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Psychotropic Drugs for the Management of Chronic Pain and Itch

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Psychotropic Drugs for the Management of Chronic Pain and Itch pharmaceuticals Review Psychotropic Drugs for the Management of Chronic Pain and Itch 1, , 2, 1 3 Daria A. Belinskaia * y, Mariia A. Belinskaia y, Oleg I. Barygin , Nina P. Vanchakova and Natalia N. Shestakova 1 1 Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, pr. Torez 44, St. Petersburg 194223, Russia; [email protected] (O.I.B.); [email protected] (N.N.S.) 2 International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland; [email protected] 3 Department of Pedagogy and Psychology, Faculty of Postgraduate Education, First Pavlov State Medical University, L’va Tolstogo str. 6-8, St. Petersburg 197022, Russia; [email protected] * Correspondence: [email protected]; Tel.: +7-921-580-69-19 These authors contributed equally to this work. y Received: 26 May 2019; Accepted: 21 June 2019; Published: 24 June 2019 Abstract: Clinical observations have shown that patients with chronic neuropathic pain or itch exhibit symptoms of increased anxiety, depression and cognitive impairment. Such patients need corrective therapy with antidepressants, antipsychotics or anticonvulsants. It is known that some psychotropic drugs are also effective for the treatment of neuropathic pain and pruritus syndromes due to interaction with the secondary molecular targets. Our own clinical studies have identified antipruritic and/or analgesic efficacy of the following compounds: tianeptine (atypical tricyclic antidepressant), citalopram (selective serotonin reuptake inhibitor), mianserin (tetracyclic antidepressant), carbamazepine (anticonvulsant), trazodone (serotonin antagonist and reuptake inhibitor), and chlorprothixene (antipsychotic). Venlafaxine (serotonin-norepinephrine reuptake inhibitor) is known to have an analgesic effect too. The mechanism of such effect of these drugs is not fully understood. Herein we review and correlate the literature data on analgesic/antipruritic activity with pharmacological profile of these compounds. Keywords: chronic pain; psychotropic drugs; pharmacological profile; animal model; clinical trial 1. Overview Chronic pain accompanies many pathological conditions, such as diabetes, chronic renal failure, and cancer [1–3]. The nature of chronic pruritus is currently under discussion, but there are reasons to believe that it can be assumed as a specific type of pain [4,5]. At least half of patients suffering from chronic pain and itching are diagnosed with mental disorders such as depression and/or anxiety [6,7]. At the same time, chronic pain and pruritus syndromes are found in 60% of patients with depression [8,9]. Regardless of whether the mental disorders are primarily or secondarily related to chronic pain and itching, such patients need compensatory therapy with psychotropic drugs, some of which have their own analgesic and antipruritic action [10,11]. It is indicated often in medical literature that it is the class of tricyclic antidepressants (TCA) that have such efficacy. However, effective analgesic/antipruritic drugs are found among practically all antidepressant groups [12]. Anticonvulsants and antipsychotics are widely used in pain management, too [13,14]. Generally, the detection of analgesic and especially antipruritic effects of psychotropics is random, there are no certain structure criteria for determining their efficacy. In our previous studies, using molecular modelling methods, we showed that the tricyclic and tetracyclic psychotropic drugs that Pharmaceuticals 2019, 12, 99; doi:10.3390/ph12020099 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2019, 12, 99x FOR PEER REVIEW 2 of 49 studies, using molecular modelling methods, we showed that the tricyclic and tetracyclic psychotropichave the V-like drugs conformation that have ofthe their V-like heterocyclic conforma grouption of (aromatic their heterocyclic rings co-centered group (aromatic at an angle rings of 120–160co-centered degrees, at an Figure angle1) haveof 120–160 analgesic degrees, and antipruritic Figure 1) activity, have analgesic whereas theand drugs antipruritic that have activity, a plain whereasconformation the drugs of their that rings have do a notplain [15 conformation]. However, the of targettheir rings of analgesic do not and[15]. antipruritic However, the action target of the of analgesiceffective compounds and antipruritic remained action unclear. of the effective compounds remained unclear. Figure 1. V-likeV-like conformation of aromatic ri ringsngs in the example of mianserin. According toto the the data reporteddata reported in literature, in someliterature, TCAs aresome blockers TCAs of theareN -methyl-blockersd-aspartate of the N-methyl-D-aspartatereceptors (NMDAR), whichreceptors are (NMDAR), involved in which the pain are involved signal pathways in the pain [16 ,signal17]. In pathways 2009, using [16,17]. the patch-clampIn 2009, using technique, the patch-clamp Barygin and technique, co-authors Bar showedygin thatand theco-authors tricyclic compoundsshowed that that the have tricyclic V-like compoundsconfiguration that of their have rings V-like are ableconfiguration to block NMDAR of their through rings are a voltage-dependent able to block NMDAR mechanism, through unlike a plainvoltage-dependent compounds [ 18mechanism,]. We hypothesised unlike thatplain it iscompounds the anti-glutamate [18]. We mechanism hypothesised that determinesthat it is the anti-glutamateanalgesic and antipruriticmechanism ethatfficacy determines of psychotropic the analgesic drugs containingand antipruritic the V-like efficacy group. of psychotropic Later, using drugselectrophysiological containing the methods,V-like group. we showed Later, using that theelectrophysiological antidepressants desipramine methods, we and showed amitriptyline that the antidepressantsas well as antipsychotics desipramine chlorpromazine and amitriptyline and atomoxetine, as well as which antipsychotics contain the chlorpromazine V-like group in theirand atomoxetine,structure and arewhich effective contain for the chronic V-like pain group management, in their structure are able to and block are NMDAR effective by for the chronic mechanism pain management,called “trapping” are [able19]. Trappingto block blockersNMDAR do by not the prevent mechanism channel called closure “trappi and agonistng” [19]. dissociation. Trapping Afterblockers channel do not closure, prevent such channel blockers closure become and trapped agon inist the dissociation. closed state After and cannot channel leave closure, the channel such blockersuntil it opens become again. trapped in the closed state and cannot leave the channel until it opens again. However, there were mismatches,mismatches, too. Our own clinical studies at First Pavlov State Medical University havehave identified identified antipruritic antipruritic and /and/oror analgesic analgesic efficacy efficacy of the followingof the following compounds compounds (Figure2): (Figuretianeptine 2): (atypical tianeptine tricyclic (atypical antidepressant), tricyclic antidepres citalopramsant), (selective citalopram serotonin (selective reuptake serotonin inhibitors reuptake (SSRI)), inhibitorsmianserin (tetracyclic(SSRI)), antidepressant),mianserin (tetracyclic carbamazepine antidepressant (anticonvulsant),), carbamazepine trazodone (serotonin (anticonvulsant), antagonist trazodoneand reuptake (serotonin inhibitor antagonist (SARI)), chlorprothixene and reuptake (antipsychotic)inhibitor (SARI)), [9,20 chlorprothixene–22]. Mianserin, carbamazepine(antipsychotic) [9,20–22].and tianeptine Mianserin, contain carbamazepine the V-like group and in tianeptine their 3D-structure contain the (Figure V-like2), group but they in their are not 3D-structure NMDAR (Figureblockers 2), in but clinically they are relevant not NMDAR concentration blockers [23 ].in Later,clinically we showedrelevant thatconcentration besides the [23]. V-like Later, moiety, we showeda drug hasthat to besides have athe positively V-like moiety, charged a drug amine has group to have in its a positively structure tocharged block NMDARamine group [24], in and its structuremianserin, to carbamazepine block NMDAR and [24], tianeptine and mianserin, do not carbamazepine contain this. Trazodone and tianeptine and citalopram do not contain have other this. Trazodoneconfigurations and of citalopram their aromatic have rings, other and configurations we showed that of their they havearomatic no anti-glutamate rings, and we activity showed [19 that,23]. Thethey anti-glutamatehave no anti-glutamate effect of chlorprothixene activity [19,23]. is The unclear; anti-glutamate the angle betweeneffect of itschlorprothixene aromatic rings is is unclear; close to 180the angle degrees, between but the its configuration aromatic rings is not is close completely to 180 plain.degrees, Our but own the electrophysiological configuration is not experiments completely plain.showed Our that own chlorprothixene electrophysiologic is able toal inhibitexperiments NMDAR, showed but there that was chlorprothixene only partial trapping is able (seeto inhibit details NMDAR,in Section but3.6.3 there). was only partial trapping (see details in Section 3.6.3). Regarding analgesic and antipruritic activity of these psychotropics, certainly, there are some limitations in their effectiveness. Firstly, we studied their effect in patients having chronic itch and pain (musculoskeletal and/or headache) associated with chronic renal failure (CRF) and chronic haemodialysis (CH), as well as in patients with diffuse itching accompanied by depression.
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