Loss of Temporal Inhibition of Nociceptive Information Is Associated With Aging and Bodily Pain

  • Kelly M. Naugle
    Department of Kinesiology, School of Physical Education and Tourism Management, Indiana University Purdue University, Indianapolis, Indiana
    Search for articles by this author
  • Yenisel Cruz-Almeida
    Department of Aging & Geriatric Research and Neuroscience, College of Medicine, Institute on Aging, University of Florida, Gainesville, Florida

    College of Dentistry and Pain Research and Intervention Center of Excellence, University of Florida, Gainesville, Florida
    Search for articles by this author
  • Roger B. Fillingim
    College of Dentistry and Pain Research and Intervention Center of Excellence, University of Florida, Gainesville, Florida
    Search for articles by this author
  • Joseph L. Riley III
    Address reprint requests to Joseph L. Riley, III, PhD, Pain Research & Intervention Center of Excellence, University of Florida, Clinical and Translational Research Building, Room 2227, 2004 Mowry Road, Gainesville, FL 32610.
    College of Dentistry and Pain Research and Intervention Center of Excellence, University of Florida, Gainesville, Florida
    Search for articles by this author
Published:August 25, 2017DOI:


      • Older adults showed reduced offset analgesia compared with younger adults.
      • No sex differences in offset analgesia were evident in any age group.
      • A reduction stimuli as small as .4°C resulted in significant offset analgesia.
      • Reduced offset analgesia was associated with pain in daily life for all age groups.


      An age-related decline in endogenous pain inhibitory processes likely places older adults at an increased risk for chronic pain. Limited research indicates that older adults may be characterized by deficient offset analgesia, an inhibitory temporal sharpening mechanism that increases the detectability of minor decreases in noxious stimulus intensity. The primary purpose of the study was to examine age differences in offset analgesia in community-dwelling younger, middle-aged, and older adults. An additional aim of the study was to determine whether the magnitude of offset analgesia predicted self-reported bodily pain. Eighty-seven younger adults, 42 middle-aged adults, and 60 older adults completed 4 offset analgesia trials and 3 constant temperature trials in which a noxious heat stimulus was applied to the volar forearm for 40 seconds. The offset trials consisted of 3 continuous phases: an initial 10-second painful stimulus, either a 1.0°C or .4°C increase in temperature from the initial 10-second painful stimulus for 10 seconds, and either a 1.0°C or .4°C decrease back to the initial testing temperature for 20 seconds. During each trial, subjects rated pain intensity continuously using an electronic visual analog scale (0–100). All subjects also completed the Short-Form Health Survey-36 including the Bodily Pain subscale. The results indicated that older and middle-aged adults showed reduced offset analgesia compared with younger adults in the 1.0°C and .4°C offset trials. Furthermore, the magnitude of offset analgesia predicted self-reported bodily pain, with those exhibiting reduced offset analgesia reporting greater bodily pain. Dysfunction of this endogenous inhibitory system could increase the risk of developing chronic pain for middle-aged and older adults.


      Older and middle-aged adults showed reduced offset analgesia compared with younger adults. The significant association between reduced offset analgesia and pain in daily life supports the notion that pain modulatory deficits are associated with not just a chronic pain condition but with the experience of pain in general.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Allen J.S.
        • Bruss J.
        • Brown C.K.
        • Damasio H.
        Normal neuroanatomical variation due to age: The major lobes and a parcellation of the temporal region.
        Neurobiol Aging. 2005; 26: 1245-1260
        • Bartley E.J.
        • King C.D.
        • Sibille K.T.
        • Cruz-Almeida Y.
        • Riley III, J.L.
        • Glover T.L.
        • Goodin B.R.
        • Sotolongo A.S.
        • Herbert M.S.
        • Bulls H.W.
        • Staud R.
        • Fessler B.J.
        • Redden D.T.
        • Bradley L.A.
        • Fillingim R.B.
        Enhanced pain sensitivity among individuals with symptomatic knee osteoarthritis: Potential sex differences in central sensitization.
        Arthritis Care Res. 2016; 68: 472-480
        • Bernard J.A.
        • Seidler R.D.
        Moving forward: Age effects on the cerebellum underlie cognitive and motor declines.
        Neurosci Biobehav Rev. 2014; 42: 193-207
        • Campbell J.N.
        • LaMotte R.H.
        Latency to detection of first pain.
        Brain Res. 1983; 266: 203-208
        • Coghill R.C.
        • Mayer D.J.
        • Price D.D.
        The roles of spatial recruitment and discharge frequency in spinal cord coding of pain: A combined electrophysiological and imaging investigation.
        Pain. 1983; 53: 295-309
        • Derbyshire S.W.
        • Osborn J.
        Offset analgesia is mediated by activation in the region of the periaqueductal grey and rostral ventromedial medulla.
        Neuroimage. 2009; 47: 1002-1006
        • Edwards R.R.
        • Fillingim R.B.
        Effects of age on temporal summation and habituation of thermal pain: Clinical relevance in healthy older and younger adults.
        J Pain. 2001; 2: 307-317
        • Ferrell B.A.
        • Ferrell B.R.
        • Osterweil D.
        Pain in the nursing home.
        J Am Geriatr Soc. 1990; 38: 409-414
        • Good C.D.
        • Johnsrude I.S.
        • Ashburner J.
        • Henson R.N.
        • Friston K.J.
        • Frackowiak R.S.
        A voxel-based morphometric study of ageing in 465 normal adult human brains.
        Neuroimage. 2001; 14: 21-36
        • Grill J.D.
        • Coghill R.C.
        Transient analgesia evoked by noxious stimulus offset.
        J Neurophysiol. 2002; 87: 2205-2208
        • Hamaguchi T.
        • Kano M.
        • Kanazawa M.
        • Itoh M.
        • Yanai K.
        • Fukudo S.
        Effects of preceding stimulation on brain activation in response to colonic distention in humans.
        Psychosom Med. 2013; 75: 453-462
        • Helme R.D.
        • Gibson S.J.
        The epidemiology of pain in elderly people.
        Clin Geriatr Med. 2001; 17: 417-431
        • Herman L.
        • Calders P.
        • Van Oosterwijck J.
        • Vershelde A.
        • Bertel E.
        • Meeus M.
        An overview of offset analgesia and the comparison with conditioned pain modulation: A systematic Literature Review.
        Pain Physician. 2016; 19: 307-326
        • Jacobs J.M.
        • Love S.
        Qualitative and quantitative morphology of human sural nerve at different ages.
        Brain. 1985; 108: 897-924
        • Lariviere M.
        • Goffaux P.
        • Marchand S.
        • Julien N.
        Changes in pain perception and descending inhibitory controls start at middle age in healthy adults.
        Clin J Pain. 2007; 23: 506-510
        • Lautenbacher S.
        • Kunz M.
        • Strate P.
        • Nielsen J.
        • Arendt-Nielsen L.
        Age effects on pain thresholds, temporal summation and spatial summation of heat and pressure pain.
        Pain. 2005; 115: 410-418
        • Leveille S.G.
        • Zhang Y.
        • McMullen W.
        • Kelly-Hayes M.
        • Felson D.T.
        Sex differences in musculoskeletal pain in older adults.
        Pain. 2005; 116: 332-338
        • Lewis G.N.
        • Rice D.A.
        • McNair P.J.
        Conditioned pain modulation in populations with chronic pain: A systematic review and meta-analysis.
        J Pain. 2012; 13: 936-944
        • Nahman-Averbuch H.
        • Martucci K.T.
        • Granovsky Y.
        • Weissman-Fogel I.
        • Yarnitsky D.
        • Cognhill R.C.
        Distinct brain mechanisms support spatial vs. temporal filtering of nociceptive information.
        Pain. 2014; 155: 2491-2501
        • Naugle K.M.
        • Cruz-Almeida Y.
        • Fillingim R.B.
        • Riley III, J.L.
        Offset analgesia is reduced in older adults.
        Pain. 2013; 154: 2381-2387
        • Naugle K.M.
        • Cruz-Almeida Y.
        • Fillingim R.B.
        • Staud R.
        • Riley III, J.L.
        Novel method for assessing age-related differences in the temporal summation of pain.
        J Pain Res. 2016; 9: 195-205
        • Niesters M.
        • Dahan A.
        • Swartjes M.
        • Noppers I.
        • Fillingim R.B.
        • Aarts L.
        • Sarton E.Y.
        Effect of ketamine on endogenous pain modulation in healthy volunteers.
        Pain. 2011; 152: 656-663
        • Niesters M.
        • Hoitsma E.
        • Sarton E.
        • Aarts L.
        • Dahan A.
        Offset analgesia in neuropathic pain patients and effect of treatment with morphine and ketamine.
        Anesthesiology. 2011; 115: 1063-1071
        • Niesters M.
        • Proto P.L.
        • Aarts L.
        • Sarton E.Y.
        • Drewes A.M.
        • Dahan A.
        Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy.
        Br J Anaesth. 2014; 113: 148-156
        • Ochoa J.L.
        • Mair W.G.
        The normal sural nerve in man. II. Changes in the axons and Schwann cells due to ageing.
        Acta Neuropathol. 1969; 13: 217-239
        • O'Sullivan D.J.
        • Swallow M.
        The fibre size and content of the radial and sural nerves.
        J Neurol Neurosurg Psychiatry. 1968; 31: 464-470
        • Oudejans L.C.
        • Smit J.M.
        • van Velzen M.
        • Dahan A.
        • Niesters M.
        The influence of offset analgesia on the onset and offset of pain in patients with fibromyalgia.
        Pain. 2015; 156: 2521-2527
        • Popescu A.
        • LeResche L.
        • Truelove E.L.
        • Drangsholt M.T.
        Gender differences in pain modulation by diffuse noxious inhibitory controls: A systematic review.
        Pain. 2010; 150: 309-318
        • Resnick S.M.
        • Pham D.L.
        • Kraut M.A.
        • Zonderman A.B.
        • Davatzikos C.
        Longitudinal magnetic resonance imaging studies of older adults: A shrinking brain.
        J Neurosci. 2013; 23: 3295-3301
        • Riley III, J.L.
        • Gilbert G.H.
        Orofacial pain symptoms: An interaction between age and sex.
        Pain. 2001; 90: 245-256
        • Riley III, J.L.
        • King C.D.
        • Wong F.
        • Fillingim R.B.
        • Mauderli A.P.
        Lack of endogenous modulation and reduced decay of prolonged heat pain in older adults.
        Pain. 2010; 150: 153-160
        • Ruscheweyh R.
        • Kühnel M.
        • Filippopulos F.
        • Blum B.
        • Eggert T.
        • Straube A.
        Altered experimental pain perception after cerebellar infarction.
        Pain. 2014; 155: 1303-1312
        • Staud R.
        Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions.
        Expert Rev Neurother. 2012; 12: 577-585
        • Sullivan M.J.
        • Bishop S.R.
        • Pivik J.
        The Pain Catastrophizing Scale: Development and validation.
        Psychol Assess. 1995; 7: 524-532
        • Treede R.D.
        • Meyer R.A.
        • Campbell J.N.
        Myelinated mechanically insensitive afferents from monkey hairy skin: Heat-response properties.
        J Neurophysiol. 1998; 80: 1082-1093
        • Treede R.D.
        • Meyer R.A.
        • Raja S.N.
        • Campbell J.N.
        Evidence for two different heat transduction mechanisms in nociceptive primary afferents innervating monkey skin.
        J Physiol. 1995; 483: 747-758
        • Tsang A.
        • Von Korff M.
        • Lee S.
        • Alonso J.
        • Karam E.
        • Angermeyer M.C.
        • Borges G.L.
        • Bromet E.J.
        • Demytteneare K.
        • de Girolamo G.
        • de Graaf R.
        • Gureje O.
        • Lepine J.P.
        • Haro J.M.
        • Levinson D.
        • Oakley Browne M.A.
        • Posada-Villa J.
        • Seedat S.
        • Watanabe M.
        Common chronic pain conditions in developed and developing countries: Gender and age differences and comorbidity with depression-anxiety disorders.
        J Pain. 2008; 9: 883-891
        • Verdú E.
        • Ceballos D.
        • Vilches J.J.
        • Navarro X.
        Influence of aging on peripheral nerve function and regeneration.
        J Peripher Nerv Syst. 2000; 5: 191-208
        • Ware J.
        • Kosinski M.
        • Dewey J.
        How to Score Version Two of the SF-36 Health Survey.
        QualityMetric, Incorporated, Lincoln, RI2000
        • Yarnitsky D.
        Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): Its relevance for acute and chronic pain states.
        Curr Opin Anaesthesiol. 2010; 23: 611-615
        • Yarnitsky D.
        • Crispel Y.
        • Eisenberg E.
        • Granovsky Y.
        • Ben-Nun A.
        • Sprecher E.
        • Best L.A.
        • Granot M.
        Prediction of chronic post-operative pain: Pre-operative DNIC testing identifies patients at risk.
        Pain. 2008; 138: 22-28
        • Yelle M.D.
        • Oshiro Y.
        • Kraft R.A.
        • Coghill R.C.
        Temporal filtering of nociceptive information by dynamic activation of endogenous pain modulatory systems.
        J Neurosci. 2009; 29: 10264-10271