Circadian rhythmicity of pain sensitivity in humans

Abstract

Pain intensity has been reported to fluctuate during the day in some experimental and clinical conditions, but the mechanisms underlying these fluctuations are unknown. Although the circadian timing system is known to regulate a wide range of physiological functions, its implication in pain regulation is largely unknown. Using highly controlled laboratory constant-routine conditions, we show that pain sensitivity is rhythmic over the 24 h and strongly controlled by the endogenous circadian timing system. We found that the circadian component of pain sensitivity can be modelled with a sinusoidal function, with a maximum in the middle of the night and a minimum in the afternoon. We also found a weak homeostatic control of pain sensitivity, with a linear increase over the 34 h of prolonged wakefulness, which slowly builds up with sleep pressure. Using mathematical modelling, we describe that the circadian system accounts for ∼80% of the full magnitude of pain sensitivity over the 24 h, and that sleep-related processes account for only ∼20%. Overall, our data reveal the neurobiological mechanisms involved in driving the rhythmicity of pain perception in humans. We show that pain sensitivity is controlled by two superimposed processes: a strong circadian component and a modest homeostatic sleep-related component. Our findings highlight the need to consider time of day in pain assessment, and indicate that personalized circadian medicine may be a promising approach to pain management.

Pain profile during orthodontic levelling and alignment with fixed appliances reported in randomized trials: a systematic review with meta-analyses

“…This can be attributed to the reduction of inflammatory mediators within the periodontal ligament post-activation of the archwire. This gradual reduction within the day is probably not a temporal observation of circadian effects [50,51] within the day, but rather the effect of greater amounts of time having elapsed in the evening since the original archwire activation and is consistent with other studies [43,52,53].…”

Circadian acclimatization of performance, sleep, and 6-sulfatoxymelatonin using multiple phase shifting stimuli

“…Pressure at this site is gradually increased at a steady rate (0.5 kg/sec) and stopped when the subject indicates the stimulus is first perceived as painful. A circadian rhythm in pain sensitivity has recently been established ( 53 ). Responses to painful stimuli could have relevancy for many military and civilian scenarios (e.g., injuries, post-surgical pain, chronic pain ( 54 ).…”

The disruptive relationship among circadian rhythms, pain, and opioids

“…A major study was recently published to demonstrate the circadian nature of pain behavior in humans ( Daguet et al, 2022 ), although only data on men were reported. The participants were held in a constant routine protocol that prevented photic environmental cues from entraining or masking behavior.…”

“…Importantly, the authors were able to determine that the circadian system was the primary driving force of pain sensitivity rhythms. Homeostatic sleep pressure contributed to the rhythms, but only accounted for 20% of the rhythmicity ( Daguet et al, 2022 ). The observed rhythmicity and rhythmic shape observed in this study are supported by previous models ( Hagenauer et al, 2017 ) and other human studies examining pain threshold variations in humans outside of constant condition protocols ( Zhu et al, 2022 ).…”