The Biology of Stress Intolerance in Patients with Chronic Pain—State of the Art and Future Directions

Abstract

Stress has been consistently linked to negative impacts on physical and mental health. More specifically, patients with chronic pain experience stress intolerance, which is an exacerbation or occurrence of symptoms in response to any type of stress. The pathophysiological mechanisms underlying this phenomenon remain unsolved. In this state-of-the-art paper, we summarised the role of the autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis, the two major stress response systems in stress intolerance. We provided insights into such mechanisms based on evidence from clinical studies in both patients with chronic pain, showing dysregulated stress systems, and healthy controls supported by preclinical studies, highlighting the link between these systems and symptoms of stress intolerance. Furthermore, we explored the possible regulating role for (epi)genetic mechanisms influencing the ANS and HPA axis. The link between stress and chronic pain has become an important area of research as it has the potential to inform the development of interventions to improve the quality of life for individuals living with chronic pain. As stress has become a prevalent concern in modern society, understanding the connection between stress, HPA axis, ANS, and chronic health conditions such as chronic pain is crucial to improve public health and well-being.

Opioid-induced adrenal insufficiency: diagnostic and management considerations

“…This is a crucial issue, as the cutoffs established for central adrenal insufficiency might not be applicable to OAI. For example, morning total cortisol threshold levels were established in outpatients without specific consideration of pain, yet pain, as with all other stressogenic conditions, stimulates the HPA axis ( 15 ), skewing accurate assessment of cortisol level independent of any effect from the opioids. In addition, both pain and opioids have been shown to alter the circadian rhythm that controls the HPA axis ( 16 ), which, in turn, suggests the need for a different cutoff for morning cortisol screening tests particularly among hospitalized patients ( 11 ).…”

The Biology of Chronic Pain and Its Implications for Pain Neuroscience Education: State of the Art

“…The analgesic effect of stress depends on the type of stressor, but it can also differ between patients, particularly those with chronic pain [ 66 ]. Besides pain modulation, stress can induce or worsen other complaints, such as fatigue or cognitive symptoms, in people with chronic pain [ 67 , 68 , 69 ]. Such induction or worsening of symptoms due to stress can be described as stress intolerance [ 68 ].…”

“…Besides pain modulation, stress can induce or worsen other complaints, such as fatigue or cognitive symptoms, in people with chronic pain [ 67 , 68 , 69 ]. Such induction or worsening of symptoms due to stress can be described as stress intolerance [ 68 ]. Recently, Wyns, et al [ 68 ], have provided an excellent overview of how stress intolerance plays a significant role in chronic pain.…”

“…Such induction or worsening of symptoms due to stress can be described as stress intolerance [ 68 ]. Recently, Wyns, et al [ 68 ], have provided an excellent overview of how stress intolerance plays a significant role in chronic pain. Two of the primary hormonal outputs of the endocrine system during the Hypothalamus–Pituitary–Adrenal (HPA) activation are cortisol and adrenaline.…”

Winner of the Ronald Melzack– Canadian Journal of Pain 2022 Paper of the Year Award/Récipiendaire du Prix Ronald Melzack Pour L’Annee 2022 des Articles Parus Dans la Revue Canadienne de la Douleur

“…On the other hand, some may say that these competences are too generic, because they may also apply to managing other conditions (e.g., managing chronic fatigue in cancer survivors or patients with arthritis or physiotherapy for stroke patients). Specific competences for managing (persistent) pain such as assessment and treatment of relevant lifestyle factors 2 , 3 would have been useful, including a position statement about physiotherapists’ role in dealing with stress intolerance, 4 poor sleep, 5 and dietary habits 6 (beyond the mentioned physical activity). This issue is briefly acknowledged by the authors in the discussion section, 1 but a focus on competences (referred to the authors as “our focus on the does level” p. 9) in no way prevents addressing these factors in the future.…”