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Chronobiological Characteristics of Neuropathic Pain: Clinical Predictors of Diurnal Pain Rhythmicity

Gilron, Ian MD*,†; Bailey, Joan M. RN, MEd*; Vandenkerkhof, Elizabeth G. DrPH*

doi: 10.1097/AJP.0b013e318275f287
Original Articles

Objectives: Neuropathic pain is often worse at night; however, little is known about pain rhythmicity during waking hours. We aimed to replicate previous observations of diurnal pain progression, evaluate associations between diurnal rhythmicity and clinical factors, and evaluate the impact of diurnal rhythmicity on treatment response.

Methods: We performed exploratory analyses of 2 trials (The New England Journal of Medicine 2005; 352:1324; The Lancet 2009; 374:1252) in diabetic neuropathy and postherpetic neuralgia. Pain recorded at 8:00 AM, 4:00 PM, and 8:00 PM, at baseline and during drug treatment was examined.

Results: Data from the latest trial replicated our previous observation of diurnal pain progression with a relative pain intensity difference of 33% between 8:00 AM and 8:00 PM. This pattern was preserved during treatment with gabapentin, nortriptyline, and their combination. Pooled multivariable analyses suggested that difference in pain intensity from 8:00 AM to 8:00 PM was more pronounced in females (vs. males) and in diabetic peripheral neuropathy (vs. postherpetic neuralgia). The baseline magnitude of pain intensity difference from 8:00 AM to 8:00 PM failed to predict treatment response.

Discussion: These observations suggest that neuropathic pain progressively increases throughout the day with clinically relevant morning-evening differences and further indicate that sex and underlying etiology may be important determinants of diurnal rhythmicity in neuropathic pain. Consideration of these patterns may guide improved therapeutic strategies and stimulate new directions of research that will improve our understanding and treatment of neuropathic pain.

*Departments of Anesthesiology & Perioperative Medicine

Biomedical & Molecular Sciences, School of Nursing, Queen’s University and Kingston General Hospital, Kingston, ON, Canada

Supported, in part, by CIHR grants (Ottawa, Ontario, Canada) #IRI-85649 and #MCT-94187. The original trials upon which this study was based were supported, in part by Pfizer (New York, NY) and Novopharm (Toronto, Ontario, Canada) (gabapentin study medication only), by Aventis-Pharma (Montreal, Quebec, Canada) (morphine study medication only), and by Apotex (Toronto, Ontario, Canada) (nortriptyline study medication only). These companies had no other input into the study. I.G. reports having received other unrelated research support and consulting fees from Pfizer during the past 5 years. The authors declare no conflict of interest.

Reprints: Ian Gilron, MD, Department of Anesthesiology & Perioperative Medicine, Queen’s University and Kingston General Hospital, Victory 2 Pavilion, 76 Stuart St., Kingston, ON, Canada K7L 2V7 (e-mail:

Received March 10, 2012

Accepted September 24, 2012

© 2013 by Lippincott Williams & Wilkins