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Exercise-Induced Hypoalgesia in Pain-Free and Chronic Pain Populations: State of the Art and Future Directions

  • David Rice
    Correspondence
    Address reprint requests to Dr David Rice, Health and Rehabilitation Research Institute, Auckland University of Technology, Private Bag 92006, Auckland, 1142, New Zealand.
    Affiliations
    Health and Rehabilitation Research Institute, Auckland University of Technology, Auckland, New Zealand

    Waitemata Pain Services, Department of Anaesthesiology and Perioperative Medicine, Waitemata District Health Board, Auckland, New Zealand
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  • Jo Nijs
    Affiliations
    Pain in Motion International Research Group#

    Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium

    Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium
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  • Eva Kosek
    Affiliations
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Stockholm Spine Center, Löwenströmska Hospital, Upplands Väsby, Sweden
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  • Timothy Wideman
    Affiliations
    School of Physical and Occupational Therapy, McGill University, Montreal, Canada
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  • Monika I Hasenbring
    Affiliations
    Department of Medical Psychology and Medical Sociology, Faculty of Medicine, Ruhr-University of Bochum, Bochum, Germany
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  • Kelli Koltyn
    Affiliations
    Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin
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  • Thomas Graven-Nielsen
    Affiliations
    Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
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  • Andrea Polli
    Affiliations
    Pain in Motion International Research Group#

    Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium

    Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium

    Research Foundation – Flanders (FWO), Brussels, Belgium
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  • Author Footnotes
    # www.paininmotion.be
Open AccessPublished:March 20, 2019DOI:https://doi.org/10.1016/j.jpain.2019.03.005

      Highlights

      • Aerobic and resistance exercise typically lead to hypoalgesia in pain-free adults.
      • Exercise may lead to hypoalgesia or hyperalgesia in people with chronic pain.
      • Several different factors may influence the effect of exercise on pain.

      Abstract

      Exercise is considered an important component of effective chronic pain management and it is well-established that long-term exercise training provides pain relief. In healthy, pain-free populations, a single bout of aerobic or resistance exercise typically leads to exercise-induced hypoalgesia (EIH), a generalized reduction in pain and pain sensitivity that occurs during exercise and for some time afterward. In contrast, EIH is more variable in chronic pain populations and is more frequently impaired; with pain and pain sensitivity decreasing, remaining unchanged or, in some cases, even increasing in response to exercise. Pain exacerbation with exercise may be a major barrier to adherence, precipitating a cycle of physical inactivity that can lead to long-term worsening of both pain and disability. To optimize the therapeutic benefits of exercise, it is important to understand how EIH works, why it may be impaired in some people with chronic pain, and how this should be addressed in clinical practice. In this article, we provide an overview of EIH across different chronic pain conditions. We discuss possible biological mechanisms of EIH and the potential influence of sex and psychosocial factors, both in pain-free adults and, where possible, in individuals with chronic pain. The clinical implications of impaired EIH are discussed and recommendations are made for future research, including further exploration of individual differences in EIH, the relationship between exercise dose and EIH, the efficacy of combined treatments and the use of alternative measures to quantify EIH.

      Perspective

      This article provides a contemporary review of the acute effects of exercise on pain and pain sensitivity, including in people with chronic pain conditions. Existing findings are critically reviewed, clinical implications are discussed, and recommendations are offered for future research.

      Key words

      Chronic pain is a pervasive condition, affecting an estimated 20% of all people worldwide.
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      Importantly for those suffering from chronic pain, exercise can also have a pain-relieving effect. There is a substantial and growing body of evidence that long-term exercise training can provide pain relief across many different chronic pain conditions, including fibromyalgia and chronic widespread pain,
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      particularly in the initial stages of training, where short-term exacerbations in pain can occur in some people.
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      In healthy, pain-free participants, the typical response to an acute bout of exercise is a period of hypoalgesia. Exercise-induced hypoalgesia (EIH) is characterized by a decrease in sensitivity to painful stimuli, with variable duration, lasting ≤30 minutes after a single bout of exercise.
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      In laboratory-based research studies, EIH is usually quantified by applying a painful stimulus to the body before and after a defined dose of exercise and measuring changes in pain sensitivity, such as increased pain thresholds or decreased pain intensity to a standardized painful stimulus. Using these methods, EIH has been consistently demonstrated in healthy, pain-free populations,
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      • Riley III, JL
      A meta-analytic review of the hypoalgesic effects of exercise.
      with both aerobic and resistance exercise attenuating several different measures of pain sensitivity, including pressure, thermal, and electrocutaneous pain thresholds,
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      Psychosocial influences on exercise-induced hypoalgesia.
      and mechanical pain.
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      Isometric exercises reduce temporal summation of pressure pain in humans.
      Aerobic exercise more consistently elicits EIH at higher intensities (approximately 200 W or 70% maximal oxygen consumption).
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      Exercise-induced hypoalgesia and intensity of exercise.
      Both dynamic and isometric resistance exercise induce EIH, with isometric loads as low as 10 to 30% of maximum voluntary contraction capable of inducing EIH, provided the duration of contraction is sufficient
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      Dose response of isometric contractions on pain perception in healthy adults.
      —often held to exhaustion or for ≤5 minutes.
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      Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls.
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      Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls—antagonistic effects between opioid and serotonin-related genes.
      Aerobic exercise typically leads to widespread EIH while resistance exercise may lead to reduced pain sensitivity close to the site of muscle contraction (local EIH) and at remote sites of the body, distant to the contracting muscle (global EIH).
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      • Ekholm J
      • Hansson P
      Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls.
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      Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
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      • Handberg G
      • Graven-Nielsen T
      Kinesiophobia is associated with pain intensity but not pain sensitivity before and after exercise: An explorative analysis.
      The acute effect of exercise on pain sensitivity is more variable in chronic pain populations, with some studies demonstrating no change or even increased pain sensitivity in response to a single bout of exercise.
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      Acute resistance exercise and pressure pain sensitivity in knee osteoarthritis: A randomised crossover trial.
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      • Koltyn KF.
      Exercise-induced modulation of pain in adults with and without painful diabetic neuropathy.
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      • Ekholm J
      • Hansson P
      Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls.
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      • Kosek E.
      Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
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      • Sterling M
      Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders.
      • Staud R
      • Robinson ME
      • Price DD
      Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls.
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      • Löfgren M
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      • Gerdle B
      • Larsson A
      • Palstam A
      • Bileviciute-Ljungar I
      • Bjersing J
      • Martin I
      • Ernberg M
      Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls—antagonistic effects between opioid and serotonin-related genes.
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      • Nijs J
      • Meeus M
      • Van Loo M
      • Paul L
      Lack of endogenous pain inhibition during exercise in people with chronic whiplash associated disorders: An experimental study.
      • Whiteside A
      • Hansen S
      • Chaudhuri A
      Exercise lowers pain threshold in chronic fatigue syndrome.
      Increased pain sensitivity after exercise (ie, exercise-induced hyperalgesia) is thought to underlie flares in pain that can occur with exercise in some chronic pain populations.
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      • Smith MT
      Increased sensitivity to physical activity among individuals with knee osteoarthritis: Relation to pain outcomes, psychological factors, and responses to quantitative sensory testing.
      In turn, pain exacerbation in response to exercise is likely to be a major barrier to adherence,
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      precipitating a cycle of physical inactivity that may lead to long-term worsening of both pain and disability. Thus, to optimize the therapeutic benefits of exercise, it is important to understand how EIH works, why it may be impaired in some people with chronic pain and how this should be addressed in clinical practice.
      The aim of this article was to provide a contemporary review of EIH in response to acute exercise, including in people with chronic pain. We begin by giving an overview of studies that have used a standardized exercise protocol and compared the EIH response in people with chronic pain and pain-free controls. Next, we explore possible biological mechanisms of EIH and the potential influence of sex and psychosocial factors on the EIH response—both in pain-free adults, and, where possible, in chronic pain populations. The clinical implications of impaired EIH are discussed and recommendations are made for future research on EIH, including in people with chronic pain.

      Overview of EIH in People With Chronic Pain

      To provide an overview of studies exploring EIH in chronic pain conditions, a keyword list was developed (eg, exercise, aerobic, resistance, isometric, isotonic, hypoalgesia, analgesia, hyperalgesia, chronic pain, pain threshold, pain sensitivity, quantitative sensory testing). An initial check of the keyword list was made against several databases (CINAHL, MEDLINE, and Scopus) and, where appropriate, additional keywords were added and modifications to the keyword list were made. This was supplemented with a review of the bibliographies of past review articles on EIH, as well as the personal libraries of the contributing authors. Studies that compared the effects of a standardized, single bout of exercise on a measure of pain or pain sensitivity between a control group and a group with chronic pain are presented in Table 1, with key findings summarized herein.
      Table 1Acute Exercise-Induced Change in Pain Sensitivity or Pain Intensity After a Single Bout of Exercise in Studies Comparing Healthy Controls With Individuals With Chronic Pain
      Control GroupPain Group
      Pain ConditionFirst Author, ReferenceExercise TypeDosePain MeasureLocal EffectGlobal EffectLocal EffectGlobal Effect
      Chronic low back painMeeus
      • Meeus M
      • Roussel NA
      • Truijen S
      • Nijs J
      Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study.
      Aerobic (cycle ergometer)Incremental 20–130 W, 17–29 minutesPressure pain threshold (kg/cm2)
      Chronic neck painChristensen
      • Christensen SW
      • Hirata RP
      • Graven‐Nielsen T
      Altered pain sensitivity and axioscapular muscle activity in neck pain patients compared with healthy controls.
      Resistance (dynamic shoulder abduction)6 × 6 repeated bilateral shoulder abductions against gravity to a 140 degree anglePressure pain threshold (kPa)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Chronic neck painChristensen
      • Christensen SW
      • Hirata RP
      • Graven‐Nielsen T
      Altered pain sensitivity and axioscapular muscle activity in neck pain patients compared with healthy controls.
      Resistance (dynamic shoulder abduction)6 × 6 repeated bilateral shoulder abductions against gravity to a 140 degree anglePain intensity (VAS)N/A
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      N/A
      Chronic widespread pain (chronic fatigue syndrome)Whiteside
      • Whiteside A
      • Hansen S
      • Chaudhuri A
      Exercise lowers pain threshold in chronic fatigue syndrome.
      Aerobic (treadmill)Incremental incline, 5 km/h, 15 minutesPressure pain threshold (s)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Chronic widespread pain (chronic fatigue syndrome)Meeus
      • Meeus M
      • Roussel NA
      • Truijen S
      • Nijs J
      Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study.
      Aerobic (cycle ergometer)Incremental 20–130 W, 3–29 minutesPressure pain threshold (kg/cm2)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Van Oosterwijck
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Lefever I
      • Huybrechts L
      • Lambrecht L
      • Paul L
      Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study.
      Aerobic (cycle ergometer)Incremental, 25 W/min up to 75% HRmax, approximately 3–5 minutesPressure pain threshold (kg/cm2)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Van Oosterwijck
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Lefever I
      • Huybrechts L
      • Lambrecht L
      • Paul L
      Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study.
      Aerobic (cycle ergometer)Incremental, 25 W/min up to 75% HRmax, approximately 3–5 minutesPain intensity (VAS)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Van Oosterwijck
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Lefever I
      • Huybrechts L
      • Lambrecht L
      • Paul L
      Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study.
      Aerobic (cycle ergometer)Self-paced up to 80% of AT, approximately 5–9 minutesPressure pain threshold (kg/cm2)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Van Oosterwijck
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Lefever I
      • Huybrechts L
      • Lambrecht L
      • Paul L
      Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study.
      Aerobic (cycle ergometer)Self-paced up to 80% of AT, approximately 5–9 minutesPain intensity (VAS)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Van Oosterwijck
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Van Loo M
      • Paul L
      Lack of endogenous pain inhibition during exercise in people with chronic whiplash associated disorders: An experimental study.
      Aerobic (cycle ergometer)Incremental, 25 W/min to 75% of HRmax, approximately 3–4 minutesPain intensity (VAS)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Chronic widespread pain (chronic fatigue syndrome)Malfliet
      • Malfliet A
      • Pas R
      • Brouns R
      • De JW
      • Hatem S
      • Meeus M
      • Ickmans K
      • Nijs J
      Cerebral blood flow and heart rate variability in chronic fatigue syndrome: A randomized cross-over study.
      Aerobic (cycle ergometer)50 W at 55–65 rpm, 12 minutesTemporal summation of pressure pain (VAS)
      Chronic widespread pain (Gulf War syndrome)Cook
      • Cook DB
      • Stegner AJ
      • Ellingson LD
      Exercise alters pain sensitivity in Gulf War veterans with chronic musculoskeletal pain.
      Aerobic (cycle ergometer)70% VO
      • Bačkonja MM
      • Attal N
      • Baron R
      • Bouhassira D
      • Drangholt M
      • Dyck PJ
      • Edwards RR
      • Freeman R
      • Gracely R
      • Haanpaa MH
      • Hansson P
      • Hatem SM
      • Krumova EK
      • Jensen TS
      • Maier C
      • Mick G
      • Rice AS
      • Rolke R
      • Treede R-D
      • Serra J
      • Toelle T
      • Tugnoli V
      • Walk D
      • Walalce MS
      • Ware M
      • Yarnitsky D
      • Ziegler D
      Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus.
      max 50–60 rpm, 30 minutes
      Heat pain threshold (°C)
      Cook
      • Cook DB
      • Stegner AJ
      • Ellingson LD
      Exercise alters pain sensitivity in Gulf War veterans with chronic musculoskeletal pain.
      Aerobic (cycle ergometer)70% VO
      • Bačkonja MM
      • Attal N
      • Baron R
      • Bouhassira D
      • Drangholt M
      • Dyck PJ
      • Edwards RR
      • Freeman R
      • Gracely R
      • Haanpaa MH
      • Hansson P
      • Hatem SM
      • Krumova EK
      • Jensen TS
      • Maier C
      • Mick G
      • Rice AS
      • Rolke R
      • Treede R-D
      • Serra J
      • Toelle T
      • Tugnoli V
      • Walk D
      • Walalce MS
      • Ware M
      • Yarnitsky D
      • Ziegler D
      Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus.
      max, 50–60 rpm, 30 minutes
      Pressure pain threshold (s)
      Cook
      • Cook DB
      • Stegner AJ
      • Ellingson LD
      Exercise alters pain sensitivity in Gulf War veterans with chronic musculoskeletal pain.
      Aerobic (cycle ergometer)70% VO
      • Bačkonja MM
      • Attal N
      • Baron R
      • Bouhassira D
      • Drangholt M
      • Dyck PJ
      • Edwards RR
      • Freeman R
      • Gracely R
      • Haanpaa MH
      • Hansson P
      • Hatem SM
      • Krumova EK
      • Jensen TS
      • Maier C
      • Mick G
      • Rice AS
      • Rolke R
      • Treede R-D
      • Serra J
      • Toelle T
      • Tugnoli V
      • Walk D
      • Walalce MS
      • Ware M
      • Yarnitsky D
      • Ziegler D
      Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus.
      max, 50–60 rpm, 30 minutes
      Suprathreshold heat pain intensity (NRS)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Chronic widespread painGhafouri
      • Ghafouri N
      • Ghafouri B
      • Larsson B
      • Stensson N
      • Fowler C
      • Gerdle B
      Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity.
      Resistance (dynamic arm movement)Repeated 30 cm movement of 11.8 g peg back and forth at 1.3 Hz for 20 minutesPain intensity (NRS)N/A
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      N/A
      FibromyalgiaVierck
      • Vierck CJ
      • Staud R
      • Price DD
      • Cannon RL
      • Mauderli AP
      • Martin AD
      The effect of maximal exercise on temporal summation of second pain (windup) in patients with fibromyalgia syndrome.
      Aerobic (treadmill)Incremental increase in incline, speed to exhaustion, approximately 11–14 minutes
      Vierck
      • Vierck CJ
      • Staud R
      • Price DD
      • Cannon RL
      • Mauderli AP
      • Martin AD
      The effect of maximal exercise on temporal summation of second pain (windup) in patients with fibromyalgia syndrome.
      Aerobic (treadmill)Incremental increase in incline, speed to exhaustion, approximately 11–14 minutesHeat pain aftersensations (VAS)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Staud
      • Staud R
      • Robinson ME
      • Weyl EE
      • Price DD
      Pain variability in fibromyalgia is related to activity and rest: Role of peripheral tissue impulse input.
      Aerobic (arm ergometer)60 W, 60 rpm up to 15 minutes or exhaustionPain intensity (VAS)
      Staud
      • Staud R
      • Robinson ME
      • Weyl EE
      • Price DD
      Pain variability in fibromyalgia is related to activity and rest: Role of peripheral tissue impulse input.
      Aerobic (arm ergometer)60 W, 60 rpm up to 15 minutes or exhaustionSuprathreshold heat pain (VAS)
      Staud
      • Staud R
      • Robinson ME
      • Weyl EE
      • Price DD
      Pain variability in fibromyalgia is related to activity and rest: Role of peripheral tissue impulse input.
      Aerobic (arm ergometer)60 W, 60 rpm up to 15 minutes or exhaustionPressure pain threshold (kPa)
      Kosek
      • Kosek E
      • Ekholm J
      • Hansson P
      Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls.
      Resistance (Isometric knee extension)25% of MVC, up to 5 minutes or to exhaustionPressure pain threshold (kPa)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      FibromyalgiaStaud
      • Staud R
      • Robinson ME
      • Price DD
      Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls.
      Resistance (isometric gripping)30% of MVC, 90 secondsPressure pain threshold (kPa)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Staud
      • Staud R
      • Robinson ME
      • Price DD
      Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls.
      Resistance (isometric gripping)30% of MVC, 90 secondsSuprathreshold heat pain intensity (VAS)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Kadetoff
      • Kadetoff D
      • Kosek E.
      The effects of static muscular contraction on blood pressure, heart rate, pain ratings and pressure pain thresholds in healthy individuals and patients with fibromyalgia.
      Resistance (isometric knee extension)10–15% of MVC, up to 15 minutes or to exhaustionPressure pain threshold (kPa)
      Lannersten
      • Lannersten L
      • Kosek E.
      Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
      Resistance (isometric shoulder rotation)20–25% of MVC, up to 5 minutes or to exhaustionPressure pain threshold (kPa)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Lannersten
      • Lannersten L
      • Kosek E.
      Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
      Resistance (isometric knee extension)20–25% of MVC, up to 5 minutes or to exhaustionPressure pain threshold (kPa)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Ge
      • Ge HY
      • Nie H
      • Graven‐Nielsen T
      • Danneskiold‐Samsøe B
      • Arendt‐Nielsen L
      Descending pain modulation and its interaction with peripheral sensitization following sustained isometric muscle contraction in fibromyalgia.
      Resistance (isometric shoulder abduction)Hold shoulder at 90 degrees of abduction against gravity to exhaustionPressure pain threshold (kPa)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Tour
      • Tour J
      • Löfgren M
      • Mannerkorpi K
      • Gerdle B
      • Larsson A
      • Palstam A
      • Bileviciute-Ljungar I
      • Bjersing J
      • Martin I
      • Ernberg M
      Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls—antagonistic effects between opioid and serotonin-related genes.
      Resistance (isometric knee extension)30% of MVC, up to 5 minutes or to exhaustionPressure pain threshold (kPa)ncN/A
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Local shoulder myalgiaLannersten
      • Lannersten L
      • Kosek E.
      Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
      Resistance (isometric shoulder rotation)20–25% of MVC, up to 5 minutes or to exhaustionPressure pain threshold (kPa)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Lannersten
      • Lannersten L
      • Kosek E.
      Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
      Resistance (isometric knee extension)20–25% of MVC, up to 5 minutes or to exhaustionPressure pain threshold (kPa)
      Ghafouri
      • Ghafouri N
      • Ghafouri B
      • Larsson B
      • Stensson N
      • Fowler C
      • Gerdle B
      Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity.
      Resistance (Dynamic arm movement)Repeated 30-cm movement of 11.8 g peg at 1.3 Hz for 20 minutesPain intensity (NRS)N/A
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      N/A
      OsteoarthritisKosek
      • Kosek E
      • Roos E
      • Ageberg E
      • Nilsdotter A
      Increased pain sensitivity but normal function of exercise induced analgesia in hip and knee osteoarthritis–treatment effects of neuromuscular exercise and total joint replacement.
      Resistance (isometric knee extension)50% of MVC, up to 5 minutes or to exhaustionPressure pain threshold (kPa)
      Burrows
      • Burrows N
      • Booth J
      • Sturnieks D
      • Barry B
      Acute resistance exercise and pressure pain sensitivity in knee osteoarthritis: A randomised crossover trial.
      Resistance (isotonic upper limb exercises)60% of 1 RM, 3 sets of 10 contractionsPressure pain threshold (kg/cm2)
      Burrows
      • Burrows N
      • Booth J
      • Sturnieks D
      • Barry B
      Acute resistance exercise and pressure pain sensitivity in knee osteoarthritis: A randomised crossover trial.
      Resistance (isotonic upper limb exercises)60% of 1 RM, 3 sets of 10 contractionsPressure pain tolerance (seconds)N/AN/A
      OsteoarthritisBurrows
      • Burrows N
      • Booth J
      • Sturnieks D
      • Barry B
      Acute resistance exercise and pressure pain sensitivity in knee osteoarthritis: A randomised crossover trial.
      Resistance (isotonic lower limb exercises)60% of 1 RM, 3 sets of 10 contractionsPressure pain threshold (kg/cm2)
      Burrows
      • Burrows N
      • Booth J
      • Sturnieks D
      • Barry B
      Acute resistance exercise and pressure pain sensitivity in knee osteoarthritis: A randomised crossover trial.
      Resistance (isotonic lower limb exercises)60% of 1 RM, 3 sets of 10 contractionsPressure pain tolerance (s)N/AN/A
      Painful diabetic neuropathyKnauf
      • Knauf MT
      • Koltyn KF.
      Exercise-induced modulation of pain in adults with and without painful diabetic neuropathy.
      Resistance (isometric gripping)25% of MVC, 3 minutesSuprathreshold heat pain (NRS)N/A
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      N/A
      Knauf
      • Knauf MT
      • Koltyn KF.
      Exercise-induced modulation of pain in adults with and without painful diabetic neuropathy.
      Resistance (isometric gripping)25% of MVC, 3 minutesHeat pain temporal summation (∆NRS)N/A
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      N/A
      Rheumatoid arthritisFridén
      • Fridén C
      • Thoors U
      • Glenmark B
      • Kosek E
      • Nordmark B
      • Lundberg IE
      • Opava CH
      Higher pain sensitivity and lower muscle strength in postmenonpausal women with early rheumatoid arthritis compared with age-matched healthy women–a pilot study.
      Resistance (isometric knee extension)30% of MVC, up to 5 minutes or to exhaustionPressure pain threshold (kPa)
      Löfgren
      • Löfgren M
      • Opava CH
      • Demmelmaier I
      • Fridén C
      • Lundberg IE
      • Nordgren B
      • Kosek E
      Pain sensitivity at rest and during muscle contraction in persons with rheumatoid arthritis: A substudy within the Physical Activity in Rheumatoid Arthritis 2010 study.
      Resistance (isometric knee extension)30% of MVC, up to 5 minutes or to exhaustionPressure pain threshold (kPa)
      Whiplash-associated disorderVan Oosterwijck
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Van Loo M
      • Paul L
      Lack of endogenous pain inhibition during exercise in people with chronic whiplash associated disorders: An experimental study.
      Aerobic (cycle ergometer)Incremental, 25 W/min to 75% of HRmax, approximately 4–5 minutesPressure pain threshold (kg/cm2)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Van Oosterwijck
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Van Loo M
      • Paul L
      Lack of endogenous pain inhibition during exercise in people with chronic whiplash associated disorders: An experimental study.
      Aerobic (cycle ergometer)Incremental, 25 W/min to 75% of HRmax, approximately 4–5 minutesPain intensity (VAS)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Van Oosterwijck
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Van Loo M
      • Paul L
      Lack of endogenous pain inhibition during exercise in people with chronic whiplash associated disorders: An experimental study.
      Aerobic (cycle ergometer)Self-paced up to 80% of AT, approximately 10–13 minutesPressure pain threshold (kg/cm2)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Van Oosterwijck
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Van Loo M
      • Paul L
      Lack of endogenous pain inhibition during exercise in people with chronic whiplash associated disorders: An experimental study.
      Aerobic (cycle ergometer)Self-paced up to 80% of AT, approximately 10–13 minutesPain intensity (VAS)
      Ickmans
      • Ickmans K
      • Malfliet A
      • De Kooning M
      • Goudman L
      • Hubloue I
      • Schmitz T
      • Goubert D
      • Aguilar-Ferrandiz M
      Lack of gender and age differences in pain measurements following exercise in people with chronic whiplash-associated disorders.
      Aerobic (cycle ergometer)Incremental, 25 W/min to 75% of HRmax, approximately 4–6 minutesPressure pain threshold (kg/cm2)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Ickmans
      • Ickmans K
      • Malfliet A
      • De Kooning M
      • Goudman L
      • Hubloue I
      • Schmitz T
      • Goubert D
      • Aguilar-Ferrandiz M
      Lack of gender and age differences in pain measurements following exercise in people with chronic whiplash-associated disorders.
      Aerobic (cycle ergometer)Incremental, 25 W/min to 75% of HRmax, approximately 4–6 minutesPressure pain threshold (mm Hg)
      Whiplash-associated disorderIckmans
      • Ickmans K
      • Malfliet A
      • De Kooning M
      • Goudman L
      • Hubloue I
      • Schmitz T
      • Goubert D
      • Aguilar-Ferrandiz M
      Lack of gender and age differences in pain measurements following exercise in people with chronic whiplash-associated disorders.
      Aerobic (cycle ergometer)Incremental, 25 W/min to 75% of HRmax, approximately 4–6 minutesSuprathreshold pressure pain (mm Hg)
      Ickmans
      • Ickmans K
      • Malfliet A
      • De Kooning M
      • Goudman L
      • Hubloue I
      • Schmitz T
      • Goubert D
      • Aguilar-Ferrandiz M
      Lack of gender and age differences in pain measurements following exercise in people with chronic whiplash-associated disorders.
      Aerobic (cycle ergometer)Incremental, 25 W/min to 75% of HRmax, approximately 4–6 minutesTemporal summation (∆VAS)
      Ickmans
      • Ickmans K
      • Malfliet A
      • De Kooning M
      • Goudman L
      • Hubloue I
      • Schmitz T
      • Goubert D
      • Aguilar-Ferrandiz M
      Lack of gender and age differences in pain measurements following exercise in people with chronic whiplash-associated disorders.
      Aerobic (cycle ergometer)Incremental, 25 W/min to 75% of HRmax, approximately 4–6 minutesConditioned pain modulation (∆VAS)
      Smith
      • Smith A
      • Ritchie C
      • Pedler A
      • McCamley K
      • Roberts K
      • Sterling M
      Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders.
      Aerobic (cycle ergometer)75% of age-predicted HRmax, 30 minutesPressure pain threshold (kPa)
      Smith
      • Smith A
      • Ritchie C
      • Pedler A
      • McCamley K
      • Roberts K
      • Sterling M
      Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders.
      Resistance (isometric wall squat)Static squat 100 degrees of knee flexion, up to 3 minutes or to exhaustionPressure pain threshold (kPa)
      Whiplash-associated disorderChristensen
      • Christensen SW
      • Hirata RP
      • Graven‐Nielsen T
      Altered pain sensitivity and axioscapular muscle activity in neck pain patients compared with healthy controls.
      Resistance (dynamic shoulder abduction)6 × 6 repeated bilateral shoulder abductions against gravity to a 140 degree anglePressure pain threshold (kPa)
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Christensen
      • Christensen SW
      • Hirata RP
      • Graven‐Nielsen T
      Altered pain sensitivity and axioscapular muscle activity in neck pain patients compared with healthy controls.
      Resistance (dynamic shoulder abduction)6 × 6 repeated bilateral shoulder abductions against gravity to a 140 degree anglePain intensity (VAS)N/A
      Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      N/A
      Abbreviations: ↓, decrease in pain sensitivity or pain intensity; ↑, increase in pain sensitivity or pain intensity; ∼, equivocal findings or no change in pain sensitivity or pain intensity; VAS, visual analogue scale; rpm, revolutions per minute; N/A, measurement not available (not completed); AT, anaerobic threshold; NRS, numerical rating scale; 1 RM, 1 repetition maximum; MVC, maximum voluntary contraction; HRmax, maximum heart rate; ∆, change; W, Watt; Hz, Cycles per second.
      low asterisk Significantly impaired exercise-induced hypoalgesia response compared with healthy controls (P < .05). Local effect = pain measurement at a site local to the contracting muscle group. Global effect = pain measurement at a site remote to the contracting muscle group. NOTE: As aerobic exercise involves contraction of several muscle groups and induces a widespread hypoalgesic response, its effects were considered global.
      Compared with pain-free adults, several studies have demonstrated reduced EIH or, in some cases, exercise-induced hyperalgesia in response to either aerobic or resistance exercise in chronic pain populations, including fibromyalgia
      • Ge HY
      • Nie H
      • Graven‐Nielsen T
      • Danneskiold‐Samsøe B
      • Arendt‐Nielsen L
      Descending pain modulation and its interaction with peripheral sensitization following sustained isometric muscle contraction in fibromyalgia.
      • Kosek E
      • Ekholm J
      • Hansson P
      Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls.
      • Lannersten L
      • Kosek E.
      Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
      • Meeus M
      • Hermans L
      • Ickmans K
      • Struyf F
      • Van Cauwenbergh D
      • Bronckaerts L
      • De Clerck LS
      • Moorken G
      • Hans G
      • Grosemans S
      Endogenous pain modulation in response to exercise in patients with rheumatoid arthritis, patients with chronic fatigue syndrome and comorbid fibromyalgia, and healthy controls: A double‐blind randomized controlled trial.
      • Staud R
      • Robinson ME
      • Price DD
      Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls.
      • Tour J
      • Löfgren M
      • Mannerkorpi K
      • Gerdle B
      • Larsson A
      • Palstam A
      • Bileviciute-Ljungar I
      • Bjersing J
      • Martin I
      • Ernberg M
      Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls—antagonistic effects between opioid and serotonin-related genes.
      • Vierck CJ
      • Staud R
      • Price DD
      • Cannon RL
      • Mauderli AP
      • Martin AD
      The effect of maximal exercise on temporal summation of second pain (windup) in patients with fibromyalgia syndrome.
      and chronic widespread pain associated with chronic fatigue syndrome
      • Meeus M
      • Roussel NA
      • Truijen S
      • Nijs J
      Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study.
      • Van Oosterwijck J
      • Marusic U
      • De Wandele I
      • Paul L
      • Meeus M
      • Moorkens G
      • Lambrecht L
      • Danneels L
      • Nijs J
      The role of autonomic function in exercise-induced endogenous analgesia: A case-control study in myalgic encephalomyelitis/chronic fatigue syndrome and healthy people.
      • Whiteside A
      • Hansen S
      • Chaudhuri A
      Exercise lowers pain threshold in chronic fatigue syndrome.
      and Gulf War syndrome.
      • Cook DB
      • Stegner AJ
      • Ellingson LD
      Exercise alters pain sensitivity in Gulf War veterans with chronic musculoskeletal pain.
      Those with widespread body pain often demonstrate both a local and a global EIH dysfunction in response to resistance exercise, with pain sensitivity increasing or remaining unchanged at remote body sites (ie, distant to the muscle[s] undergoing contraction) as well as sites local to the contraction.
      • Ge HY
      • Nie H
      • Graven‐Nielsen T
      • Danneskiold‐Samsøe B
      • Arendt‐Nielsen L
      Descending pain modulation and its interaction with peripheral sensitization following sustained isometric muscle contraction in fibromyalgia.
      • Lannersten L
      • Kosek E.
      Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
      • Staud R
      • Robinson ME
      • Price DD
      Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls.
      In contrast, patients with a localized shoulder myalgia showed impaired EIH during isometric contractions of pain-afflicted muscles,
      • Ghafouri N
      • Ghafouri B
      • Larsson B
      • Stensson N
      • Fowler C
      • Gerdle B
      Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity.
      • Lannersten L
      • Kosek E.
      Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
      but normal EIH when contracting remote, nonafflicted muscles.
      • Lannersten L
      • Kosek E.
      Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
      Similarly, people with painful knee OA had an intact EIH response to dynamic resistance exercise of the upper limb, but impaired EIH when resistance exercise was undertaken in the painful lower limb.
      • Burrows N
      • Booth J
      • Sturnieks D
      • Barry B
      Acute resistance exercise and pressure pain sensitivity in knee osteoarthritis: A randomised crossover trial.
      These findings suggest that, even in the presence of impaired EIH, people with localized pain conditions might be able to obtain pain-relieving effects by exercising remote, nonpainful parts of the body, because this strategy may still elicit EIH.
      It is important to emphasize that not all chronic pain populations consistently demonstrate an impaired EIH response and different measures have been used to quantify EIH (eg, clinical pain intensity vs pressure pain threshold) that may influence both the underlying mechanism and observed response to exercise. Although limited to a few studies, impaired EIH has also been observed in painful diabetic neuropathy
      • Knauf MT
      • Koltyn KF.
      Exercise-induced modulation of pain in adults with and without painful diabetic neuropathy.
      and chronic neck pain,
      • Christensen SW
      • Hirata RP
      • Graven‐Nielsen T
      Altered pain sensitivity and axioscapular muscle activity in neck pain patients compared with healthy controls.
      whereas a normal EIH response has been observed in those with rheumatoid arthritis
      • Fridén C
      • Thoors U
      • Glenmark B
      • Kosek E
      • Nordmark B
      • Lundberg IE
      • Opava CH
      Higher pain sensitivity and lower muscle strength in postmenonpausal women with early rheumatoid arthritis compared with age-matched healthy women–a pilot study.
      • Löfgren M
      • Opava CH
      • Demmelmaier I
      • Fridén C
      • Lundberg IE
      • Nordgren B
      • Kosek E
      Pain sensitivity at rest and during muscle contraction in persons with rheumatoid arthritis: A substudy within the Physical Activity in Rheumatoid Arthritis 2010 study.
      and chronic low back pain.
      • Meeus M
      • Roussel NA
      • Truijen S
      • Nijs J
      Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study.
      Furthermore, in contrast with the findings of Burrows et al,
      • Burrows N
      • Booth J
      • Sturnieks D
      • Barry B
      Acute resistance exercise and pressure pain sensitivity in knee osteoarthritis: A randomised crossover trial.
      Kosek et al
      • Kosek E
      • Roos E
      • Ageberg E
      • Nilsdotter A
      Increased pain sensitivity but normal function of exercise induced analgesia in hip and knee osteoarthritis–treatment effects of neuromuscular exercise and total joint replacement.
      observed intact local and global EIH in individuals with end-stage hip and knee OA. Impaired EIH has been observed after repeated shoulder movements in people with whiplash-associated disorder (WAD),
      • Christensen SW
      • Hirata RP
      • Graven‐Nielsen T
      Altered pain sensitivity and axioscapular muscle activity in neck pain patients compared with healthy controls.
      whereas a normal EIH response was seen after an isometric leg muscle contraction.
      • Smith A
      • Ritchie C
      • Pedler A
      • McCamley K
      • Roberts K
      • Sterling M
      Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders.
      In contrast, impaired EIH is typically,
      • Ickmans K
      • Malfliet A
      • De Kooning M
      • Goudman L
      • Hubloue I
      • Schmitz T
      • Goubert D
      • Aguilar-Ferrandiz M
      Lack of gender and age differences in pain measurements following exercise in people with chronic whiplash-associated disorders.
      • Smith A
      • Ritchie C
      • Pedler A
      • McCamley K
      • Roberts K
      • Sterling M
      Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders.
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Van Loo M
      • Paul L
      Lack of endogenous pain inhibition during exercise in people with chronic whiplash associated disorders: An experimental study.
      observed in patients with WAD after aerobic exercise, highlighting the variability of the EIH response in chronic pain populations and suggesting a possible difference in EIH according to the type of exercise and pain condition.
      To further explore the individual variability of EIH among people with chronic pain, Vaegter et al
      • Vaegter HB
      • Handberg G
      • Graven-Nielsen T
      Hypoalgesia after exercise and the cold pressor test is reduced in chronic musculoskeletal pain patients with high pain sensitivity.
      split people with chronic musculoskeletal pain of various etiologies into 2 groups based on their widespread sensitivity to pressure pain. Interestingly, the high pain sensitivity group showed a decreased EIH compared with the low pain sensitivity group. Similarly, Fingleton et al
      • Fingleton C
      • Smart KM
      • Doody CM
      Exercise-induced hypoalgesia in people with knee osteoarthritis with normal and abnormal conditioned pain modulation.
      examined EIH in people with knee OA according to their conditioned pain modulation response. Although pressure pain sensitivity decreased after exercise in both controls and those with knee OA who had a normal conditioned pain modulation response, it increased after both isometric and aerobic exercise in those with deficient conditioned pain modulation, indicating impaired EIH in this subgroup of patients. Although preliminary, these findings suggest that impaired EIH occurs more frequently in individuals with augmented central nociceptive processing, indicated by widespread pain sensitivity and an imbalance in endogenous descending pain inhibitory or facilitatory function.

      Biological Mechanisms That May Contribute to EIH

      Currently, the mechanisms responsible for EIH are not entirely understood, either in healthy adults or individuals with chronic pain (Table 2). Historically, the opioid hypothesis has received the most attention, which states that activation of the endogenous opioid system during exercise may be responsible for EIH. A number of studies have been conducted in which an opioid receptor antagonist was administered before and/or during an exercise session (for a review see
      • Koltyn KF
      Analgesia following exercise.
      ). Most of the early research in this area involved either pain-free adults or animals. Results from human research seems to be equivocal, with more consistent support for the opioid hypothesis in the animal research.
      • Koltyn KF
      Analgesia following exercise.
      However, EIH that is insensitive to opioid antagonists can also occur, providing evidence for nonopioid mechanisms in EIH.
      • Crombie KM
      • Brellenthin AG
      • Hillard CJ
      • Koltyn KF
      Endocannabinoid and opioid system interactions in exercise-induced hypoalgesia.
      • Koltyn KF
      Analgesia following exercise.
      • Koltyn KF
      • Brellenthin AG
      • Cook DB
      • Sehgal N
      • Hillard C
      Mechanisms of exercise-induced hypoalgesia.
      • Lima L
      • Abner T
      • Sluka K
      Does exercise increase or decrease pain? Central mechanisms underlying these two phenomena.
      In the sections below, we discuss some additional biological mechanisms that may contribute to the EIH response in humans, with a focus on recent findings. It is important to note that other mechanisms may also be involved and that much of the research regarding the potential mechanisms of EIH has been performed in healthy, pain-free adults. However, where possible, we include studies undertaken in people with chronic pain and discuss their potential relevance to EIH in these populations.
      Table 2Overview of Main Biological Mechanisms Explored in Relation to EIH in Pain-Free Adults and Those With Chronic Pain Conditions
      SystemMechanism ExaminedPopulationMain Findings [Reference]
      Opioid systemOPRM1 gene polymorphismPain-free adults

      People with Fibromyalgia
      OPRM1 polymorphism alone is not associated with EIH in either group.
      • Tour J
      • Löfgren M
      • Mannerkorpi K
      • Gerdle B
      • Larsson A
      • Palstam A
      • Bileviciute-Ljungar I
      • Bjersing J
      • Martin I
      • Ernberg M
      Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls—antagonistic effects between opioid and serotonin-related genes.
      Endogenous opioid activityPain-free adultsOpioid antagonists have either no or limited effects in reducing EIH.
      • Crombie KM
      • Brellenthin AG
      • Hillard CJ
      • Koltyn KF
      Endocannabinoid and opioid system interactions in exercise-induced hypoalgesia.
      • Koltyn KF
      Analgesia following exercise.
      • Koltyn KF
      • Brellenthin AG
      • Cook DB
      • Sehgal N
      • Hillard C
      Mechanisms of exercise-induced hypoalgesia.
      Endocannabinoid systemEndocannabinoid ligands circulationPain-free adultsAEA and 2-AG concentrations increase after exercise.

      Opioid antagonists block AEA increase, while they have no effect on 2-AG. Relationship between endocannabinoid ligands and EIH not reported.
      • Crombie KM
      • Brellenthin AG
      • Hillard CJ
      • Koltyn KF
      Endocannabinoid and opioid system interactions in exercise-induced hypoalgesia.
      Interstitial endocannabinoid related lipidsPain-free adults,

      people with localized shoulder myalgia,

      people with CWP
      Lower levels of PEA and SEA associated with increased pain after exercise in localized myalgia and CWP groups.
      • Ghafouri N
      • Ghafouri B
      • Larsson B
      • Stensson N
      • Fowler C
      • Gerdle B
      Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity.
      Serotonergic systemHTR1a and 5-HTT gene polymorphismsPain-free adults, people with fibromyalgiaNeither of the serotonergic polymorphisms alone are associated with EIH in either group.132

      However, the combination of genetically inferred strong opioid tone (ORPM1 G genotype) and weak serotonergic signaling (5HT1a G genotype and low expressing 5-HTT) was associated with more pronounced EIH in both groups.132
      Immune systemIL-10 gene expressionPain-free adults, people with CFS and CWPIL-10 gene expression increased more after exercise in people with CFS and CWP than controls and was moderately correlated with postexercise pain.
      • Light AR
      • White AT
      • Hughen RW
      • Light KC
      Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects.
      TLR-4 gene expressionPain-free adults, people with CFS and CWPTLR-4 gene expression increased more after exercise in people with CFS and CWP than controls but was not correlated with postexercise pain.
      • Light AR
      • White AT
      • Hughen RW
      • Light KC
      Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects.
      Complement systemPain-free adults, people with CFS and CWPC4a products increase soon after exercise in people with CFS and CWP. Relationship to EIH not reported.
      • Sorensen B
      • Streib JE
      • Strand M
      • Make B
      • Giclas PC
      • Fleshner M
      • Jones JF
      Complement activation in a model of chronic fatigue syndrome.
      Oxidative stressPain-free adults, people with CFS and CWPExercise may increase pro-oxidants such as TBARS and reduce antioxidants such as heat shock protein, in people with CFS and CWP. Relationship to EIH not reported.
      • Jammes Y
      • Steinberg J
      • Delliaux S
      • Brégeon F
      Chronic fatigue syndrome combines increased exercise‐induced oxidative stress and reduced cytokine and Hsp responses.
      • Jammes Y
      • Steinberg J
      • Mambrini O
      • Bregeon F
      • Delliaux S
      Chronic fatigue syndrome: Assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise.
      Autonomic nervous systemHeart rate variabilityPain-free adults, people with CFS and CWPHeart rate variability is reduced after exercise, with no difference between groups and no association with EIH.
      • Malfliet A
      • Pas R
      • Brouns R
      • De JW
      • Hatem S
      • Meeus M
      • Ickmans K
      • Nijs J
      Cerebral blood flow and heart rate variability in chronic fatigue syndrome: A randomized cross-over study.
      Cerebral blood flowPain-free adults, people with CFS and CWPCerebral blood flow increases with exercise, with no difference between groups and no association with EIH.
      • Malfliet A
      • Pas R
      • Brouns R
      • De JW
      • Hatem S
      • Meeus M
      • Ickmans K
      • Nijs J
      Cerebral blood flow and heart rate variability in chronic fatigue syndrome: A randomized cross-over study.
      Abbreviations: ORPM1, mu opioid receptor; EIH, exercise induced hypoalgesia; AEA, N-arachidonylethanolamine; 2-AG, 2-arachidonoylglycerol; CWP, chronic widespread pain; PEA, palmitoyletholamide; SEA, stearoylethanolamide; 5HT1a, serotonin-1a receptor; 5HTT, serotonin transporter; CFS, chronic fatigue syndrome; TLR-4, Toll-like receptor 4; TBARS, thiobarbituric acid-reactive substances; IL-10, Interleukin 10; C4a, complement component 4a.

       The Role of Endocannabinoid System in EIH

      The specific neurochemistry of nonopioid hypoalgesia is not fully understood, but it has been suggested that the endocannabinoid system may be involved.
      • Dietrich A
      • McDaniel WF
      Endocannabinoids and exercise.
      The endocannabinoid system is a neuromodulatory system composed of cannabinoid receptors (CB1, CB2), their endogenous ligands, that is, the endocannabinoids (N-arachidonylethanolamine [AEA] and 2-arachidonoylglycerol [2-AG]), and proteins responsible for their metabolism. The presence of cannabinoid receptors in nociceptive-processing areas of the brain and spinal cord suggests that endocannabinoids contribute to the control of pain through the activation of CB1 receptors. Exercise increases circulating levels of endocannabinoids and there is evidence of increased expression of CB1 receptors in the brains of rodents that exercised,
      • Galdino G
      • Romero T
      • da Silva JFP
      • Aguiar D
      • de Paula AM
      • Cruz J
      • Parrella C
      • Piscitelli F
      • Duarte I
      • Di Marzo V
      Acute resistance exercise induces antinociception by activation of the endocannabinoid system in rats.
      • Galdino G
      • Romero TR
      • Silva JFP
      • Aguiar DC
      • de Paula AM
      • Cruz JS
      • Parrella C
      • Piscitelli F
      • Duarte ID
      • Di Marzo V
      The endocannabinoid system mediates aerobic exercise-induced antinociception in rats.
      with cannabinoid receptor antagonists preventing the EIH response in animals.
      • Galdino G
      • Romero TR
      • Silva JFP
      • Aguiar DC
      • de Paula AM
      • Cruz JS
      • Parrella C
      • Piscitelli F
      • Duarte ID
      • Di Marzo V
      The endocannabinoid system mediates aerobic exercise-induced antinociception in rats.
      In pain-free human adults, Koltyn et al
      • Koltyn KF
      • Brellenthin AG
      • Cook DB
      • Sehgal N
      • Hillard C
      Mechanisms of exercise-induced hypoalgesia.
      examined endocannabinoid and opioid mechanisms of EIH. Participants completed pain testing and had their blood drawn before and following isometric exercise in 2 conditions, that is, administration of an opioid antagonist and administration of a placebo. Results indicated that nonopioid mechanisms contribute to EIH and there were significant increases in circulating endocannabinoids and their associated lipids suggesting that these could contribute to EIH after isometric exercise. Thus, there is converging human and animal research supporting of the role of endocannabinoids in EIH. Furthermore, there is evidence of an interplay between the endocannabinoid and opioid systems, such that the activation of one system is mediated by the other system.
      • da Fonseca Pacheco D
      • Klein A
      • Perez AC
      • da Fonseca Pacheco CM
      • de Francischi JN
      • Reis GML
      • Duarte IDG
      Central antinociception induced by µ-opioid receptor agonist morphine, but not δ-or κ-, is mediated by cannabinoid CB1 receptor.
      For example, preclinical studies in animals involving exogenous administration of cannabinoids and opiates have indicated significant interactions between opioid and endocannabinoid systems in pain responses,
      • Welch SP.
      Interaction of the cannabinoid and opioid systems in the modulation of nociception.
      but little research has examined the interaction between these systems in EIH.
      Crombie et al
      • Crombie KM
      • Brellenthin AG
      • Hillard CJ
      • Koltyn KF
      Endocannabinoid and opioid system interactions in exercise-induced hypoalgesia.
      examined endocannabinoid and opioid system interactions in EIH in pain-free human adults. Participants were administered an opioid antagonist (naltrexone) and placebo before pain testing and exercise. Concentrations of cannabinoid ligand 2-AG increased significantly after exercise and were unaffected by naltrexone pretreatment. In contrast, increases in AEA found in the placebo condition were blocked by pretreatment with naltrexone. These results suggest that 2-AG, in particular, may be the endocannabinoid involved in EIH after isometric exercise. Moreover, the block of exercise-induced increases in AEA by naltrexone pretreatment suggests the opioid system may be involved in AEA release after exercise. Very little research has explored the role of the endocannabinoid system in EIH among people with chronic pain. Ghafouri et al
      • Ghafouri N
      • Ghafouri B
      • Larsson B
      • Stensson N
      • Fowler C
      • Gerdle B
      Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity.
      examined endocannabinoid-related lipids palmitoyletholamide and stearoylethanolamide in the trapezius muscle of 3 groups of women, including women with chronic localized shoulder myalgia, women with chronic widespread pain, and healthy controls before and after exercise consisting of 20 minutes of repetitive arm movement. Pain was found to increase during arm movement for the women with localized myalgia and chronic widespread pain, in contrast with the control group. The increase in pain intensity was found to be associated with lower levels of interstitial palmitoyletholamide and stearoylethanolamide, consistent with the hypothesis that reduced activation of the endocannabinoid system may be associated with impaired EIH. Additional research is required to further our understanding of the role of endocannabinoids and related lipids in EIH, both in pain-free and chronic pain populations.

       The Role of Serotonergic and Opioid System Interactions in EIH

      Animal experiments have indicated that opioid and serotonergic mechanisms may also interact to produce EIH.
      • Lima L
      • Abner T
      • Sluka K
      Does exercise increase or decrease pain? Central mechanisms underlying these two phenomena.
      This finding is in line with reports of antagonistic effects of mu-opioid receptor and the serotonergic serotonin 1A receptor agonists.
      • Colpaert FC
      • Deseure K
      • Stinus L
      • Adriaensen H
      High-efficacy 5-hydroxytryptamine 1A receptor activation counteracts opioid hyperallodynia and affective conditioning.
      Genetic association studies offer a unique method to assess the importance of opioid and serotonin interactions for EIH in humans without depending on invasive or pharmacologic interventions. Tour et al
      • Tour J
      • Löfgren M
      • Mannerkorpi K
      • Gerdle B
      • Larsson A
      • Palstam A
      • Bileviciute-Ljungar I
      • Bjersing J
      • Martin I
      • Ernberg M
      Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls—antagonistic effects between opioid and serotonin-related genes.
      investigated the effects of 3 functional genetic polymorphisms on EIH, both in healthy pain-free controls (n = 134) and in people with fibromyalgia (n = 130). These polymorphisms were 1) the single nucleotide polymorphism rs1799971 in the OPRM1 gene, regulating the activation of the mu-opioid receptor (G-allele associated with increased tone in the endogenous opioid system), 2) the single nucleotide polymorphism rs6295 in the HTR1a gene regulating serotonin 1A receptor expression (G-allele associated with reduced serotonergic tone), and 3) the polymorphisms 5-HTTLPR and rs25531 of the serotonin transporter (5-HTT) gene that jointly modulate 5-HTT expression. EIH was assessed by having the participants perform isometric contractions (knee extension) corresponding with 30% of their individual maximal voluntary force. The contractions were performed until exhaustion (maximum of 5 minutes). Pressure pain thresholds were determined at the deltoid muscle before and during the contraction, and the relative increase in pressure pain thresholds at the end of contraction compared with baseline was calculated as EIH. The fibromyalgia group had reduced EIH compared with controls, but none of the single polymorphisms had an effect on EIH in either group. However, significant gene-to-gene interactions were found between different combinations of opioid and serotonin genes, without statistically significant group differences. The results were in agreement with the hypothesis of antagonistic effects of opioid and serotonergic signaling on EIH as the combination of genetically inferred strong opioid tone (ORPM1 G genotype) combined with weak serotonergic signaling (5HT1a G genotype and low expressing 5-HTT) resulted in more pronounced EIH. The fibromyalgia group did not differ from controls in these respects, despite demonstrating significantly less EIH. Therefore, the data do not support an altered interaction between opioid and serotonergic polymorphisms as the basis for impaired EIH in fibromyalgia. The opposite interaction, that is, that genetically inferred low opioid tone combined with high serotonergic signaling, would yield better EIH was less consistently observed. The only statistically significant finding in this direction was that healthy controls with genetically inferred weaker opioid tone (ORPM1 AA genotype) had more pronounced EIH if they also had a stronger serotonergic tone (5HT1a CC genotype) compared with those with weak serotonergic tone (5HT1a G genotype).

       The Relationship Between EIH and Conditioned Pain Modulation

      Exercise is often painful,
      • Dannecker EA
      • Koltyn KF.
      Pain during and within hours after exercise in healthy adults.
      particularly at high intensity or in the presence of muscle fatigue, where muscle nociceptors are activated.
      • Taylor JL
      • Butler JE
      • Gandevia S
      Changes in muscle afferents, motoneurons and motor drive during muscle fatigue.
      Nociception is known to trigger the activation of endogenous descending inhibitory and facilitatory pathways from the brain,
      • Villanueva L
      • Bouhassira D
      • Le Bars D
      The medullary subnucleus reticularis dorsalis (SRD) as a key link in both the transmission and modulation of pain signals.
      which can be assessed using the conditioned pain modulation paradigm. Experimentally, conditioned pain modulation is measured by comparing pain sensitivity at one site in the body (ie, test stimulus), first in the absence of and then during or immediately after a second painful input (ie, conditioning stimulus) is applied to an anatomically distant body part.
      • Graven-Nielsen T
      • Arendt-Nielsen L.
      Assessment of mechanisms in localized and widespread musculoskeletal pain.
      Similar to EIH, in pain-free controls the conditioned pain modulation paradigm typically induces a multisegmental decrease in pain sensitivity that may involve both serotonergic
      • Chitour D
      • Dickenson AH
      • Le Bars D
      Pharmacological evidence for the involvement of serotonergic mechanisms in diffuse noxious inhibitory controls (DNIC).
      • Treister R
      • Pud D
      • Ebstein RP
      • Laiba E
      • Raz Y
      • Gershon E
      • Haddad M
      • Eisenberg E
      Association between polymorphisms in serotonin and dopamine-related genes and endogenous pain modulation.
      and opioidergic
      • Le Bars D
      • Chitour D
      • Kraus E
      • Dickenson AH
      • Besson JM
      Effect of naloxone upon diffuse noxious inhibitory controls (DNIC) in the rat.
      • Willer JC
      • Le Bars D
      • De Broucker T
      Diffuse noxious inhibitory controls in man: Involvement of an opioidergic link.
      mechanisms. Moreover, similar to EIH, conditioned pain modulation is often impaired in chronic pain populations.
      • Lewis GN
      • Rice DA
      • McNair PJ
      Conditioned pain modulation in populations with chronic pain: A systematic review and meta-analysis.
      Hence, it has been suggested that EIH and conditioned pain modulation may have shared mechanisms and that EIH occurs, at least in part, due to the activation of the same descending inhibitory pathways involved in conditioned pain modulation, which are triggered by exercise-induced activation of muscle nociceptors.
      • Ellingson LD
      • Koltyn KF
      • Kim JS
      • Cook DB
      Does exercise induce hypoalgesia through conditioned pain modulation.
      • Kosek E
      • Lundberg L.
      Segmental and plurisegmental modulation of pressure pain thresholds during static muscle contractions in healthy individuals.
      • Lemley K
      • Hunter S
      • Bement M
      Conditioned pain modulation predicts exercise-induced hypoalgesia in healthy adults.
      • Vaegter H
      • Handberg G
      • Graven-Nielsen T
      Similarities between exercise-induced hypoalgesia and conditioned pain modulation in humans.
      To further explore the similarities between conditioned pain modulation and EIH, Ellingson et al
      • Ellingson LD
      • Koltyn KF
      • Kim JS
      • Cook DB
      Does exercise induce hypoalgesia through conditioned pain modulation.
      examined changes in heat pain sensitivity in pain-free female participants under 3 conditions: quiet rest, nonpainful aerobic exercise, and matched intensity painful aerobic exercise, achieved through the partial occlusion of blood flow to the exercising lower limbs. Interestingly, both painful and nonpainful exercise decreased heat pain sensitivity, whereas quite rest had no effect. Although statistically significant differences were not observed consistently between the EIH response to painful and nonpainful exercise, the effect size of the EIH response was greater with painful exercise, and a moderate linear relationship was reported between the peak muscle pain reported during exercise and the magnitude of EIH. These findings are supported by other studies that have reported a significant association between the magnitude of conditioned pain modulation and EIH, both in healthy controls
      • Lemley KJ
      • Hunter SK
      • Bement MKH
      Conditioned Pain Modulation Predicts Exercise-Induced Hypoalgesia in Healthy Adults.
      • Stolzman S
      • Bement M.
      Does exercise decrease pain via conditioned pain modulation in adolescents.
      • Vaegter HB
      • Handberg G
      • Jørgensen MN
      • Kinly A
      • Graven-Nielsen T
      Aerobic exercise and cold pressor test induce hypoalgesia in active and inactive men and women.
      and chronic pain populations.
      • Fingleton C
      • Smart KM
      • Doody CM
      Exercise-induced hypoalgesia in people with knee osteoarthritis with normal and abnormal conditioned pain modulation.
      • Vaegter HB
      • Handberg G
      • Graven-Nielsen T
      Hypoalgesia after exercise and the cold pressor test is reduced in chronic musculoskeletal pain patients with high pain sensitivity.
      However, the strength of the association is typically weak to moderate, and findings are not always consistent, with other studies reporting no relationship between conditioned pain modulation and EIH.
      • Samuelly-Leichtag G
      • Kodesh E
      • Meckel Y
      • Weissman-Fogel I
      A fast track to hypoalgesia: The anaerobic exercise effect on pain sensitivity.
      • Vaegter H
      • Handberg G
      • Graven-Nielsen T
      Similarities between exercise-induced hypoalgesia and conditioned pain modulation in humans.
      Furthermore, because conditioned pain modulation only occurs with a painful conditioning stimulus, it cannot explain EIH observed after nonpainful exercise.
      • Ellingson LD
      • Koltyn KF
      • Kim JS
      • Cook DB
      Does exercise induce hypoalgesia through conditioned pain modulation.
      Finally, more in-depth experiments in pain-free adults have demonstrated differences in both the time course and spatial distribution of EIH and conditioned pain modulation. Vaegter et al
      • Vaegter H
      • Handberg G
      • Graven-Nielsen T
      Similarities between exercise-induced hypoalgesia and conditioned pain modulation in humans.
      • Vaegter HB
      • Handberg G
      • Jørgensen MN
      • Kinly A
      • Graven-Nielsen T
      Aerobic exercise and cold pressor test induce hypoalgesia in active and inactive men and women.
      found that conditioned pain modulation only occurred during a painful stimulus, whereas in the same group of participants, EIH continued 15 minutes after isometric contraction, at a time when conditioned pain modulation was absent. Moreover, the magnitude of EIH was greatest at sites local to the exercising muscles and weakest at remote body sites.
      • Vaegter H
      • Handberg G
      • Graven-Nielsen T
      Similarities between exercise-induced hypoalgesia and conditioned pain modulation in humans.
      In contrast, the magnitude of conditioned pain modulation was greatest at remote sites and weaker at sites closer to the painful conditioning stimulus.
      • Vaegter H
      • Handberg G
      • Graven-Nielsen T
      Similarities between exercise-induced hypoalgesia and conditioned pain modulation in humans.
      Thus, although it is possible that the same descending pain inhibitory pathways contribute to conditioned pain modulation and EIH during painful exercise, spatial and temporal differences in these responses and the presence of EIH during nonpainful exercise suggests that the neurophysiological mechanisms explaining EIH may be at least partly independent of those involved in conditioned pain modulation.

       The Potential Role of the Immune System in Impaired EIH

      The interactions between the immune and the nervous systems have been thoroughly discussed in recent decades.
      • Watkins L
      • Maier S.
      Immune regulation of central nervous system functions.
      Peripheral immune cells like macrophages and glial cells in the central nervous system can increase excitability of the nociceptive system by releasing pro-inflammatory mediators, such as IL-6.
      • Dina OA
      • Green PG
      • Levine JD
      Role of interleukin-6 in chronic muscle hyperalgesic priming.
      • Gong W-Y
      • Abdelhamid RE
      • Carvalho CS
      • Sluka KA
      Resident macrophages in muscle contribute to development of hyperalgesia in a mouse model of noninflammatory muscle pain.
      • Grace PM
      • Hutchinson MR
      • Maier SF
      • Watkins LR
      Pathological pain and the neuroimmune interface.
      People with chronic widespread pain often show altered levels of innate and adaptive markers of immune function such as the complement system, tumor necrosis factor-α, tumor necrosis factor-ß, IL-11, IL-6, IL-8, interferon (INF)-γ, C-reactive protein, and oxidative stress, whereas anti-inflammatory markers might be reduced or unaltered.
      • Bansal A
      • Bradley A
      • Bishop K
      • Kiani-Alikhan S
      • Ford B
      Chronic fatigue syndrome, the immune system and viral infection.
      • Blundell S
      • Ray K
      • Buckland M
      • White P
      Chronic fatigue syndrome and circulating cytokines: A systematic review.
      • Ortega E
      • García J
      • Bote M
      • Martín-Cordero L
      • Escalante Y
      • Saavedra J
      • Northoff H
      • Giraldo E
      Exercise in fibromyalgia and related inflammatory disorders: Known effects and unknown chances.
      • Rajeevan MS
      • Dimulescu I
      • Murray J
      • Falkenberg VR
      • Unger ER
      Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome.
      • Üçeyler N
      • Häuser W
      • Sommer C
      Systematic review with meta-analysis: Cytokines in fibromyalgia syndrome.
      A systematic review on the effect of exercise on the immune system of people with chronic inflammatory diseases showed that a single session of exercise aggravated inflammation (IL-6 and tumor necrosis factor-α).
      • Ploeger H
      • Takken T
      • de Greef M
      • Timmons B
      The effects of acute and chronic exercise on inflammatory markers in children and adults with a chronic inflammatory disease: A systematic review.
      Importantly, altered immune responses may occur within minutes of a single exercise session.
      • Jammes Y
      • Steinberg J
      • Delliaux S
      • Brégeon F
      Chronic fatigue syndrome combines increased exercise‐induced oxidative stress and reduced cytokine and Hsp responses.
      • Jammes Y
      • Steinberg J
      • Mambrini O
      • Bregeon F
      • Delliaux S
      Chronic fatigue syndrome: Assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise.
      • LaManca JJ
      • Sisto SA
      • Ottenweller JE
      • Cook S
      • Peckerman A
      • Zhang Q
      • Denny TN
      • Gause WC
      • Natelson BH
      Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion.
      Inflammatory mediators released in the periphery or in the central nervous system have the potential to activate nociceptive neurons and glial cells, contributing to sensitization and lowered pain thresholds.
      • Dina OA
      • Green PG
      • Levine JD
      Role of interleukin-6 in chronic muscle hyperalgesic priming.
      • Gong W-Y
      • Abdelhamid RE
      • Carvalho CS
      • Sluka KA
      Resident macrophages in muscle contribute to development of hyperalgesia in a mouse model of noninflammatory muscle pain.
      • Grace PM
      • Hutchinson MR
      • Maier SF
      • Watkins LR
      Pathological pain and the neuroimmune interface.
      Thus, it is possible that a further increase in inflammation could contribute to impaired EIH and/or the postexercise flare in pain that may be observed in some people with chronic pain conditions.
      • Busch AJ
      • Schachter CL
      • Overend TJ
      • Peloso PM
      • Barber KA
      Exercise for fibromyalgia: A systematic review.
      • Naugle KM
      • Fillingim RB
      • Riley III, JL
      A meta-analytic review of the hypoalgesic effects of exercise.
      • Nijs J
      • Nees A
      • Paul L
      • Kooning D
      • Ickmans K
      • Meeus M
      • Oosterwijck V
      Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyeltitis: A systematic literature review.
      Indeed, complement system,
      • Sorensen B
      • Jones JF
      • Vernon SD
      • Rajeevan MS
      Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome.
      • Sorensen B
      • Streib JE
      • Strand M
      • Make B
      • Giclas PC
      • Fleshner M
      • Jones JF
      Complement activation in a model of chronic fatigue syndrome.
      oxidative stress,
      • Jammes Y
      • Steinberg J
      • Mambrini O
      • Bregeon F
      • Delliaux S
      Chronic fatigue syndrome: Assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise.
      IL-10 and toll-like receptor-4 gene expression
      • Light AR
      • White AT
      • Hughen RW
      • Light KC
      Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects.
      • Nijs J
      • Nees A
      • Paul L
      • Kooning D
      • Ickmans K
      • Meeus M
      • Oosterwijck V
      Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyeltitis: A systematic literature review.
      have been found to be associated with symptom exacerbations after a single bout of exercise in people with chronic widespread pain associated with chronic fatigue syndrome.
      However, the effects of altered immune responses on impaired EIH and/or postexercise pain is far from conclusive. Other studies in people with chronic widespread pain associated with chronic fatigue syndrome failed to find an exercise-induced alteration of complement system or toll-like receptor-4, despite exercise induced symptoms worsening.
      • Keech A
      • Vollmer-Conna U
      • Barry B
      • Lloyd A
      Gene expression in response to exercise in patients with chronic fatigue syndrome: A pilot study.
      • Nijs J
      • Van Oosterwijck J
      • Meeus M
      • Lambrecht L
      • Metzger K
      • Frémont M
      • Paul L
      Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: The role of elastase, complement C4a and interleukin‐1β.
      Furthermore, in people with knee OA, a single session of resistance exercise was shown increase the level of IL-10, an anti-inflammatory cytokine.
      • Helmark IC
      • Mikkelsen UR
      • Børglum J
      • Rothe A
      • Petersen MC
      • Andersen O
      • Langberg H
      • Kjaer M
      Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: A randomized controlled trial.
      A similar anti-inflammatory response has also been reported in a study of people with fibromyalgia.
      • Bote M
      • García J
      • Hinchado M
      • Ortega E
      An exploratory study of the effect of regular aquatic exercise on the function of neutrophils from women with fibromyalgia: Role of IL-8 and noradrenaline.
      Unfortunately, no clinical measures were taken in these studies to allow the relationship between immune system changes and pain to be evaluated. More work exploring the potential link between the immune system and impaired EIH in different chronic pain populations is warranted.

       The Potential Role of the Autonomic Nervous System in EIH, Including Cerebral Blood Flow

      Both pain and exercise activate the body's stress response systems, including the hypothalamus-pituitary-adrenal axis and autonomic nervous system.
      • Chrousos GP
      • Gold PW.
      The concepts of stress and stress system disorders: Overview of physical and behavioral homeostasis.
      • Kvetnanský R
      • Pacák K
      • Fukuhara K
      • Viskupic E
      • Hiremagalur B
      • Nankova B
      • Goldstein D
      • Sabban E
      • Kopin I
      Sympathoadrenal system in stress. Interaction with the hypothalamic-pituitary-adrenocortical system.
      This results in the release of stress hormones like (nor)adrenaline and cortisol, which exert analgesic effects at the level of the brain (eg, noradrenaline is an important neurotransmitter for enabling descending nociceptive inhibition
      • Millan MJ.
      Descending control of pain.
      ) and spinal cord (eg, dorsal horn neurons contain glucocorticoid receptors, having nociceptive inhibitory capacity
      • McLean SA
      • Clauw DJ
      • Abelson JL
      • Liberzon I
      The development of persistent pain and psychological morbidity after motor vehicle collision: Integrating the potential role of stress response systems into a biopsychosocial model.
      ). In addition, the autonomic nervous system is responsible for cardiac output and blood distribution (vasodilatation) to the exercising muscle, which has potential implications for muscle fatigue, ischemia, and muscle nociceptor activation in the context of EIH. In people with chronic widespread pain, lower parasympathetic activity rather than dysregulated sympathetic tone is associated with greater pain intensity, suggesting that intense pain is a chronic stressor interfering with parasympathetic activity.
      • Barakat A
      • Vogelzangs N
      • Licht CM
      • Geenen R
      • MacFarlane GJ
      • de Geus EJ
      • Smith JH
      • Penninx BW
      • Dekker J
      Dysregulation of the autonomic nervous system and its association with the presence and intensity of chronic widespread pain.
      Autonomic nervous system function can be evaluated by measuring heart rate variability (ie, the variation over time of the period between consecutive heartbeats), with a greater heart rate variability corresponding with better parasympathetic tone.
      Heart rate variability is also related to cerebral blood flow.
      • Jones JB
      • Shatat IF
      • Egan BM
      • Paulo RC
      Decreased heart rate variability is associated with increased transcranial Doppler velocities in children with sickle cell disease.
      Cerebral autoregulation aims at maintaining an adequate and stable cerebral blood flow. During exercise, perfusion pressure may exceed the autoregulatory range (60–160 mm Hg),
      • Ogoh S.
      Autonomic control of cerebral circulation: Exercise.
      which in turn requires activation of the baroreceptor reflex to restore “normal” cerebral blood flow.
      • Miyazawa T
      • Horiuchi M
      • Ichikawa D
      • Sato K
      • Tanaka N
      • Bailey DM
      • Ogoh S
      Kinetics of exercise-induced neural activation; interpretive dilemma of altered cerebral perfusion.
      Available evidence suggests that experimentally induced pain leads to a decrease in global cerebral blood flow (velocity).
      • Micieli G
      • Tassorelli C
      • Bosone D
      • Cavallini A
      • Viotti E
      • Nappi G
      Intracerebral vascular changes induced by cold pressor test: A model of sympathetic activation.
      However, less is understood about cerebral blood flow in chronic pain conditions or whether autonomic dysfunction is related to EIH. To investigate this hypothesis, a recent study examined cerebral blood flow and heart rate variability changes in response to exercise and emotional stress in healthy, pain-free controls and patients suffering from chronic widespread pain associated with chronic fatigue syndrome.
      • Malfliet A
      • Pas R
      • Brouns R
      • De JW
      • Hatem S
      • Meeus M
      • Ickmans K
      • Nijs J
      Cerebral blood flow and heart rate variability in chronic fatigue syndrome: A randomized cross-over study.
      It was found that both groups display a similar and normal decrease in heart rate variability during physical exercise, which normalizes (back to baseline values) during emotional stress.
      • Malfliet A
      • Pas R
      • Brouns R
      • De JW
      • Hatem S
      • Meeus M
      • Ickmans K
      • Nijs J
      Cerebral blood flow and heart rate variability in chronic fatigue syndrome: A randomized cross-over study.
      Likewise, none of the cerebral blood flow parameters differed between groups, and both groups showed a similar cerebral blood flow evolution over the different experimental conditions, despite an impaired EIH response being observed in the group with chronic widespread pain.
      • Malfliet A
      • Pas R
      • Brouns R
      • De JW
      • Hatem S
      • Meeus M
      • Ickmans K
      • Nijs J
      Cerebral blood flow and heart rate variability in chronic fatigue syndrome: A randomized cross-over study.
      Neither changes in heart rate variability nor cerebral blood flow were associated with EIH efficacy or symptoms of postexertional malaise.
      • Malfliet A
      • Pas R
      • Brouns R
      • De JW
      • Hatem S
      • Meeus M
      • Ickmans K
      • Nijs J
      Cerebral blood flow and heart rate variability in chronic fatigue syndrome: A randomized cross-over study.
      These results fail to provide evidence of a role for dysregulated autonomic control of cerebral blood flow or heart rate variability in explaining pain exacerbations after exercise or emotional stress in people with chronic widespread pain associated with chronic fatigue syndrome.

      Sex Effects on EIH

      As outlined in different reviews,
      • Berkley KJ.
      Sex differences in pain.
      • Fillingim RB
      • King CD
      • Ribeiro-Dasilva MC
      • Rahim-Williams B
      • Riley JL
      Sex, gender, and pain: A review of recent clinical and experimental findings.
      • Unruh AM.
      Gender variations in clinical pain experience.
      there is substantial evidence of sex differences in chronic pain, with higher prevalence rates among women in many chronic pain diagnoses and, at least in some studies, greater pain intensity ratings in females. A higher female prevalence occurs in many chronic pain conditions where an impaired EIH response also has been observed, including fibromyalgia, chronic widespread pain, and WAD (Table 1). Thus, it could be hypothesized that sex differences may at least partly explain the impaired EIH that is often observed in these conditions.
      However, studies to date provide no evidence that EIH is less efficient in females. A number of laboratory studies in pain-free adults have addressed the question of sex differences in pain sensitivity and endogenous pain inhibition, including the EIH response. Although early reviews suggested increased pain sensitivity in women,
      • Fillingim RB
      • King CD
      • Ribeiro-Dasilva MC
      • Rahim-Williams B
      • Riley JL
      Sex, gender, and pain: A review of recent clinical and experimental findings.
      • Unruh AM.
      Gender variations in clinical pain experience.
      a comprehensive systematic review analyzing 172 articles published between 1998 and 2008 came to the conclusion that sex differences in pain sensitivity are dependent on the type of stimulus.
      • Racine M
      • Tousignant-Laflamme Y
      • Kloda LA
      • Dion D
      • Dupuis G
      • Choinière M
      A systematic literature review of 10 years of research on sex/gender and experimental pain perception–Part 1: Are there really differences between women and men?.
      Although men and women showed comparable thresholds for cold and ischemic pain, thresholds for pressure pain seem to be lower in females.
      • Racine M
      • Tousignant-Laflamme Y
      • Kloda LA
      • Dion D
      • Dupuis G
      • Choinière M
      A systematic literature review of 10 years of research on sex/gender and experimental pain perception–Part 1: Are there really differences between women and men?.
      Furthermore, pain tolerance times for thermal and pressure pain were shorter for women compared with men, but comparable for ischemic pain.
      • Racine M
      • Tousignant-Laflamme Y
      • Kloda LA
      • Dion D
      • Dupuis G
      • Choinière M
      A systematic literature review of 10 years of research on sex/gender and experimental pain perception–Part 1: Are there really differences between women and men?.
      Studies examining sex differences in the severity of delayed onset muscle soreness after exercise are also equivocal.
      • Dannecker EA
      • Hausenblas HA
      • Kaminski TW
      • Robinson ME
      Sex differences in delayed onset muscle pain.
      • Flores DF
      • Gentil P
      • Brown LE
      • Pinto RS
      • Carregaro RL
      • Bottaro M
      Dissociated time course of recovery between genders after resistance exercise.
      With respect to EIH in pain-free adults, some studies report no sex differences,
      • Brellenthin AG
      • Crombie KM
      • Cook DB
      • Sehgal N
      • Koltyn KF
      Psychosocial influences on exercise-induced hypoalgesia.
      • Koltyn KF
      • Brellenthin AG
      • Cook DB
      • Sehgal N
      • Hillard C
      Mechanisms of exercise-induced hypoalgesia.
      • Naugle KM
      • Naugle KE
      • Fillingim RB
      • Riley 3rd JL
      Isometric exercise as a test of pain modulation: Effects of experimental pain test, psychological variables, and sex.
      whereas, surprisingly, several other studies report more robust EIH in women after both isometric
      • Gajsar H
      • Titze C
      • Hasenbring MI
      • Vaegter HB
      Isometric back exercise has different effect on pressure pain thresholds in healthy men and women.
      • Koltyn KF
      • Trine MR
      • Stegner A
      • Tobar D
      Effect of isometric exercise on pain perception and blood pressure in men and women.
      • Lemley K
      • Senefeld J
      • Hunter S
      • Bement MH
      Only women report increase in pain threshold following fatiguing contractions of the upper extremity.
      • Lemley KJ
      • Hunter SK
      • Bement MKH
      Conditioned Pain Modulation Predicts Exercise-Induced Hypoalgesia in Healthy Adults.
      and aerobic exercise.
      • Sternberg WF
      • Boka C
      • Kas L
      • Alboyadjia A
      • Gracely RH
      Sex-dependent components of the analgesia produced by athletic competition.
      • Vaegter H
      • Handberg G
      • Graven-Nielsen T
      Similarities between exercise-induced hypoalgesia and conditioned pain modulation in humans.
      Although the potential mechanisms remain unclear, it is possible that this effect may be at least partially ascribed to lower baseline pain thresholds in women (eg,
      • Koltyn KF
      • Trine MR
      • Stegner A
      • Tobar D
      Effect of isometric exercise on pain perception and blood pressure in men and women.
      • Lemley KJ
      • Hunter SK
      • Bement MKH
      Conditioned Pain Modulation Predicts Exercise-Induced Hypoalgesia in Healthy Adults.
      ), potentially leading to a larger relative change in pain sensitivity with exercise. However, other studies observed stronger EIH in females despite no baseline sex differences in pain sensitivity.
      • Gajsar H
      • Titze C
      • Hasenbring MI
      • Vaegter HB
      Isometric back exercise has different effect on pressure pain thresholds in healthy men and women.
      • Lemley K
      • Senefeld J
      • Hunter S
      • Bement MH
      Only women report increase in pain threshold following fatiguing contractions of the upper extremity.
      Thus, results of laboratory research in pain-free adults remain inconclusive regarding possible sex differences in EIH, leaving findings of impaired EIH in chronic pain disorders with a greater prevalence in women (eg, fibromyalgia and WAD) largely unanswered. When it comes to sex differences in EIH among chronic pain populations, much less in known. One study explored possible sex differences in EIH in patients with chronic WAD, but failed to find any differences.
      • Ickmans K
      • Malfliet A
      • De Kooning M
      • Goudman L
      • Hubloue I
      • Schmitz T
      • Goubert D
      • Aguilar-Ferrandiz M
      Lack of gender and age differences in pain measurements following exercise in people with chronic whiplash-associated disorders.

      Psychosocial Influences on EIH

      Research indicates that psychosocial factors contribute to the experience of pain in both healthy and patient populations.
      • Goodin BR
      • McGuire L
      • Allshouse M
      • Stapleton L
      • Haythornthwaite JA
      • Burns N
      • Mayes LA
      • Edwards RR
      Associations between catastrophizing and endogenous pain-inhibitory processes: Sex differences.
      • Jensen MP
      • Moore MR
      • Bockow TB
      • Ehde DM
      • Engel JM
      Psychosocial factors and adjustment to chronic pain in persons with physical disabilities: A systematic review.
      However, less is known regarding the impact of psychosocial factors on EIH. Only a limited number of studies have been conducted in this area, but some studies in healthy, pain-free adults suggest that EIH can be influenced by psychosocial factors. Pain catastrophizing, for example, which is characterized by maladaptive emotional and cognitive processes (ie, perception of helplessness, rumination, and magnification of painful sensations) has been found to attenuate the EIH response and was associated with increased ratings of perceived exertion and muscle pain during exercise in healthy adults.
      • Brellenthin AG
      • Crombie KM
      • Cook DB
      • Sehgal N
      • Koltyn KF
      Psychosocial influences on exercise-induced hypoalgesia.
      • Naugle KM
      • Naugle KE
      • Fillingim RB
      • Riley 3rd JL
      Isometric exercise as a test of pain modulation: Effects of experimental pain test, psychological variables, and sex.
      • Weissman-Fogel I
      • Sprecher E
      • Pud D
      Effects of catastrophizing on pain perception and pain modulation.
      Fear of pain and mood disturbance have also been reported to attenuate the hypoalgesic response after exercise in healthy adults.
      • Brellenthin AG
      • Crombie KM
      • Cook DB
      • Sehgal N
      • Koltyn KF
      Psychosocial influences on exercise-induced hypoalgesia.
      Furthermore, family-related factors such as family environment and a family history of chronic pain seem to influence EIH. Positive family environments were found to predict greater EIH, whereas negative and chronic pain-present family environments predicted worse pain and EIH outcomes.
      • Brellenthin AG
      • Crombie KM
      • Cook DB
      • Sehgal N
      • Koltyn KF
      Psychosocial influences on exercise-induced hypoalgesia.
      Less is known regarding the relationship between psychosocial factors and EIH in adults with chronic pain. However, findings to date provide no evidence that selected psychosocial factors are associated with EIH in chronic pain populations. For example, in adults with chronic musculoskeletal pain, anxiety, depression, and pain catastrophizing did not predict changes in pressure pain thresholds after exercise,
      • Vaegter HB
      • Handberg G
      • Graven-Nielsen T
      Hypoalgesia after exercise and the cold pressor test is reduced in chronic musculoskeletal pain patients with high pain sensitivity.
      and kinesiophobia (ie, fear of movement or injury) was not found to be associated with EIH.
      • Vægter HB
      • Madsen AB
      • Handberg G
      • Graven-Nielsen T
      Kinesiophobia is associated with pain intensity but not pain sensitivity before and after exercise: An explorative analysis.
      Similarly, no relationship was found between state anxiety and EIH in women with fibromyalgia
      • Hoeger Bement MK
      • Weyer A
      • Hartley S
      • Drewek B
      • Harkins A
      • Hunter SK
      Pain perception after isometric exercise in women with fibromyalgia.
      and in adults with chronic WAD, the relationship between selected psychosocial factors (ie, pain catastrophizing, kinesiophobia, and stress symptoms) and EIH were examined, and results indicated no significant associations between the change in pressure pain sensitivity and psychosocial factors.
      • Smith A
      • Ritchie C
      • Pedler A
      • McCamley K
      • Roberts K
      • Sterling M
      Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders.
      Exercise should be considered both a physiological and a psychological stressor. However, whether the way exercise is perceived changes the EIH response is relatively unexplored. People who perceive exercising as potentially harmful or uncontrollable might respond differently to exercise. The stress literature offers interesting insights on this. Animal studies show that voluntarily wheel running improves health, reducing stress and inflammation.
      • Duman CH
      • Schlesinger L
      • Russell DS
      • Duman RS
      Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice.
      On the contrary, forced—and thus uncontrollable—exercise can induce detrimental effects, including increased inflammation and a heightened stress response.
      • Cook MD
      • Martin SA
      • Williams C
      • Whitlock K
      • Wallig MA
      • Pence BD
      • Woods JA
      Forced treadmill exercise training exacerbates inflammation and causes mortality while voluntary wheel training is protective in a mouse model of colitis.
      • Svensson M
      • Rosvall P
      • Boza-Serrano A
      • Andersson E
      • Lexell J
      • Deierborg T
      Forced treadmill exercise can induce stress and increase neuronal damage in a mouse model of global cerebral ischemia.
      In healthy, pain-free humans, a minor increase (10%) in exercise intensity beyond the level that the participants would choose for themselves can significantly decrease pleasantness, with no additional fitness gains.
      • Lind E
      • Ekkekakis P
      • Vazou S
      The affective impact of exercise intensity that slightly exceeds the preferred level: 'Pain' for no additional 'gain'.
      In general, increasing perceived control alleviates stress and increases activity levels.
      • Bhanji JP
      • Kim ES
      • Delgado MR
      Perceived control alters the effect of acute stress on persistence.
      Very little of this evidence has been transferred to the context of EIH. However, in pain-free adults when a physical stimulus is perceived as more threatening, pain tolerance decreases.
      • Wang Y
      • Jackson T
      • Cai L
      Causal effects of threat and challenge appraisals on coping and pain perception.
      In addition, specific education about the beneficial and hypoalgesic (thus safe) effects of exercise, seems to increase the magnitude of EIH, at least in healthy controls.
      • Jones MD
      • Valenzuela T
      • Booth J
      • Taylor JL
      • Barry BK
      Explicit education about exercise-induced hypoalgesia influences pain responses to acute exercise in healthy adults: A randomized controlled trial.
      The evidence is less clear in chronic pain populations. Van Oosterwijck et al
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Lefever I
      • Huybrechts L
      • Lambrecht L
      • Paul L
      Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study.
      manipulated exercise intensity in patients with chronic widespread pain associated with chronic fatigue syndrome. Although one exercise was a submaximal one, the other was a self-paced, physiologically limited bout of exercise. Both exercises had negative effects on participants, increasing pain and worsening their other symptoms such as fatigue. This finding seems to contradict the evidence cited, because the second bout of exercise was specifically design to decrease threat and increase safety. A possible explanation is that people with chronic fatigue syndrome are arguably the people that fear physical activity the most. Exercise itself—even if self-paced and controllable—may be perceived as harmful, facilitating negative responses. Additional research is required to further explore other psychosocial factors and different chronic pain conditions to expand our understanding of the relationship between psychosocial factors and EIH, both in pain-free adults and chronic pain populations.

      How Should We Address Impaired EIH in Clinical Practice?

      Although it is clear that impaired EIH occurs in some people with chronic pain, how should this issue be addressed in clinical practice? The vast majority of the literature on exercise prescription in the context of rehabilitation focuses on matching exercise parameters to fitness levels. In this context, exercise is designed to reverse deconditioning and may be based on factors relating to strength, cardiovascular function, biomechanics, and/or flexibility. However, basing exercise prescription on fitness levels alone will likely be problematic for people with impaired EIH.
      • Daenen L
      • Varkey E
      • Kellmann M
      • Nijs J
      Exercise, not to exercise or how to exercise in patients with chronic pain? Applying science to practice.
      • Nijs J
      • Kosek E
      • Van Oosterwijck J
      • Meeus M
      Dysfunctional endogenous analgesia during exercise in patients with chronic pain: To exercise or not to exercise.
      • Wideman TH
      • Edwards RR
      • Finan PH
      • Haythornthwaite JA
      • Smith MT
      Comparing the predictive value of task performance and task-specific sensitivity during physical function testing among people with knee osteoarthritis.
      • Wideman TH
      • Finan PH
      • Edwards RR
      • Quartana PJ
      • Buenaver LF
      • Haythornthwaite JA
      • Smith MT
      Increased sensitivity to physical activity among individuals with knee osteoarthritis: Relation to pain outcomes, psychological factors and responses to quantitative sensory testing.
      For these people, pain exacerbations are a major barrier to activity engagement that likely needs to be addressed for them to benefit from treatment. Unfortunately, there is currently very little evidence to specifically inform us how to tailor the parameters of exercise prescription for those people with impaired EIH.
      Although the role of psychosocial factors in impaired EIH remains unclear, the broader literature exploring how to increase exercise engagement among people living with pain suggests that decreasing the threat value of pain and movement may be an effective way of helping these people.
      • Louw A
      • Zimney K
      • Puentedura EJ
      • Diener I
      The efficacy of pain neuroscience education on musculoskeletal pain: A systematic review of the literature.
      • Moseley GL
      • Butler DS.
      Fifteen years of explaining pain: The past, present, and future.
      • Vlaeyen JWS
      • Crombez G
      • Linton SJ
      The fear-avoidance model of pain.
      • Vlaeyen JWS
      • Linton SJ.
      Fear-avoidance model of chronic musculoskeletal pain: 12 years on.
      • Wideman TH
      • Asmundson GGJ
      • Smeets RJEM
      • Zautra AJ
      • Simmonds MJ
      • Sullivan MJL
      • Haythornthwaite JA
      • Edwards RR
      Rethinking the fear avoidance model: Toward a multidimensional framework of pain-related disability.
      For instance, recent work has highlighted the potential advantages of applying therapeutic neuroscience education and cognitive interventions (eg, graded exposure) within the context of physical activity to specifically help people with chronic pain reappraise the threat value that they associate with pain and movement.
      • Malfliet A
      • Kregel J
      • Meeus M
      • Cagnie B
      • Roussel N
      • Dolphens M
      • Danneels L
      • Nijs J
      Applying contemporary neuroscience in exercise interventions for chronic spinal pain: Treatment protocol.
      • Nijs J
      • Lluch Girbés E
      • Lundberg M
      • Malfliet A
      • Sterling M
      Exercise therapy for chronic musculoskeletal pain: Innovation by altering pain memories.
      As a starting point, clinicians can explain EIH when delivering a pain neuroscience education intervention before delivering a therapeutic exercise program. For instance, when explaining descending nociceptive inhibition clinicians can use a Socratic-style dialogue
      • Siemonsma PC
      • Schroder CD
      • Dekker JH
      • Lettinga AT
      The benefits of theory for clinical practice: Cognitive treatment for chronic low back pain patients as an illustrative example.
      to explain that exercise can activate it, resulting in hypoalgesia. Clinicians can also highlight that people with chronic pain may experience hyperalgesic responses to the early stages of an exercise program, which can result in more pain. Again, Socratic-style dialogue can be used to discuss the threat value of such pain flares after exercise (eg, Does it imply more damage in the muscles or joints?). When integrated in a comprehensive pain neuroscience education program, people with impaired EIH are expected to benefit through decreases in their catastrophic thinking about potential exercise-induced symptom flares, increased acceptance about such flares, and improved confidence that these negative reactions will dissipate with time.

      Future Research Perspectives

      An important question that remains largely unexplored is whether combining exercise with other interventions might help to restore impaired EIH. For example, pain neuroscience education emphasizing the hypoalgesic effects of exercise seems to enhance the EIH response in healthy controls,
      • Jones MD
      • Valenzuela T
      • Booth J
      • Taylor JL
      • Barry BK
      Explicit education about exercise-induced hypoalgesia influences pain responses to acute exercise in healthy adults: A randomized controlled trial.
      but this has not yet been examined in chronic pain populations with decreased EIH. Similarly, the use of centrally acting analgesics (eg, serotonin-noradrenaline reuptake inhibitors) in combination with exercise interventions has been suggested, especially in the early phase of exercise programs.
      • Nijs J
      • Kosek E
      • Van Oosterwijck J
      • Meeus M
      Dysfunctional endogenous analgesia during exercise in patients with chronic pain: To exercise or not to exercise.
      Yet studies exploring this combination are currently lacking. Emerging work suggests that certain analgesic interventions may have unique benefits for decreasing pain during activity.
      • Srikandarajah S
      • Gilron I.
      Systematic review of movement-evoked pain versus pain at rest in postsurgical clinical trials and meta-analyses: A fundamental distinction requiring standardized measurement.
      For instance, several placebo-controlled studies suggest that transcutaneous electrical nerve stimulation can specifically improve movement-related pain, even when levels of pain at rest remain unchanged.
      • Dailey DL
      • Rakel BA
      • Vance CGT
      • Liebano RE
      • Amrit AS
      • Bush HM
      • Lee KS
      • Lee JE
      • Sluka KA
      Transcutaneous electrical nerve stimulation reduces pain, fatigue and hyperalgesia while restoring central inhibition in primary fibromyalgia.
      • Rakel B
      • Frantz R.
      Effectiveness of transcutaneous electrical nerve stimulation on postoperative pain with movement.
      • Vance CGT
      • Dailey DL
      • Rakel BA
      • Sluka KA
      Using TENS for pain control: The state of the evidence.
      These findings may have particular clinical importance for rehabilitation professionals, because transcutaneous electrical nerve stimulation is commonly used at rest and may be have some added value when used in conjunction with exercise.
      To date, most studies of EIH have focused on comparing between-group differences among people living with different chronic pain conditions versus individuals who are pain free.
      • Daenen L
      • Varkey E
      • Kellmann M
      • Nijs J
      Exercise, not to exercise or how to exercise in patients with chronic pain? Applying science to practice.
      • Naugle KM
      • Fillingim RB
      • Riley JL
      A meta-analytic review of the hypoalgesic effects of exercise.
      • Nijs J
      • Kosek E
      • Van Oosterwijck J
      • Meeus M
      Dysfunctional endogenous analgesia during exercise in patients with chronic pain: To exercise or not to exercise.
      This type of research is essential to better understand and characterize the mechanisms that underlie EIH. However, it provides little guidance in understanding and characterizing the within-group clinical differences related to EIH. For instance, it remains unclear whether the prognoses of patients with similar pain conditions (eg, nonspecific low back pain) differ based on their individual levels of EIH. The development of this within-group line of research is essential to characterize the clinical prognostic profiles related to EIH and to subsequently develop tailored interventions for people with impaired EIH. Preliminary findings suggest that such an approach holds promise.
      • Vaegter HB
      • Handberg G
      • Emmeluth C
      • Graven-Nielsen T
      Preoperative hypoalgesia after cold pressor test and aerobic exercise is associated with pain relief 6 months after total knee replacement.
      Establishing the measurement reliability of the EIH response is also fundamental for understanding its future clinical implications. At this time, only one study has assessed the test–retest reliability of the EIH response, measured using the change in pressure pain threshold in response to aerobic exercise in healthy subjects.
      • Vaegter HB
      • Dørge DB
      • Schmidt KS
      • Jensen AH
      • Graven-Nielsen T
      Test-retest reliability of exercise-induced hypoalgesia after aerobic exercise.
      Although pressure pain threshold measurements alone showed excellent reliability (intraclass correlation coefficients of >.8), the between-session reliability of the EIH response was only fair (intraclass correlation coefficient of .45) and agreement in EIH responders between sessions was not significant. Further research examining the test–retest reliability of the EIH response is needed, including in chronic pain populations and with other forms of exercise (ie, dynamic and/or isometric resistance exercise). Moreover, rather than assessing EIH as an isolated phenomenon, it should be combined with other quantitative sensory testing measures of pronociceptive and antinociceptive function. This research is important both for improving the mechanistic understanding of EIH and for developing an individualized approach that may better predict those patients who are likely to be EIH responders.
      Few studies have actively explored the effects of varying exercise dose on EIH in chronic pain populations. Some studies
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Lefever I
      • Huybrechts L
      • Lambrecht L
      • Paul L
      Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study.
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Van Loo M
      • Paul L
      Lack of endogenous pain inhibition during exercise in people with chronic whiplash associated disorders: An experimental study.
      have directly compared the EIH response after a prescribed aerobic exercise intensity (eg, 75% of heart rate maximum) with a condition where aerobic exercise intensity is self-selected. Despite self-selection leading to a significantly decreased exercise intensity and lower ratings of perceived exertion, these studies have largely failed to find a difference in the magnitude of EIH between prescribed and self-selected exercise intensities.
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Lefever I
      • Huybrechts L
      • Lambrecht L
      • Paul L
      Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study.
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Van Loo M
      • Paul L
      Lack of endogenous pain inhibition during exercise in people with chronic whiplash associated disorders: An experimental study.
      In addition, many studies exploring EIH in chronic pain populations have used exercise doses that may not accurately reflect clinical practice. For example, several have used aerobic exercise protocols that last <15 minutes in duration.
      • Ickmans K
      • Malfliet A
      • De Kooning M
      • Goudman L
      • Hubloue I
      • Schmitz T
      • Goubert D
      • Aguilar-Ferrandiz M
      Lack of gender and age differences in pain measurements following exercise in people with chronic whiplash-associated disorders.
      • Malfliet A
      • Pas R
      • Brouns R
      • De JW
      • Hatem S
      • Meeus M
      • Ickmans K
      • Nijs J
      Cerebral blood flow and heart rate variability in chronic fatigue syndrome: A randomized cross-over study.
      • Meeus M
      • Roussel NA
      • Truijen S
      • Nijs J
      Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study.
      • Van Oosterwijck J
      • Marusic U
      • De Wandele I
      • Paul L
      • Meeus M
      • Moorkens G
      • Lambrecht L
      • Danneels L
      • Nijs J
      The role of autonomic function in exercise-induced endogenous analgesia: A case-control study in myalgic encephalomyelitis/chronic fatigue syndrome and healthy people.
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Lefever I
      • Huybrechts L
      • Lambrecht L
      • Paul L
      Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study.
      • Van Oosterwijck J
      • Nijs J
      • Meeus M
      • Van Loo M
      • Paul L
      Lack of endogenous pain inhibition during exercise in people with chronic whiplash associated disorders: An experimental study.
      • Vierck CJ
      • Staud R
      • Price DD
      • Cannon RL
      • Mauderli AP
      • Martin AD
      The effect of maximal exercise on temporal summation of second pain (windup) in patients with fibromyalgia syndrome.
      Furthermore, EIH studies using resistance exercise have often used isometric, rather than dynamic, resistance exercises and, typically, these are performed at low loads (10–30% of maximum voluntary contraction), with a single muscle contraction held for several minutes.
      • Kadetoff D
      • Kosek E.
      The effects of static muscular contraction on blood pressure, heart rate, pain ratings and pressure pain thresholds in healthy individuals and patients with fibromyalgia.
      • Kosek E
      • Ekholm J
      • Hansson P
      Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls.
      • Lannersten L
      • Kosek E.
      Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
      • Löfgren M
      • Opava CH
      • Demmelmaier I
      • Fridén C
      • Lundberg IE
      • Nordgren B
      • Kosek E
      Pain sensitivity at rest and during muscle contraction in persons with rheumatoid arthritis: A substudy within the Physical Activity in Rheumatoid Arthritis 2010 study.
      • Staud R
      • Robinson ME
      • Price DD
      Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls.
      • Tour J
      • Löfgren M
      • Mannerkorpi K
      • Gerdle B
      • Larsson A
      • Palstam A
      • Bileviciute-Ljungar I
      • Bjersing J
      • Martin I
      • Ernberg M
      Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls—antagonistic effects between opioid and serotonin-related genes.