between 12-70 years), present percentage of burned body area higher than 5%, including predominance of second degree burns and lesions in healing process or already healed up to 3 months. As exclusion criteria, the same comorbid conditions were marked: diabetes mellitus, skin disease, kidney disease, pregnancy, lactation or surface of grafted area greater than 2%.
In the first study, Ahuja conducted a clinical trial with 80 subjects who were subdivided into four groups, divided equally, arranged in the subsequent order: cetirizine and pheniramine maleate (antihistamine group); pregabalin, cetirizine and pheniramine maleate (combined group); placebo (vitamin B complex); and an-other group which received only pregabalin. In this trial, VAS was used not only for subsequent itch ratings, but also to determine the dosage of each drug used in accordance with the categorization in mild itch (2)(3)(4)(5), moderate itch (6-8) and severe itch (9 and 10). Therefore, cetirizine doses ranged from 10 to 30 mg/day; pregabalin doses ranged from 75 to 300 mg; and pheniramine doses was maintained at 25 mg/da.
In mild to moderate itch, the almost complete remission was achieved in the combined and pregabalin group, with a significant difference compared with the antihistamine and the placebo group. Regarding the severe itch, there was also a significant improvement in the combined and pregabalin groups when VAS was evaluated on the 28th day. There were no reported adverse events in the placebo and pregabalin groups, however, the antihistamine and combined groups, 11 and 9 patients complained of drowsiness, respectively. 28 The second trial included in this review was conducted by the same author, with the objective to test gabapentin in itch secondary to severe burns as well as to test if the association of gabapentin to an antihistamine would result in significant superiority of the junction of the two neurophysiological mechanisms. 29

Itch for non-dermatological causes (malignant diseases)
A single study was included, whose central theme was the psychopharmacological treatment of non-dermatological itch due to, mostly, malignancies and serious systemic diseases in order to test paroxetine 20 mg/day ( Table 3).
The inclusion criteria used were: adult patients, who experience intense itching during at least one month, not associated with skin disease, able to assess the intensity, as well as having more than a month of life expectancy. Patients with known hypersensitivity to paroxetine, such as pregnant women or women who were breastfeeding, with bipolar disorder, uncontrolled epilepsy, use of MAOIs (monoamine oxidase inhibitors), chronic nausea, dependence on antihistamines and creatinine clearance estimated at less than 30 ml per minute were excluded from the study. Even with these results, we cannot fail to emphasize the low amount of controlled clinical trials using psychotropic drugs for itch of various causes, given the importance of this theme. Furthermore, we observe the absence of clinical trials including or focusing on mental disorders that may cause or be comorbid to itch of several causes. Possibly one of the factors that justify this lack is the high prevalence of mental disorders in the general population.
That said, it was observed that only one of the clinical trials used as an exclusion criterion "uncontrolled" mental illness, which may have influenced so as to cause biased results in other studies. 15 In another study, the authors were careful to investigate the depression according to HDRS and SCID, and concluded that the underlying disease and itch could be one of the causes of the depressive symptomatology. 27 It was observed that there is a direct and statistically significant correlation between the severity of itch and the severity of depressive symptoms. 31 Most of patients enrolled in studies relating to itch consequent to CKD had diabetes mellitus as underlying disease of renal dysfunction. Symptoms of pain and itch resulting from peripheral neuropathy were perceived as chronic complaints and were proven through the assessment by electromyography. 15 Solak conducted this test carefully correlating the cause of itch to medication tested for itch -gabapentin and pregabalin. 15 It would be a great addition to the knowledge that is being established in this branch of medicine studies comparing gabapentin, pregabalin and placebo.
It is understood that the pathophysiological mechanism of itch in renal and hepatic causes is the same (neuropathic pruritus).
Therefore, the use of gabapentin and pregabalin would have a good indication, although we can highlight the lack of uniformity related to difference of dose used in these trials (100 to 300 mg after hemodialysis; or daily in cases of hepatic impairment).
Gabapentin and pregabalin are part of the class of anticonvulsant, derivatives of the inhibitory neurotransmitter GABA (gamma amino butyric acid), but may have indications for peripheral neuropathy and peripheral neuralgia. Through the mechanism of action, they act so the post-synaptic excitability attenuates through depolarization changes in calcium and potassium channels and may be related to improvement of itch. 32,33 In one of the results in that the hypotheses of the author has been refuted (that psychotropic would have greater statistical effectiveness in itch), it was discussed why the itch showed better response and behavior change after use of placebo. 27 In this study, in a contradictory manner, even with high doses of gabapentin (maximum of 2400 mg/day), there was no significant improvement in itch. The author argues that the itch caused by the cholestatic disease is mediated by tone of opioid neuromodulators and should therefore be treated with opioid antagonists, demonstrated by controlled clinical trials. 27,34 To treat itch with skin disease origin (pruritoceptive), capsaicin cream, doxepin and aspirin can be used. 9 Nevertheless, this review did not show enough clinical trials able to reinforce this behavior in clinical practice in a guided way.
Even in the treatment of itch in skin diseases, the psychotropic drug most commonly used in clinical practice is doxepin, a tricyclic antidepressant with a strong antihistamine action. 23 Doxepin was used in two trials whose basal cause of itch was dermatologic.
However, the way doxepin was used (in a study as treatment and in another as pretreatment) and the type of skin disorder diverge. 23,25 So it is not possible to infer that doxepin shows good results related to itch. When the use of doxepin was directed to chronic urticaria, the two studies evaluated showed efficacy of antidepressant, yet both suffered from methodological flaws and follow without further replication of results. 24 Part of this may be explained by the fact that these are two publications with about 30 years and can be used as an example of the lack of more objective tools for evaluation of itch, already present in the most recent publications.
It is important to add that psychosomatic factors modulate the perception of itch in a large amount of skin diseases. 35 It is estimated that, in dermatological clinics, the prevalence of psychogenic itch complaints can be considered high, about 2% of patients treated. 36 Furthermore, the diagnosis of psychogenic itch is performed excluding other causes. However, there may occur simultaneously the other type of itch. 6,7 Given this difficult differential diagnosis, we understand the objections to conduct controlled clinical trials for psychogenic pruritus. However, these studies are needed, as itch requires an interface between specialties as well as more evidence is needed on the effectiveness of psychotropics.
We can conclude that most of the clinical trials performed so far show statistically significant efficacy of the psychotropic in the treatment of itch for various causes. Controlled studies stood out, whose basic cause of the itch is chronic kidney disease. In these, a greater effectiveness was observed in most psychiatric drugs used compared with placebo. However, due to the small amount of con-