Wager Mage
Wager Mage
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Moreover, further medications, including aripiprazole, modafinil, rotigotine, sertraline, citalopram, and lamotrigine, were associated to the occurrence of gambling disorder (George et al.
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Read More »Our results demonstrated that, from 2002 until July 31st 2018, 94 ICSRs describing the occurrence of gambling disorders were reported into the RNF on the entire Italian territory. Drugs most commonly related to gambling disorder were pramipexole, listed as suspected drug in 56% of all ICSRs, ropinirole in 15% of all ICSRs, levodopa in association with benserazide/entacapone and carbidopa in 11%, aripiprazole and rotigotine, each one in 5%. Out of 94 ICSRs reported on the whole Italian territory, 3 were reported to the RNF in Campania Region. Such reports referred to the occurrence of gambling disorder in patients treated with pramipexole (one of which associated to domperidone) and aripiprazole. Although there is no reasonable explanation for a so limited number of gambling disorder cases related to drugs evaluated in our study in Campania Region, it should be highlighted that, according to the data recently reported by the AIFA, the most commonly used drugs in our Region are those with ATC code A, C, J or R and not ATC N drugs (subjects of our study) (L’uso dei farmaci in Italia. Rapporto Nazionale anno 2017. http://www.aifa.gov.it/sites/default/files/Campania-Uso_dei_farmaci_nel_2017.pdf). At present, several studies have confirmed a strict correlation between dopamine agonists and pathological gambling. A cross-sectional study, which enrolled 3090 patients diagnosed with Parkinson’s disease and treated with either levodopa or a dopamine agonist, found that those drugs were associated with a 2- to 3.5-fold increased risk of presenting an impulse control disorder (Weintraub et al. 2010). Furthermore, according to Santangelo et al. (2013) the prevalence of pathological gambling is 2.2–7% in patients with Parkinson’s disease receiving medications. In line with our results, several case reports described the occurrence of gambling disorder in patients treated with pramipexole for the treatment of Parkinson’s disease, restless legs syndrome or bipolar disorder. In these cases, the time of ADR occurrence from the first administration of pramipexole or other dopamine agonists ranged from 1 to 10 months (d’Orsi et al. 2011; Kolla et al. 2010; Strejilevich et al. 2011). The possible explanation of pramipexole-induced pathological gambling has to be found in its pharmacodynamic properties. Indeed, pramipexole is a dopamine agonist, relatively selective for D3 receptors, which are mainly located in the mesolimbic pathways where cognitive and emotional functions, including pleasure and addiction, are overseen. Apart from limbic areas, D3 receptors are also co-expressed with D2 in sensory thalamic nuclei, mammillothalamic tract, amygdala, and therefore they play a key role in controlling physiologic and sensitive aspects of novelty and reward (Kelley et al. 2012). The same pharmacodynamic properties are also shared by ropinirole and rotigotine (Seeman 2015), both associated to the occurrence of impulse control disorders in our study. Post-marketing safety data showed that the most commonly reported ADRs with ropinirole are hypersensitivity, somnolence and psychotic reactions, including pathological gambling (Stocchi et al. 2014). Similarly, rotigotine was associated to the occurrence of impulse control disorders in three patients with Parkinson’s disease (Wood et al. 2015; Wingo et al. 2009). All of them were concomitantly receiving further medications, including levodopa, entacapone, amantadine, and selegiline. In all patients, gambling disorder improved with the reduction in rotigotine dose or its discontinuation. Likewise, cabergoline and pergolide are ergot derivatives that act as dopamine agonists with highest affinity for D2 and D3 receptors; cabergoline is also a 5-HT receptors agonist (Leggio et al. 2016). Two case reports describing the correlation between these ergot derivatives and pathological gambling are reported in the literature. The first one refers to a 46-year-old man who developed gambling disorder after the initiation of cabergoline for the treatment of prolactinoma (Gahr et al. 2011), while the second one refers to a 42-year-old man who developed gambling disorder during treatment with pergolide and levodopa for Parkinson’s disease (Larner 2006). Though it seems that D3 agonists may be preferentially related to gambling and similar behavioral disorders, recent literature data have suggested a correlation also between this ADR and aripiprazole, which is an atypical antipsychotic, that acts as a partial agonist at D2 receptors and 5-HT1a and 5-HT2 serotonin receptors (Khanna et al. 2014). Therefore, aripiprazole could induce gambling due to its agonist activity in the mesocortical pathway, where a low dopamine activity seems to be related to cognitive changes (Gavaudan et al. 2010). In this respect, several case reports have described the occurrence of gambling disorder in patients diagnosed with mood, depressive and schizoaffective disorder and treated with aripiprazole. Most of these cases occurred from few days to one year since the initiation of aripiprazole treatment and tended to resolved after drug’s discontinuation (Gaboriau et al. 2014; Smith et al. 2011; Cohen et al. 2011). According to the results of a retrospective analysis of reports sent to the FDA Adverse Event Reporting System from 2003 to 2012, 1580 impulse control disorders cases were identified. Among suspected drugs, dopamine agonists, including pramipexole and aripiprazole, showed the strongest association with impulse control disorders (Moore et al. 2014). Similar results were obtained from a cohort study conducted on the health claims LifeLink database (Etminan et al. 2017).
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Read More »In our study, few cases of gambling disorder were related to levodopa, levodopa in association with decarboxylase inhibitors or entacapone, and apomorphine. Levodopa has been used for the treatment of Parkinson’s disease for over 50 years. It is a dopamine precursor that passes the blood–brain barrier, normally administered in combination with decarboxylase inhibitors (benserazide/carbidopa), which increase levodopa brain concentration, tolerance and clinical efficacy (LeWitt 2015) and with entacapone, a monoamine oxidase inhibitor, that improve wearing off symptoms (Kouppamäki et al. 2015). According to literature data, both levodopa and apomorphine were associated to gambling disorder (Symmonds et al. 2013; Pontieri et al. 2015; Boyle and Ondo 2015; van Eimeren et al. 2010). Among ICSRs reported into the RNF in Campania region, patients were concomitantly administered other drugs, including benzodiazepines. Although such medicines do not seem directly related to the occurrence of gambling disorder, benzodiazepines, together with amphetamines, methylphenidate, and hydrocodone, are frequently used as cognitive and performance enhancing medications among poker players (Caballero et al. 2016), suggesting in our opinion a possible role in increasing the degree of gambling. Moreover, among our cases, patients who experienced gambling disorder were concomitantly receiving other drugs, including amantadine and domperidone. Although amantadine is associated with impulse control disorders (Thomas et al. 2010), currently data are conflicting. In fact, according to Pettorruso et al. amantadine seems to be an efficacious treatment of pathological gambling, leading to a reduction in severity of gambling symptoms. Authors have suggested that these effects are related to the ability of amantadine to interact with glutamate homeostasis and dopamine function which lead to a reduction in gambling craving and behavior (Pettorusso et al. 2012). Finally, to our knowledge, no data supporting the association domperidone/gambling disorder exists; nevertheless, since this drug is a peripheral D2 receptor antagonist with a low pass through the blood–brain barrier, we should suppose that domperidone-induced gambling disorder is very rare (Barone 1999). In conclusion, although it is widely recognized that dopamine agonists may induce behavioral disorders, it should be noted that Parkinson’s disease is itself characterized by several non-motor symptoms which include pathological gambling, compulsive shopping and eating. In this context, the dysregulation of the dopamine system/dopamine receptor functionality could possibly represent the main neurobiological mechanism underlying the association pathological gambling/Parkinson’s disease, although alterations in serotonin and opioid transmission cannot be excluded (Weintraub and Claassen 2017; Majuri et al. 2017). In particular, literature data have suggested that gambling occur in approximatively 1.7–6.1% of patients with Parkinson’s disease (Balconi et al. 2018). Those symptoms usually occur in the early stages of disease and negatively affect patients’ quality of life (Manning et al. 2015). Similarly, patients with mood and bipolar disorder are more likely to suffer of any form of addiction, including pathological gambling (Voon et al. 2006; Jones et al. 2015).
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