The effect of pain on cognitive function: A review of clinical and preclinical research

https://doi.org/10.1016/j.pneurobio.2011.01.002Get rights and content

Abstract

Cognitive impairment is commonly associated with the pain experience. This impairment represents a major obstacle to daily activities and rehabilitation, especially in the chronic pain population. Here we review clinical and preclinical studies that have investigated pain-related alterations in cognition. These include impaired attentional, executive and general cognitive functioning. We describe the anatomical, neurochemical and molecular substrates common to both cognitive processing and supraspinal pain processing, and present the evidence for their involvement in pain-related cognitive impairment. We also examine the added complexity of cognitive impairment caused by analgesic medications and how this can further impact on morbidity in chronic pain patients. The need for a better understanding of the mechanisms of both pain-induced and treatment-related cognitive impairment is highlighted. Further research in this area will aid our understanding of patient symptoms and their underlying pathophysiology, ultimately leading to increased provision of guided therapy.

Research highlights

▶ Pain is associated with impaired cognitive function. ▶ Pain-related cognitive impairment might be a consequence of competing limited neural resources, neuroplasticity and/or dysregulated brain neurochemistry. ▶ Analgesics may also affect cognitive performance.

Introduction

Pain is a subjective, multidimensional experience that can have a marked impact on both the physiological and psychological state of an individual. The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (IASP Task Force on Taxonomy, 1994). This definition is based on the concept of pain as a perception rather than as a purely sensory modality, and takes into account the fact that for pain to be consciously experienced, cognitive processing is required. Melzack and Casey's (1968) division of pain into sensory-discriminative, motivational-affective and cognitive-evaluative dimensions also supports this concept. Chronic pain (defined as pain persisting for 3–6 months or longer) generally exceeds the duration of the precipitating noxious stimulus or injury, and may be neuropathic, inflammatory or idiopathic in nature (Aguggia, 2003). Epidemiological studies have indicated the extent of the problem of chronic pain in the general population. It has been estimated that 19% of adult Europeans suffer from chronic pain of moderate to severe intensity, of which approximately half receive inadequate pain management (Breivik et al., 2006). Chronic pain has biopsychosocial implications, affecting relationships, capacity for work, mood and quality of life (Hart et al., 2000). Chronic pain patients report disabling limitations on physical function (van Dijk et al., 2009). In addition to sensory symptoms including allodynia (pain in response to a non-nociceptive stimulus) and hyperalgesia (increased pain sensitivity), cognitive functioning is thought to be affected in chronic pain patients. It is hypothesised that because neural systems involved in cognition and pain processing are closely linked, they may modulate one another reciprocally.

Cognition has been described as the brain's acquisition, processing, storage and retrieval of information (Lawlor, 2002). However, cognition may be considered an umbrella term that can also be used to describe integrative neuropsychological processes such as mental imaging, problem solving and perception, and is pertinent to the experience of emotion and affect. Pain and cognition share an inherent overlap owing to the fact that pain itself has a cognitive-evaluative component, requiring learning, recall of past experiences and active decision making. This should be borne in mind when assessing the effects of pain on cognitive function. For the purposes of this review, we have chosen to focus on the effects of chronic pain on a subset of cognitive domains including: attention, learning and memory, speed of information processing, psychomotor ability and executive function. Loss of function in these domains is likely to impact on the execution of daily tasks and, therefore, negatively affect the individual. Detailed evaluation of the interaction of pain with mood, stress and anxiety, as well as parameters such as coping, disability and quality of life is beyond the scope of this review, but may be found elsewhere (Anton, 2009, Breivik et al., 2006, Campbell et al., 2003, Dersh et al., 2002, Hart et al., 2003, Jensen et al., 2007, McCracken and Eccleston, 2003, Munoz and Esteve, 2005, Pincus et al., 2007, Vowles and McCracken, 2008). We have also omitted studies that examine the analgesic effects of cognitive interventions (examples include distraction, hypnosis and mindfulness), except where the converse effects of pain on cognition have also been examined, or where the results provide insights into potential mechanisms of pain-induced cognitive impairment. We review the clinical studies which have directly measured cognitive function in chronic pain patients, in an attempt to establish whether chronic pain negatively affects cognition. We examine the neural substrates which may be responsible for impaired cognition during the experience of chronic pain, including the neuroanatomical structures, neurotransmitter systems and other neuromodulators common to pain and cognition. Based on the data available, we put forward a theoretical model for the mechanisms involved in pain-related cognitive impairment. The manuscript also reviews the limited literature available on cognitive performance in animal models of pain, and we highlight how these and future preclinical studies may contribute to our understanding of pain-cognition interactions. The possible confounding effects of pharmacological treatment with analgesics on cognition are also considered.

Section snippets

Clinical studies: evidence for pain-related cognitive impairment

The increasing prevalence of pain-related illnesses, and their economic and psychological consequences, has resulted in a heightened interest in both the neurobiological mechanisms underpinning pain, and the effects of pain on a range of processes, including cognition. Disruption of cognitive processing has been investigated in a variety of common chronic pain syndromes with studies focusing on a number of different types of cognitive output. The methodology employed in these studies is most

Clinical studies: insights into potential mechanisms involved in pain-related cognitive impairment

Although the precise mechanisms have yet to be elucidated, several theories have emerged regarding the mechanisms mediating cognitive impairment in conditions of persistent pain. As discussed in the previous section, it may be argued that the cognitive impairments observed in chronic pain may simply be a consequence of the division of limited resources in discrete brain regions. The persistent nociceptive inputs associated with chronic pain may compete with other sensory inputs resulting in

Preclinical studies: evidence for pain-related cognitive impairment

Pre-clinical studies provide an opportunity to further explore the mechanisms mediating pain-related impairment of cognition. However, this type of basic research has been under-utilised, with few published studies attempting to model the clinical phenomenon of pain-related cognitive impairment in laboratory animals despite the availability of well-validated animal models of pain and cognitive impairment.

There is some evidence that pain impacts negatively on cognition in rodents (see Table 2).

Brain morphology and electrophysiology

Animal models of neuropathic pain, including SNI, SNL and chronic constriction injury (CCI) models have been used to examine pain-related changes in brain morphology. A recent study by Seminowicz et al. (2009) used MRI to examine pain-related alterations in the brain of SNI rats. These authors found that decreases in cortical volume in SI and SII regions, the ACC and the IC correlated with the degree of mechanical hyperalgesia. They also showed that SNI rats had decreased PFC volume. The

The effects of analgesic treatments for chronic pain on cognitive function

Treatment of chronic pain represents a major challenge for healthcare professionals. Multimodal analgesia is often necessary to achieve adequate pain relief and protracted medical management is frequently required in patients suffering from chronic pain. Current strategies for the management of pain focus mainly on its sensory component. Pharmacological interventions treat inflammation and associated sensitization of nociceptors (non-steroidal anti-inflammatory drugs; NSAIDs), enhance

Conclusions and future directions

There appears to be sufficient evidence from preclinical and clinical investigations to support the theory that pain is associated with impaired cognitive function. Cognitive deficits in tests with high ethological validity, suggest that cognitive impairment in pain patients may be an obstacle to everyday tasks. As such, this impairment may have a marked impact on patients’ quality of life. There is also some evidence for a mechanistic, neuropathological basis for pain-related cognitive

Acknowledgements

This work was supported through the National Biophotonics and Imaging Platform, Ireland, and funded by the Irish Government's Programme for Research in Third Level Institutions, Cycle 4, National Development Plan 2007–2013. Dr. David O’ Gorman, Consultant in Anaesthesia and Pain Management, University College Hospital, Galway and Lucie Low, Department of Cell and Developmental Biology, University College London, are gratefully acknowledged for critical reading of this manuscript.

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