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Unexpected effect of aripiprazole on nociceptive pain

Aripiprazole (ARP) is an antipsychotic that acts as a modulating partial agonist of the dopamine-2 (D2) receptor, approved for the treatment of schizophrenic disorders [DeLeon et al. 2004] and recently for the treatment of manic mixed episodes associated with bipolar type I disorder [Aitchison et al. 2009; Dhillon, 2012]. Compared with other antipsychotics, its safety and tolerability (low risk of extrapyramidal symptoms [EPS], weight gain and hyperprolactinemia) encourage its use in psychiatric patients with comorbidities. 
 
Five psychiatric patients with severe painful internal comorbidities showed unexpected pain improvements during effective treatments of their psychopathological conditions by ARP monotherapy (from 2.5 to 15 mg daily). Pain was assessed regularly in relation to the fact that is considered the ‘fifth vital sign’. These patients had developed nociceptive painful syndromes that responded poorly to opioid and/or non-steroidal anti- inflammatory drugs therapy. They had no symptoms related to non-nociceptive (neurological) pain. With reference to pain and psychology, patients showed a moderate improvement after 2 weeks of treatment and a significant improvement after 4 weeks, as demonstrated by CGI (Clinical Global Impression for severity and improvement scales with endpoints labelled 1 ‘normal, not at all ill’ to 7 ‘among the most extremely ill patients’ and 1 ‘very much improved’ to 7 ‘very much worse’, respectively) and NRS-o (0–10 oral Numeric Rating Scale: visual scale anchored with the endpoints labelled ‘no pain’ near the ‘0’ number and ‘extreme pain’ near the ‘10’ number) scales’ scores used for the assessment of psychopathological state and pain level, respectively (Table 1). No changes in the internal condition, which could account for the improvements concerning pain, were observed. 
 
 
 
Table 1. 
 
Sample features 
 
 
 
These clinical observations suggest the involvement of brain dopamine (DA) transmission in nociceptive pain pathways as a result of the ‘modulation’ of the dopaminergic system by ARP, although ARP-mediated antagonism on 5HT2A receptors [DeLeon et al. 2004] known as facilitating spinal nociception [Oyama et al. 1996], is possible. The activation of nigrostriatal (dorsal nucleus caudate and putamen) DA D2 receptor-mediated neurotransmission is positively associated with individual variations in subjective ratings of sensory and affective qualities of pain with an increased threshold as outcome [Scott et al. 2006]. In contrast, mesolimbic (nucleus accumbens) DA activation, which may have an impact on both D2 and D3 receptors, is exclusively associated with variations in the emotional responses of the individual during pain challenge (increases in negative affect and fear ratings) [Stahl, 2002]. The ARP antipsychotic mechanism is based on the blockade of mesolimbic D3 receptors, whereas nigrostriatal D2 receptor-mediated activity is not changed by it [Oyama et al. 1996]. So its effect could result in a direct involvement on reduction of pain perception even if a positive unspecific role on pain threshold psychological-mediated is possible. However, these effects on pain perception could be particularly evident owing to the poor effectiveness of common pain treatments in our sample. This is the first report about the relationship between aripiprazole and subjective experience of pain.