During the past two decades, the amount of literature on pain in specific patient groups has grown substantially. Several studies suggest a disturbed pain experience in neurodegenerative diseases such as Alzheimer’s disease (Benedetti et al. 1999), vascular dementia (Scherder et al. 2003), multiple sclerosis, and Parkinson’s disease (Scherder et al. 2005b). An example of disturbed pain experience can be found in patients with Alzheimer’s disease, who appear to have an increased tolerance to pain compared to healthy subjects (Benedetti et al. 1999) although other more recent studies have failed to replicate this finding (Jensen-Dahm et al. 2014). This could be explained by reduced neural functioning of brain structures involved in pain processing, such as the anterior cingulate cortex, hippocampus, and insula (Scherder et al. 2003). Insight into possible alterations in pain experience in specific patient groups is essential for adequate pain treatment (Scherder et al. 2005a).

Nevertheless, the amount of literature in the field of pain in psychiatry remains sparse. Based on the hypothesis of altered prefrontal and medial temporal functioning in schizophrenia (Harrison 2008; Keshavan et al. 2008), a disturbed pain experience is plausible as well. Indeed, various case studies have described how persons with schizophrenia appear unaffected by severe medical conditions (e.g., appendicitis, abdominal surgical emergencies, fractures) and have put forward the possibility of reduced sensitivity to pain (Murakami et al. 2010; Murthy et al. 2004; Rosenthal et al. 1990). The question whether patients with schizophrenia are indeed “insensitive” to pain has been addressed in experimental studies in persons with schizophrenia. Thermal (de la Fuente-Sandoval et al. 2011; de la Fuente-Sandoval et al. 2010; Dworkin et al. 1993), electrical (Blumensohn et al. 2002; Collins and Stone 1966; Kudoh et al. 2000), cold (Atik et al. 2007), reflex (Guieu et al. 1994), and tactile stimulations (Girard et al. 2011; Karst et al. 2005) have been utilized to assess pain threshold and pain tolerance in schizophrenia. Several experimental pain studies found persons with schizophrenia to be less sensitive to pain compared to healthy controls, as measured by pain threshold or tolerance (Atik et al. 2007; Blumensohn et al. 2002; de la Fuente-Sandoval et al. 2010; Kudoh et al. 2000). A reduced reactivity to pain, instead of an “endogenous analgesia,” has been proposed as a possible alternative explanation for this finding (Bonnot et al. 2009). Merely considering experimental and case studies might not fully represent pain in schizophrenia. Abilities such as a fast response and an adequate expression of pain might be impaired in people with schizophrenia, consequently biasing results (Girard et al. 2011). Pain reaction might also depend on the type of experimental manipulation. For example, in people with major depression disorder, hypoalgesia for heat and electrical pain was present compared to healthy controls, but hyperalgesia was present for ischemic muscle pain compared to healthy controls (Bär et al. 2005).

The goal of this chapter is to explore possible alterations in the experience of pain in people with schizophrenia. Possible interactions based on theoretical considerations of the underlying neuropathology in schizophrenia will be discussed as well as examination of a few possible confounders of pain research in schizophrenia.

A recent review of the literature regarding clinical pain in schizophrenia (Engels et al. 2014) examined clinical pain without experimental provocation. Intensity and prevalence of clinical pain appeared to be diminished in people with schizophrenia compared to control subjects in medically severe situations, such as headache after a lumbar puncture or post-surgery pain. For less severe situations, intensity and prevalence of pain appear to be similar. For a detailed description, see Engels et al. (2014). A recent meta-analysis concluded that prevalence of clinical pain was similar to controls for everyday pain (Stubbs et al. 2014).

The sensory-discriminative, motivational-affective, and cognitive-evaluative aspects of pain (Melzack and Casey 1968; Scherder et al. 2003) are processed in two neural pain systems (Vogt and Sikes 2000; Willis and Westlund 1997). The lateral pain system comprises the spinothalamic tract, which reaches to primary and secondary somatosensory areas, insula, and parietal operculum through the lateral thalamus (Scherder et al. 2003). The lateral pain system entails the sensory-discriminative aspects of pain experience (Sewards and Sewards 2002).

The medial pain system encompasses the spinothalamic tract, projecting to the medial and intralaminar thalamic nuclei, the spinoreticular tract, and the spinomesencephalic tract. These tracts reach to areas such as the amygdala, anterior cingulate cortex (ACC), hypothalamic nuclei, and hippocampus. The medial pain system mainly processes motivational-affective and cognitive-evaluative aspects of pain. A schematic view of the neural processing of pain, as well as a more detailed description of the pain systems, can be found elsewhere (Scherder et al. 2003; Willis and Westlund 1997).

A number of areas play a crucial role in pain processing, such as the prefrontal cortex (PFC), the hippocampus, and the thalamus. These areas also appear affected in schizophrenia, although the neuropathology remains elusive (Harrison 2008). Nonetheless, several neurobiological substrates show changes in schizophrenia quite consistently. The most robust findings on affected brain areas have been found on the prefrontal cortex and the medial temporal lobe (Harrison 2008; Keshavan et al. 2008) and, more specifically, the hippocampus (Harrison 2004). Activity in the dorsolateral prefrontal cortex (DLPFC) (Perlstein et al. 2001) and connectivity between the DLPFC and the hippocampal formation are thought to underlie certain cognitive deficits such as working memory impairment (Meyer-Lindenberg et al. 2005). An impaired connectivity between the prefrontal cortex, hippocampus, and thalamus has been proposed as an underlying neuropathological mechanism in schizophrenia (Lewis and Lieberman 2000), and variability in the dysconnectivity within prefrontal areas strongly correlates with cognitive deficits in schizophrenia (Cole et al. 2011). It has also been suggested that hubs (i.e., most highly connected brain regions) which are frontally located in controls are replaced by inferior temporal, insular, and anterior cingulate areas in schizophrenia (Bassett et al. 2008), emphasizing the deviant-functioning PFC in schizophrenia.

Gray matter deficits have also been found in the insular cortex (Sigmundsson et al. 2001), and a reduction in neuronal number has been found in the mediodorsal thalamic nucleus and in the anterior nuclei of the thalamus (Lewis and Lieberman 2000; Young et al. 2000). This reduced thalamic volume appears to be present already in early stages of the disorder, before any effects of medication can be detected (Gur et al. 1998). The mediodorsal nucleus forms the major projection from the thalamus to the prefrontal cortex, and the anterior nuclei additionally project to the ACC (Popken et al. 2000), an area which shows anatomical abnormalities (Fornito et al. 2009). Thalamic volume has been found to correlate with prefrontal white matter volume in persons with schizophrenia (Portas et al. 1998), indicating that prefrontal white matter is decreased as well.

With regard to the experience of pain, impairment of the mediodorsal thalamus and hippocampus, which are both part of the medial pain system, suggests an alteration of motivational-affective and cognitive-evaluative aspects of pain in schizophrenia. The ACC is part of the medial pain system and plays an important role in attentional control (Tracey and Mantyh 2007; Willis and Westlund 1997). Since this structure exerts its inhibition by projecting to, among others, the pain suppressing periaqueductal gray (PAG) (Valet et al. 2004), a change in pain could be anticipated.

Impairment in the insula might not be confined to one single aspect, since the insula is part of both the medial and lateral pain system (Treede et al. 1999). Impairment of the (anterior) insula therefore suggests an alteration of the sensory-discriminative and the motivational-affective and cognitive-evaluative aspects of pain.

A close relation exists between the DLPFC, the midbrain-medial thalamic pathway, and the anterior insula. A strengthened flow of neural information in the DLPFC coincided with a decreased activity between midbrain and medial thalamus, as well as between midbrain and perigenual ACC, suggesting that the DLPFC inhibits the medial pain system (Lorenz et al. 2003). Consequently, impaired functioning of the DLPFC may cause an increase of the affective component of pain: dysfunctioning of the DLPFC might additionally result in a stronger association between insular activity and pain (Lorenz et al. 2003), resulting in an increase of pain. It must be noted, however, that an fMRI study found a significant correlation between unpleasantness and insular activity in healthy controls but not in persons with schizophrenia, where activity in primary somatosensory cortex correlated with unpleasantness (de la Fuente-Sandoval et al. 2011). The perigenual ACC is the part of the ACC associated with the affective experience of pain (Vogt and Sikes 2000). This additionally suggests that the affective aspect of pain is altered in schizophrenia.