The pain I don’t get
Recently I have been thinking about confirmation bias and responses to interventions commonly administered by Physiotherapists and healthcare professionals. Being surrounded by inspiring people and having the occasion to see how patients respond differently to various treatment modalities such as different forms of manual therapy and exercise is an invaluable constant opportunity to analyse and reflect about “what is this thing called pain” [1].
It has been shown that a bidirectional communication between the brain and the immune system exists and that the stress response system responds to exercises [2, 3].
One of the most fascinating aspect I strive hardly to understand is how to predict treatment responses. Assessing patients with persistent pain and trying to correctly identify a profile that best describes their condition is underpinned by a careful clinical examination.
It is disappointing when a patient demonstrates significant positive results after a simple intervention prescribed in the clinic that is either not maintained or, repeated in a different context, produces an opposite effect such as flare ups, despite the effort in providing evidence of safety.
Think about exercises. Ever happened that an exercise supervised in a clinical setting produces a significant improvement, whereas when performed at home without the therapist shows opposite results?
How could we interpret these phenomena?
Pain is now seen as perceptual inference that urges protective action. This means that “any input – exogenous, endogenous, cognitive, social or contextual that provides ‘credible evidence of danger’ to body tissue, as well as the current state of the organism, will increase the likelihood and intensity of pain” [4].
It is widely accepted that the context, considered as a combination of sensory inputs, cognitive, emotional and social factors has got an extraordinary modulatory power [4]. In the last decades several questionnaires and screening tools have been developed to help clinicians understanding these psychosocial factors. Furthermore, the research has showed their impact on the pain experience [5-7].
It is generally agreed that understanding these factors requires a broader subjective and objective assessment [8].
Several studies identified abnormal intra-cortical inhibitory mechanisms in persistent pain. It is however still not clear how to predict when these factors are capable to increase symptoms and to create a further unpleasant sensory experience. Hence, recently the researchers have started employing the Quantitative Sensory Testing (QST) which tests a participant’s response to a controlled stimulus of known intensity (heat, cold, pressure).
Furthermore, they also measure the Conditioned Pain Modulation (CPM) with a conditioning stimulus. These measures are believed to give an estimation of the functioning of the excitatory and inhibitory mechanisms [9]. These information together, theoretically, allow the clinician to choose the best intervention for the profile examined at the time the tests are conducted.
While in healthy participants almost all types of acute bouts of exercise reduce pain sensitivity, both hypoalgesic and hyperalgesic responses have been reported in patients with persistent pain [10]. So how do we choose our intervention? How do we predict those who will incur in a negative response?
In the clinic we tend to rely on our clinical judgment and testing CPM as well as Quantitative Sensory Testing (QST) is not often possible. During the assessment we are able to clinically detect whether features such as allodynia, referred pain, spontaneous pain, temporal summation, widespread pain and hyperalgesia (primary and secondary) are present or not. This, in theory and not thoroughly, may help us identifying the neurophysiological profile of the patient in our clinical context and it may also provide valuable information regarding the potential side effects of certain type of interventions. For example, interventions such as isotonic exercises increase the hyperexcitability of the central nervous system, therefore they are not recommended in presence of central sensitization [3].
All these measures do not fulfil our needs to comprehensively understand the functioning of the stress response system and the reactivity of the adrenal-hypothalamo-pituitary axis to exercise tolerance [3]. First of all, because we are testing a complex system in an unusual and safe environment (a patient in a clinic); secondly, because we are testing it in a determined temporal moment with a specific social interaction (therapist-patient); thirdly, because we do not have time to test its responses several hours after the acute effect of the intervention has been administered.
Instead, the interactions between genetic and psychological factors are far more reliable predictors of exercise induced pain . George et al. [11] found that the strongest statistical evidence was for interactions between genetic traits and pain catastrophizing or depressive symptoms. It may appear that people with pro-nociceptive phenotypes and genetic predisposition are more likely to develop chronic pain due to a facilitated system that, combined with psychosocial factors, enables the release of ongoing nociceptive substances.
Indeed, it appears that an intricate relationship between the immune system, psychosocial traits, genetics and nociceptive phenotypes exists. Hence, we may not be able to prevent or predict dysfunctional exercise-induced endogenous analgesia until better screening tools will be developed, although our neurophysiological pain assessment and treatment responses in the clinic room appeared immaculate.
For example, exaggerated or recurrent negative cognitions, rumination or worry and helplessness are all maladaptive catastrophizing responses to pain or non–pain-related stress that may prolong cortisol secretion thus increasing HPA axis activation [12]. Likewise, depression promotes inflammation and viceversa. Also, elevated blood levels of IL-6 and C-reactive protein are present in depressive states, obese and sleep deprived people [13, 14]. In fact, low grade inflammation, defined as “the chronic production, but a low-grade state, of inflammatory factors”, appears to be a barrier to positive outcomes in people with persistent pain [15]. In fact low-grade increase in systemic concentrations of inflammatory markers, including IL-6, IL-8 and tumor necrosis factor (TNF), have been observed in patients with chronic pain and were associated, together with psychological inflexibility, with lesser improvement in pain intensity following treatment [15].
This suggests that interventions aimed to reduce this low grade inflammation shall be employed before the specific treatment thus avoiding the risk of severe symptom flares following exercise therapy that may promote negative appraisal and cognitions regarding the active management.
The use of medications needs to be interpreted with care as well: for example, CPM has been used to predict response to NSAIDS treatment in patients with knee OA [16] but we still do not know whether this supposedly non-respondent group characterized by higher inflammatory status is homogeneous in QST testing. Data from Rabey et al. [17] suggest the presence of different somatosensory profiles but blood samples were not taken.
Furthermore, behavioural treatment is found to have a positive effect on subjects with lower combined concentrations of IL-6, TNF-a and IL-8, not in those with higher concentrations [15].
Does this mean that the first barrier to “demolish” is this low grade inflammation? Shall we adopt aerobic exercise programmes starting at a tolerable tolerance [3] until inflammatory markers in blood samples reach lower concentrations so that BT is more effective? We know that cardiovascular exercise induces large psychosocial benefits, promote self-efficacy and down-regulation of sensitized nervous system (6 mile run stimulates endorphin release that is equivalent to 10 mg of morphine) [18]. Simultaneously, isometric exercises could be adopted knowing that they are able to produce moderate to large pain reducing effects through central mechanisms such as increased secretion of β-endorphins, attention mechanisms, activation of diffuse noxious inhibitory controls, or an interaction of the cardiovascular and pain regulatory systems [10].
Or shall we wait until QST/CPM reaches optimal values so that also conventional NSAIDS have a stronger effect?
Well, these are some of my reflections over the last few weeks, influenced by the observations of people in pain and their responses to commonly prescribed interventions.
Your insights are welcome!
REFERENCES
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