Do patients with chronic pain have higher cortisol levels?

Cortisol Levels in Chronic Pain: A Complex and Variable Pattern

The relationship between chronic pain and cortisol levels is not straightforward—patients with chronic pain can exhibit either elevated or reduced cortisol levels depending on pain duration, severity, and individual stress responses, with evidence suggesting that untreated severe chronic pain often leads to elevated cortisol, while established chronic pain conditions frequently show reduced basal cortisol levels. 1, 2

Evidence for Elevated Cortisol

• Patients with chronic back pain demonstrate significantly higher basal cortisol levels compared to healthy controls, measured over seven consecutive days 1
• Higher cortisol in chronic pain patients correlates with smaller hippocampal volumes and stronger pain-evoked activity in brain regions involved in anticipatory anxiety 1
• Untreated severe chronic pain shows abnormal serum cortisol concentrations in 65% of patients, which normalizes to only 17.5% after 90 days of opioid treatment, suggesting that severe pain drives cortisol elevation 3
• Recent data from 2024 demonstrates that chronic pain patients have higher late-day cortisol levels, indicating hypothalamic-pituitary-adrenal (HPA) axis dysregulation 4

Evidence for Reduced Cortisol

• Patients with chronic low back pain without depression show lower cortisol area-under-the-curve values compared to both healthy controls and depressed patients across multiple time points 2
• Population studies reveal that those with chronic widespread pain are 3.1 times more likely to have salivary cortisol scores in the lowest third compared to controls 5
• Long COVID patients with chronic pain manifestations demonstrate low blood cortisol levels more than 1 year into symptom duration, without compensatory increases in ACTH, supporting HPA axis dysfunction 6

Mechanistic Understanding

• Chronic pain acts as a potent stressor that can activate the HPA axis, which may be hypoactive or hyperactive under chronic or persistent stress conditions 6
• The HPA axis modulation directly affects glucocorticoid release, which at physiological levels plays an important regulatory role in the immune system 6
• Path modeling demonstrates that cortisol levels and pain responses mediate a negative association between hippocampal volume and chronic pain intensity, supporting a stress model of chronic pain 1

Clinical Implications by Pain Stage

Early/Severe Untreated Pain

• Expect elevated cortisol as the body responds to ongoing severe pain as a stressor 1, 3
• This elevation is associated with smaller hippocampal volumes and increased pain-related brain activity 1

Established Chronic Pain

• Anticipate reduced basal cortisol reflecting HPA axis exhaustion or dysregulation 2, 5
• This pattern occurs in 65% of patients with chronic widespread pain 5
• The reduction is not fully explained by accompanying psychological distress, as it persists even after adjusting for psychosocial factors 5

Important Caveats

• Experimental acute pain stimuli do not elicit significant cortisol responses in chronic pain patients, distinguishing chronic from acute pain physiology 2
• Patients with comorbid depression show different cortisol patterns than those with pain alone—depressed patients without pain have cortisol levels similar to controls 2
• Opioid treatment can normalize cortisol abnormalities in severe chronic pain, suggesting the pain itself drives the dysregulation 3
• The "at risk" group (high somatization without chronic widespread pain) shows intermediate cortisol abnormalities, being 1.8 times more likely to have low cortisol 5

Practical Assessment Approach

• Measure both early morning and evening salivary cortisol to capture diurnal patterns, as late-day elevations are particularly characteristic 4
• Consider cortisol assessment as a potential biomarker for severe chronic pain, particularly when abnormal levels normalize with effective treatment 3
• Recognize that HPA axis dysregulation in chronic pain is associated with poorer health outcomes, including increased inflammation and psychological distress 4