Exploring Pain Processing in Schizophrenia: Research, Limitations, Theories, and Concerns

Picture depicting both the anatomy and a brief explanation of the related function processing of the brain. Picture courtesy of the Dana Foundation.
Picture depicting both the anatomy and a brief explanation of the related function processing of the brain. Picture courtesy of the Dana Foundation.

My best friend works in psychiatric care.  Of the patients she treats most often are those individuals that have been diagnosed with the disease, schizophrenia.  This post is for her.  Knowing that I have dedicated my professional life to helping people heal from disabling injuries, diseases, and disfigurement and that a significant amount of my personal life revolves around maintaining my own disability, she often remarks that many of her patients seem to process pain differently than individuals who do not have schizophrenia.  She questions if this is due to the inability to verbally and behaviorally communicate the pain experience or if there is a fundamental change in the pain-processing mechanisms of the brain. Since in this blog I research and write about the psychology, science, and sociology of pain, I told her that I would research this question for her and see if any insight can be gleaned from the schizophrenic experience of pain.  Although there is a deficit in the research of this topic, much of the literature is inconclusive and controversial. Similarly, while I mined through several articles on this topic, this is in no way all-encompassing of the available literature.  Also, please note that while many of these studies while interesting and important involve medical jargon, terminology, and anatomy.  I do my best to define the terms in order to convey the underlying results of the research to a wider population. I believe that the topic and question at hand is interesting enough and deserves a survey of the available literature.

According to the Diagnostic and Statistical Manual of Mental Disorder, Fifth Edition, (DSM V) schizophrenia is characterized by symptoms such as delusions, hallucinations, and disorganized speech and behavior that must persist for six months with at least one month of active symptoms. In order to receive a diagnosis of schizophrenia, individuals must exhibit two of the identified symptoms. The literature and studies performed to assess the quantity and type of pain in patients with schizophrenia draws no definitive consensus and leads to many questions about how pain is evaluated in a clinical setting for these patients.  A study entitled, “Experimental Pain Hypersensitivity in Schizophrenic Patients” authored by Girard et al., 2011, explains some of the many reasons why pain sensation is difficult to study in the population that experiences schizophrenia.  Some of the reasons the authors observe are the altered states of perception, attention, vigilance, and memory in patients with schizophrenia, as well as difficulty expressing pain.  On the research level, some complicating influences are the varied methodologies consisting of different sample sizes, diverse criteria to select participants or the method used to recreate pain in participants, and the fact that many pain studies depend on a pain threshold that requires patients to evaluate their subjective pain tolerance and pain intensity.  Using pressure and ischemic (cutting off oxygen to the tissue) tests to induce moderate pain with a 20-second lag between stimuli, Girard and colleagues tested pain responses to 35 patients with schizophrenia who were pain free and without psychotic features and also to a control group who did not have a history of psychiatric or pain disorders.  They found that controls and patients with schizophrenia seemed to experience pain differently depending on the type of pain that was being administered. Patients with schizophrenia, when symptoms of their illness were controlled, were hypersensitive to pressure pain. However, they were less sensitive to ischemia.  Ischemic pain imitates the pain experienced with chronic disease and is more unpleasant than pressure pain.  The authors theorize that individuals with schizophrenia may be more sensitive to acute pain but less responsive to chronic pain. They also believe that what is mistaken for a pain free experience by patients with schizophrenia is actually a diminished frequency of complaints, and this behavioral reaction to pain is overlooked when clinicians are evaluating pain in their patients.

An unrelated study that yielded similar findings was performed by Lévesque et al., 2012, entitled“Pain Perception in Schizophrenia: Evidence of a Specific Pain Response Profile.” Utilizing transcutaneous stimulation, reflex responses and verbal pain ratings were monitored in 12 patients with schizophrenia and healthy controls. Results revealed that participants with schizophrenia had elevated responses to acute pain but decreased responses to chronic pain.  What is particularly interesting about this study is that the volunteers with schizophrenia that had only acute psychotic episodes and a favorable prognosis exhibited a greater response to pain than those that had dissociation of affect, disorganization, and a poor prognosis. This finding led the authors to propose that the characteristic symptoms (distortions of thought and function) of schizophrenia play a role in pain sensitivity. Furthermore, they argue that an elevated sensitivity to acute pain but decreased sensitivity to chronic pain is a biological profile unique to the disease of schizophrenia.

The chronic pain question and its correlation to schizophrenia was analyzed by de Almeida et al., 2011, and reported in an article entitled “Chronic Pain and Quality of Life in Schizophrenic Patients.” However, researchers were exploring whether patients with schizophrenia experienced pain chronically by evaluating 205 diagnosed patients without acute psychiatric symptoms of the disease.  This study was performed using a questionnaire and interview without clinical testing.  The authors concluded from their statistical analysis of the questionnaire that patients with schizophrenia had similar prevalence of chronic pain as the rest of the population but may not volunteer this information as readily as non-diagnosed patients.  A noted limitation to their study was that chronic pain was determined by patients’ verbal report of pain but clinical history or physical examination were not verified.

Both the Girard et al. and the de Almeida et al. study evaluated patients that were medicated for the disease and were not presenting associated symptoms. In the article, “Functional Magnetic Resonance Imaging Response to Experimental Pain in Drug-free Patients With Schizophrenia,” de la Fuente-Sandovala et al., 2010, examined the blood oxygen level-dependent (BOLD) changes while inducing pain at below threshold temperature and examining functional magnetic resonance imaging (fMRI) on patients during an acute psychotic episode. They, then, compared the results to healthy controls subjected to the same protocol. To record neural action in the brain and spinal cord, an fMRI is used while monitoring BOLD response in order to image blood flow changes in the brain. The researchers found that in drug-free patients with schizophrenia, pain tolerance was higher than in the controls and had a reduced BOLD response in three areas of the brain associated with pain: the insula, posterior cingulate cortex (PCC), and brainstem.  The insula assimilates the perception of pain with the emotion, behavior, and awareness of the pain experience. The authors note that the insular gray- matter volume has been inversely correlated with the severity of psychotic features in patients with schizophrenia. As gray-matter volume of the insula increases, the severity of psychotic symptoms decreases.  The PCC’s role in pain is not completely clear but is consistently activated in acute and chronic pain patients and plays a major role in navigation, memory, motor behavior, and spatial awareness.  The brainstem contains structures by which noxious stimuli reach the cerebral cortex.  This study also found that primary (S1) somatosensory cortices, a part of the cerebral cortex that facilitates sensation from the skin, muscle, and joints of the body, had a higher activation in patients with schizophrenia than in controls.  The authors believe that there is indeed abnormal pain processing occurring when patients are in a psychotic state but cannot comment on the role of prior or future treatment in pain determination in schizophrenia patients.

A unique and creative approach to analyzing the pain and schizophrenia connection was performed by Martins et al., 2011.  In the article, “Sensitivity to Expressions of Pain in Schizophrenia Patients,” investigators examined the facial expressions of pain and whether participants with schizophrenia could discriminate the distinct emotion of pain.  Their findings reveal that patients with schizophrenia were hampered compared to healthy controls when discriminating the facial recognition of pain intensity on people’s faces that were experiencing pain.  While several studies have been conducted showing that patients with schizophrenia have difficulty identifying emotions and facial mirroring of emotions, this was the first study that addressed the expression of pain.  The authors postulate that a decreased reactivity to pain may result in a decreased expression of pain and not from a physiological response.

Picture of the brain reflecting where fMRI revealed previous pain processing. Areas that are shown are areas mentioned in this post including the insula, PCC, and brainstem.   Image courtesy of BioMed Central
Picture of the brain reflecting where fMRI revealed previous pain processing. Areas that are shown are areas mentioned in this post including the insula, PCC, and brainstem. Image courtesy of BioMed Central

All of this research made me question if there have been studies performed that compared the brain of individuals that have schizophrenia to those that have been diagnosed with chronic pain conditions.  The literature on this topic is even more restrictive than the initial question.  However, one study, entitled “Dysregulated Src Upregulation of NMDA Receptor Activity:A Common Link in Chronic Pain and Schizophrenia” authored by Michael W. Salter and Graham M. Pitcher, 2011, analyzed the role of Src upregulation of N-methyl-d-aspartate (NMDA) receptors in chronic pain conditions and compared it to schizophrenia.  N-methyl-d-aspartate (NMDA) is a receptor that facilitates excitatory transmission at several regions of the central nervous system (CNS).  A receptor is a structure that senses a change in the body and reacts accordingly. Activity of the NMDA receptor is governed by the protein, tyrosine kinase, Src (Yu and Salter, 1998). Tyrosine kinase, Src is an enzyme and enzymes are proteins that function as a catalyst. Catalysts speed up reactions but are not consumed in the chemical process.  Up-regulation occurs when a cell increases the number of hormone receptors making it more sensitive to hormones.  Salter and Pitcher discovered that within nociceptive processing, pain receptors that respond to tissue injury or the threat of injury, increased Src upregulation of NMDA receptors play a role in pain hypersensitivity in chronic inflammatory and neuropathic pain.  They define inflammatory pain as tissue damage and inflammation and neuropathic pain as nervous system lesions.  Lesions are zones of tissue injury.  According to Salter and Pitcher, inflammatory pain is usually assuaged through treatment; whereas, neuropathic pain continues even after the injury has healed.  Salter and Pitcher explain that chronic pain involves not only sensory input into the spinal cord but magnification of the input within the CNS.  Sensory input into the spinal cord, in the simplest of definition, involves conduction.  It comprises bundles of nerves conducting information up and down the spinal cord facilitating sensory information to reach the brain allowing for not only motor commands (movement) but also input received and output conducted.  Contrasting the brain of the chronic pain sufferer to those that experience symptoms of schizophrenia, Salter and Pitcher found that upregulation of NMDA receptors by Src is blocked by a protein that has been genetically associated with the symptoms of schizophrenia. They hypothesize that over-upregulation (chronic pain) or under-upregulation (schizophrenia) of NMDA receptors by Src may indicate a pathological disorder in the CNS. What their findings mean for both disorders is that if scientist could regulate the Src upregulation of NMDA receptors they could have a new therapeutic approach to treating the diseases that affect the CNS.

While there seems to be a lack of consensus on the degree and by what means patients with schizophrenia experience pain, what seems unequivocal in the literature is a decrease of behavioral pain reactivity and expression does not indicate whether the individual is suffering from pain.  Throughout the literature it is stated that individuals with schizophrenia have impairment in thinking, communication, and social skills which alters pain expression, but perhaps not experience. Similarly many of these studies urge clinicians to pay specific attention to their patients diagnosed with schizophrenia as common pain rating scales or lack of complaints may not accurately depict their actual experience.  This could leave patients with schizophrenia vulnerable to a needless suffering of pain, cause physicians to overlook pain as a symptom of a possible fatal disease, or even result in exposing the schizophrenia population to unnecessary postsurgical pain.  This is a serious consideration for practitioners because judging pain based on complaints may greatly hinder this population’s access to proper therapeutic care

Imaging that shows a decrease in brain activity of patients with schizophrenia on fMRI scans. N stands for normal and S for schizophrenia. Image courtesy of schizophrenia.com
Imaging that shows a decrease in brain activity of patients with schizophrenia on fMRI scans. N stands for normal and S for schizophrenia. Image courtesy of schizophrenia.com
Loss of gray matter shown by red and pink colors. Unchanged regions are in blue.  STG is superior temporal gyrus, and DLPFC is the dorsolateral prefrontal cortex. Image courtesy of Psychiatric Times.
Loss of gray matter shown by red and pink colors. Unchanged regions are in blue. STG is superior temporal gyrus, and DLPFC is the dorsolateral prefrontal cortex. Image courtesy of Psychiatric Times.


3 Comments Add yours

  1. Biologist with Pain says:

    I love this blog. Always interesting, exciting, informative, and wonderfully written. Your topics are always creative and you can tell that a lot of work and research goes into it. Always look forward to what you are going to write about next. One of the best chronic pain blogs out there.

    1. Thank you for your kind words and for reading my blog. It means a lot.

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