- Psychosocial symptoms are important predictors of those that do worse with chronic low back pain.
- Currently the prevailing view is that psychosocial symptoms drive systemic inflammation.
- Psychosocial problems increase inflammation, and inflammation increases psychosocial symptoms.
- Psychosocial treatments decrease inflammation and reducing inflammation improves psychosocial symptoms.
- The relationship is bidirectional and we should remember this when dealing with patients with psychosocial symptoms.
- Explaining this relationship to patients may reduce the stigma associated with psychosocial symptoms.
Since the turn of the century there has been an increased awareness of psychosocial symptoms in chronic low back pain (CLBP) patients. It’s well established that CLBP patients with psychosocial, psychological and social, risk factors have poorer outcomes and increased management costs (Grimmer-Somers 2006, Nicholas et al. 2011). The term “yellow flags” was originally used to describe psychosocial risk factors that predict disability in LBP patients. Yellow flags are now included in most LBP guidelines although there is wide variation in suggestions in how to assess and manage these patients (Koes et al. 2010). This is discussed elsewhere on this site, see article on Yellow flags and CLBP. These risk factors are predictors of return to work and disability in CLBP patients (Glattacker et al. 2013). They can be identified using a questionnaire or a clinical diagnosis (Watson and Kendall 2000). Questions cover beliefs that are associated with delayed return to work and disability. These include fears about pain, injury, recovery and being despondent or anxious. It is suggested that having a few strongly held negative beliefs or several weaker ones could be used to identify at risk patients (Nicholas et al. 2011). These beliefs can be viewed as “thought viruses” (Butler and Moseley 2013) and increase a patient’s perception of threat and modern neuroscience suggests that pain is the conscious interpretation that tissue is in danger (Moseley 2007).
Inflammation and Psychosocial Symptoms
Inflammation and psychosocial symptoms are intimately related. Those with higher levels of systemic inflammation have more psychosocial symptoms (Hänsel et al. 2010) and Miller at al (2014) found that psychosocial treatment reduces levels of inflammation. Generally this relationship has been viewed top down, e.g. the brain affecting our systemic inflammation level. However, systemic inflammatory molecules signal the brain to induce sickness behaviours and negative affect (negative emotions and a negative view of self) (Walker et al. 2014). It’s also well established that anti-inflammatories improve psychosocial symptoms such as depression (Gallagher et al. 2014, Iyengar et al 2013). Thus perhaps we should consider this as a bidirectional relationship.
Peripherally cytokines, proteins of the immune system that communicate with other cells, interact with afferent nerves which send signals to their primary projection area. For example the nucleus of the tractus solitarius for vagal afferents. From here it propagates to secondary projections including the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala, where it can contribute towards negative affect. This partially occurs, as there is some active transport of cytokines across the blood brain barrier. With increased levels of systemic inflammation, active transport of cytokines across the blood brain barrier is increased further.
Tissue damage in the body is responded to by two main systems, pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs). In a cold it is PAMPs that give rise to the illness behaviour associated with having cold symptoms. We all tend to withdraw from activity, feel a bit ugh, and have a kind of minor low level depression with a cold. With back pain it is DAMPs that give rise to the illness behaviours. Yet with CLBP we treat patients as if they are making conscious decisions to withdraw from activity. Potentially if we understand these underlying mechanisms and view the behaviours that arise secondary to this condition as like that of an infection we might have more empathy towards understanding the CLBP patient.
The association between peripheral inflammation and depression was initially established in patients undergoing cytokine therapy. Immune stimulating therapies such interferon therapy in those with hepatitis C or malignant melanoma produced initial sickness behaviour and then a transition to depression in many patients (Raison et al. 2007). Capuron et al. (2002) established that the anti-depressant paroxetine only reduces sickness behaviours and not the cognitive and affective aspects of depression. It appears that it is prolonged elevated levels of inflammation that are required for the transition of sickness behaviour in to depression. Obviously there are multiple mechanisms interacting here and to focus on one to the exclusion of others would be negligent clinically.
In healthy individuals typhoid vaccination induces negative mood post-vaccination (Wright et al., 2005), stops the normally occurring improvement in mood as the day progresses (Strike et al., 2004), increases brain activity in depression-related regions such as the subgenual cingulate cortex, and decreases its connectivity to the amygdala, medial prefrontal cortex, and nucleus accumbens (Harrison et al., 2009). Similarly, in healthy mice increasing levels of inflammation induce initial sickness behaviours, which subside, and transition to depressive symptoms following prolonged increased inflammatory levels (O’Connor et al. 2009).
Inflamamtion is closely linked to the pain experience. Peripheral inflammation can propogate signals to key brain areas involved in pain such as the central nucleus of the amygdala. Pro-inflammatory cytokines also lower nociceptor thresholds throughout the body decreasing the temperature, pressure or pH stimulus required for nociception. Further low levels of anti-inflammatory cytokines, such as Il-10 may also lower nociceptor thresholds (Uceyler et al. 2006).
Norman et al (2010) investigated the effects of social isolation on depressive symptoms in mice post nerve injury. Only the socially isolated mice developed depression and increased inflammation in the brain seven days later as measured by Interleukin-1β. Mice that underwent social isolation but received oxytocin did not develop increased inflammation or depression. Conversely, mice that were socialising but received an oxytocin antagonist developed depression and elevated brain Interleukin-1β. This, at least in mice, very clearly demonstrates the importance of social interaction, a positive psychosocial input, on inflammation; and points to the central role of oxytocin, at least as a marker, in this process.
Tryptophan is required for the production of the “happy” neurotransmitter serotonin. Decreases in tryptophan have been theorised to cause depressive symptoms and there is some support for this (Dell’Osso et al. 2016). Under increased levels of systemic inflammation there is increased activity of indoleamine 2,3-dioxygenase, an enzyme that converts tryptophan in to kynurenine, Thus there is less available for serotonin production. In animal studies the induction of inflammation has been shown to produce increase indoleamine 2,3-dioxygenase activity, decreased circulating tryptophan and a progression from sickness behaviour to depression (O’Connor et al. 2009).
Increased activity of indoleamine 2,3-dioxygenase ultimately leads to an increase in the NMDA receptor agonist quinolinic acid. Increased glutamate and its receptor subtypes including NMDA have been implicated in the development of both chronic pain and depression (Mitani et al 2006). Glutamate is primary neurotransmitter in nociceptor afferents.
This evidence clearly indicates the role of peripheral inflammation to directly impact our behaviour. This needs to be viewed within a broad context and the central process contributing to illness behaviours must also be considered. Nonetheless this information can be powerful for patients in taking the pressure off themselves to change these behaviours under the illusion that they are 100% under our control. This can be quite empowering in a perverse way and allows for a more open and honest discussion of these behaviours with patients as the pressure for responsibility and feelings of being judged are decreased.
What does this mean for treatment?
Psychosocial interventions such as CBT, pain neurophysiology education and mindfulness are still useful when viewing this relationship as bidirectional. In my clinical experience when they are offered these treatments patients often feel like they are being judged, it’s in their head, they should think positively and pull themselves together. Explaining this relationship to patients removes some of the stigma associated with psychosocial symptoms and pain. When patients view these changes in mood as similar to when you have a cold it is easier for us to discuss these symptoms and patients often feel like it becomes more manageable.
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Butler, D.S., Moseley, G.L. (2013) Explain Pain. London: Noigroup Publications.
Capuron, L., Ravaud, A., Neveu, P.J., Miller, A.H., Maes, M. and Dantzer, R., 2002. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Molecular psychiatry, 7(5), 468.
Dell’Osso, L., Carmassi, C., Mucci, F. and Marazziti, D., 2016. Depression, Serotonin and Tryptophan. Current pharmaceutical design, 22(8), 949-954.
Gallagher, P.J., Castro, V., Fava, M., Weilburg, J.B., Murphy, S.N., Gainer, V.S., Churchill, S.E., Kohane, I.S., Iosifescu, D.V., Smoller, J.W. and Perlis, R.H., 2012. Antidepressant response in patients with major depression exposed to NSAIDs: a pharmacovigilance study. American Journal of Psychiatry, 169(10), 1065-1072.
Hänsel, A., Hong, S., Cámara, R.J. and Von Kaenel, R., 2010. Inflammation as a psychophysiological biomarker in chronic psychosocial stress. Neuroscience & Biobehavioral Reviews, 35(1), 115-121.
Harrison, N.A., Brydon, L., Walker, C., Gray, M.A., Steptoe, A. and Critchley, H.D., 2009. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biological psychiatry, 66(5), 407-414.
Iyengar, R.L., Gandhi, S., Aneja, A., Thorpe, K., Razzouk, L., Greenberg, J., Mosovich, S. and Farkouh, M.E., 2013. NSAIDs are associated with lower depression scores in patients with osteoarthritis. The American journal of medicine, 126(11), 1017-e11.
Koes, B.W., van Tulder, M., Lin, C.W.C., Macedo, L.G., McAuley, J., Maher, C. (2010) An updated overview of clinical guidelines for the management of non-specific low back pain in primary care. European Spine Journal, 19(12): 2075-2094.
Miller, G.E., Brody, G.H., Yu, T. and Chen, E., 2014. A family-oriented psychosocial intervention reduces inflammation in low-SES African American youth. Proceedings of the National Academy of Sciences, 111(31), 11287-11292.
Mitani, H., Shirayama, Y., Yamada, T., Maeda, K., Ashby, C. R., & Kawahara, R. (2006). Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 30(6), 1155-1158.
Moseley, G.L. (2007) Reconceptualising pain according to modern pain science. Physical Therapy Reviews, 12(3): 169-178.
Norman, G. J., Karelina, K., Morris, J. S., Zhang, N., Cochran, M., & DeVries, A. C. (2010). Social interaction prevents the development of depressive-like behavior post nerve injury in mice: a potential role for oxytocin. Psychosomatic medicine, 72(6), 519-526.
Nicholas, M. K., Linton, S. J., Watson, P. J., Main, C. J. (2011) Early identification and management of psychological risk factors (“yellow flags”) in patients with low back pain: a reappraisal. Physical Therapy, 91 (5): 737-753.
O’Connor JC, André C, Wang Y, Lawson MA, Szegedi SS, Lestage J, Castanon N, Kelley KW, and Dantzer R
(2009) Interferon-γ and tumor necrosis factor-α mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. J Neurosci 29:4200–4209.
Raison, C.L., Woolwine, B.J., Demetrashvili, M.F., Borisov, A.S., Weinreib, R., Staab, J.P., Zajecka, J.M., Bruno, C.J., Henderson, M.A., Reinus, J.F. and Evans, D.L., 2007. Paroxetine for prevention of depressive symptoms induced by interferon‐alpha and ribavirin for hepatitis C. Alimentary pharmacology & therapeutics, 25(10), 1163-1174.
Strike, P.C., Wardle, J. and Steptoe, A., 2004. Mild acute inflammatory stimulation induces transient negative mood. Journal of psychosomatic research, 57(2), 189-194.
Üçeyler, N., Valenza, R., Stock, M., Schedel, R., Sprotte, G., & Sommer, C. (2006). Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis & Rheumatology, 54(8), 2656-2664.
Walker, A.K., Kavelaars, A., Heijnen, C.J. and Dantzer, R., 2014. Neuroinflammation and comorbidity of pain and depression. Pharmacological reviews, 66(1), 80-101.
Watson, P., Kendall, N. (2000) Assessing psychosocial yellow flags. Topical issues in pain, 2: 111-129.
Wright, C.E., Strike, P.C., Brydon, L. and Steptoe, A., 2005. Acute inflammation and negative mood: mediation by cytokine activation. Brain, behavior, and immunity, 19(4), 345-350.