Paracetamol has not been demonstrated to have any specific deleterious effects on cognitive processing. A recent functional magnetic resonance imaging study has shown that paracetamol reduced neural responses to social rejection in brain regions previously associated with distress caused by social pain and the affective component of physical pain (dorsal anterior cingulate cortex, anterior insula). Thus, paracetamol reduces behavioral and neural responses associated with the pain of social rejection, demonstrating a substantial overlap between social/emotional and physical pain (DeWall et al. 2010).

Aspirin is widely used in stroke prevention, and atrial fibrillation is associated with a decline of cognitive function. A randomized controlled trial (Mavaddat et al. 2014) recently compared the effect of anticoagulation (warfarin) versus aspirin on cognitive function in elderly patients with atrial fibrillation and showed no superiority of aspirin over anticoagulation against cognitive decline. Several epidemiological studies (Imbimbo et al. 2010) have suggested that long-term use of NSAIDs may protect subjects carrying one or more ε4 allele of the apolipoprotein E against the onset of Alzheimer’s disease (AD). However, a Cochrane study (Jaturapatporn et al. 2012) assessed the efficacy of aspirin, steroids, traditional NSAIDs, and COX-2 inhibitors in AD and concluded that their efficacy is not proven and that these drugs cannot be recommended to prevent cognitive decline of AD. It is interesting to note that inflammation is at the heart of a number of degenerative pathologies and pain states and has also been incriminated in depression, although inflammation as a cause or consequence of depression has been questioned for a number of years. A recent study showed no significant relationship between inflammatory markers and symptoms of depression and anxiety during aging in patients with NSAID use, suggesting no particular influence of this medication on depression (Baune et al. 2012).

Over the last two decades, the clinical use of opioids for chronic pain treatment has become widespread with the development of immediate- and extended-release formulations for acute and chronic pain including cancer pain. Opioid analgesics do relieve pain and remain first-line drugs for severe, chronic pain. The continued increase in their medical use (Atluri et al. 2014) has led to concerns of misuse, abuse, and addiction in chronic pain patients (CDC 2011). Indeed the abuse liability during opioid therapy for pain treatment has been noted as a concern for a certain percentage of chronic pain patients (Fishbain et al. 2008). This point is important as opiate dependence contributes to cognitive impairment in the domains of attention and executive function, with comorbid depressive symptoms negatively affecting reaction times (Loeber et al. 2012). In general, the scientific literature devoted to the impact of opioids on cognition and emotion in chronic pain patients is poorly documented. Adverse events of opioids per se are well known, with mental dullness, somnolence, sedation, sleep disturbances, and even delirium due to opioid excess. Analgesic efficacy and side effects may however be quite heterogeneous among patients with variable pharmacological mu-opioid responses. It has also been shown that the kappa-opioid receptor modulates synaptic strength and controls neuroplasticity in different brain regions associated with cognition and emotion (Pasternak et al. 1999). The success of opioid therapy often depends on achieving a balance between analgesic effectiveness and acceptable side effects.

Current evidence for a lack of appreciable effect, benefit, or harm of a long-term stable opioid treatment on cognitive functioning in noncancer pain patients (Kendall et al. 2010) or in cancer pain patients (Kurita et al. 2009) is still limited (Ersek et al. 2004). It is interesting to note that the best-quality randomized clinical trials showed no deleterious effect on cognition and even some cognitive improvement with opioid treatment (Kendall et al. 2010). The discrepancy between studies may be linked to the different methodologies used to evaluate cognitive domains in the studies, as subjective cognitive complaints are not always associated with objective (neuropsychological tests) measures of cognitive function and may give different results. A large meta-analysis (Lindner et al. 2014) focused on cognitive impairment in cancer patients (but with no report on opioid consumption) and concluded that the likelihood to identify cognitive impairment rests on the type of design employed, as memory and attention impairments were only detected in cross-sectional studies. Repetition of cognitive neuropsychological testing (attentional capacity, psychomotor speed, information processing speed, short-term memory, semantic memory, decision-making) may bias the findings of longitudinal studies. There is a real need to establish a consensus concerning reliable assessment of cognition in patients, especially with those on opioid treatment. In the clinic, it is important to inform the patient that long-term treatment with opioids may not be harmless and may even marginally interfere with cognitive function; however, this potential side effect should not hinder clinicians from increasing opioid dosing and optimizing opioid therapy. Overmedication and undertreatment can both have detrimental consequences. Overmedication may lead to addiction, hyperalgesia and worsening of negative emotional state. Undertreatment may maintain emotional distress, depression, sleep, and anxiety disorders. A rational use of opioids for chronic pain will avoid allostatic emotional behavior and maintain or restore homeostatic regulation of emotional behavior (Shurman et al. 2010).

Antidepressants are recommended as first-line treatment for neuropathic pain (Finnerup et al. 2005; Dworkin et al. 2010). However, the mechanism of action of antidepressants in pain alleviation is complex; the safety profile of tricyclic antidepressants (TCAs) must be carefully taken into account as they may impair cognition. Newer classes of antidepressants, duloxetine and venlafaxine (serotonin and norepinephrine reuptake inhibitors SRNIs), may be less analgesic but they have less adverse effects although fatigue is frequently reported. Depression and chronic pain share a number of common mechanisms (Nekovarova et al. 2014; Blackburn-Munro 2001; Chou 2007), and depression may precede or follow after chronic pain. Chronic pain and depression are both conceptualized as stress and all three modulate brain and synaptic plasticity. Pain and depression may influence the functions of the brain default mode network (Baliki et al. 2008; Marchetti et al. 2012), a network of interacting brain regions activated during “resting” states. Plastic changes induced by pain or/and depression at synaptic, cellular, and molecular levels modify connectivity within the neuronal circuitry and contribute to structural and functional changes in the brain. Not surprisingly, an additive effect of depression and chronic pain has been shown in cancer patients in several domains of quality of life (Kroenke et al. 2010). Cognitive dysfunction accompanies depression (McIntyre et al. 2013) and pain, and this cognitive dysfunction often persists after remission of the depressive symptoms (Conradi et al. 2011). This suggests that currently used antidepressants, selective serotonin (5-HT) reuptake inhibitors (SSRI), and SNRIs may not be all that adequate to improve cognition in depressive patients (McClintock et al. 2011; Pehrson et al. 2014). We recently showed in patients with long-standing post-zoster neuropathic pain (with mild depressive symptoms) that antidepressants (mainly TCAs) prescribed for pain impaired several cognitive domains (spatial memory and semantic memory) when compared to neuropathic pain patients without antidepressants (Pickering et al. 2014a) These findings confirmed reports of an association between memory disorders and TCAs/SSRIs antidepressants (Chavant et al. 2011), but antidepressants do not always induce cognitive impairment. They seem to display a dose-dependent and etiology-dependent pluripotent action. In depressed patients, SSRIs and SNRIs may improve executive functions and attention (Herrera-Guzman et al. 2010). In nondepressed patients with Alzheimer disease, TCAs and SSRIs diminish the severity of cognitive decline (Archer et al. 2007). Animal studies show that amitriptyline (a TCA) ameliorates neuropathic pain-induced deficits in abilities of spatial learning and memory (Hu et al. 2010) and cognitive function in Alzheimer rats (Chadwick et al. 2011). Considering the complexity and heterogeneity of these results, there is a need for larger clinical trials to study cognitive dysfunction in chronic pain with or without depressive symptoms. The cognitive deficits observed in chronic pain patients receiving antidepressants could be due to the chemical properties of the prescribed antidepressant or because of inappropriate dosing. They could also be linked to residual non-alleviated pain and to the combination of pain-induced and depression-induced cognitive loads. It is also plausible to suggest that the type of antidepressant, its mechanistic action on the opioidergic system (Wattiez et al. 2011), the etiology of the pain syndrome, the duration of pain, the comorbidities, the severity of the depressive symptoms, and the extent of the memory traces of depression and pain may all contribute to the complexity of cognitive homeostasis in chronic pain. Finally, as mentioned before, there are also methodological difficulties concerning the cognitive evaluation of patients using neuropsychological tests or via self-report (Amado-Boccara et al. 1995), and isolation of the specific effects of antidepressants on cognition in a patient suffering from chronic pain remains to be established.

Gabapentin and pregabalin are also recommended first-line neuropathic pain treatment. Adverse events of gabapentin related to cognition (somnolence (27.4 %) and falls, dizziness (23.9 %), and ataxia (7.1 %)) may lead to discontinuation of treatment in 10 % of patients and are particularly important in older persons (Pickering 2014). In a recent study in the context of postherpetic neuropathic pain (Pickering et al. 2014a), antiepileptics induced less cognitive impairment than antidepressants, but the impact of antiepileptics on depression and cognition in the context of pain must be explored further.