Friday, 03 Apr 2020

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NSAIDs May Impair Healing if Taken Nightly

A new study in Scientific Reports suggest that circadian rhythms play an important role in wound healing, and that nonsteroidal anti-inflammatory drugs (NSAIDs) may be disruptive if taken at night given primary healing that occurs in a body at night. 

NSAIDs provide analgesic and antiinflammatory benefits via prostaglandin inhibition, yet NSAIDs are also thought to inhibit postoperative healing of connective tissues via the same mechanisms. 

Circadian rhythms regulate genes. This is a molecular clock that modulates the immune response and the healing processes in connective tissues  According to this rhythm, most of wound healing mediators and connective tissue formation occurs during the resting phase, at night. Conversely, pain, inflammation and tissue resorption occur during the active period of the day. 

For instance, there is a daytime, cyclic increase in macrophage activity, leukocyte recruitment, and pro-inflammatory mediators (IL-1β, IL-6, IL-12) during which there is an increase in Tol-Like Receptors TLR9 and TLR4, leading to the upregulation of CCL2, CXCL1, CCL5, and subsequent leukocyte recruitment and potential tissue damage in injured or repairing sites. It is during this phase that NSAIDs may have their most beneficial effect.

By contrast, anti-inflammatory mediators and other growth or angiogenesis factors, such as the vascular endothelial growth factor (VEGF), peak during the resting phase. The authors postulated that taking NSAIDs during this phase would impair healing.

Using a a murine tibia fracture surgical model, reseearchers showed that NSAIDs are most effective in managing postoperative pain, healing and recovery when drug administration is limited to the active phase (daytime) of the circadian rhythm.

Limiting NSAID treatment to the active phase of the circadian rhythm resulted in overexpression of circadian clock genes, such as Period 2 (Per2) at the healing callus, and increased serum levels of anti-inflammatory cytokines interleukin-13 (IL-13), interleukin-4 (IL-4) and vascular endothelial growth factor.

By contrast, NSAID administration during the resting phase resulted in severe bone healing impairment.  NSAID administration during the daily activity period resulted in better postoperative healing and recovery in this murine bone surgery model.

NSAIDs can exert a strong anti-inflammatory effect when given in the morning or early afternoon.  It is ill-advised to take these in the evening or at bedtime, largely because of an enhanced risk for adverse effects such as indigestion, stomach ulcers, and acute kidney injury, but now for the potential to impair tisue repair.

The author has no conflicts of interest to disclose related to this subject

Rheumatologists' Comments

IN MICE, John. IN MICE. This model may not apply to humans at all.

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