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Temporal and Spatial Manifestations of
Exercise-induced Hypoalgesia and Conditioned Pain Modulation
Henrik Bjarke Vægter, MSc, PT
PhD Thesis
Pain Center South
Department of Anesthesiology and Intensive Care Medicine
University Hospital Odense
Heden 9, Entrance 201
DK - 5000 Odense C
Phone: +45 60 61 68 64. Email: henrik@vaegter.com
The primary objective of this PhD thesis was to investigate the temporal and spatial manifestations of exercise-induced hypoalgesia (EIH) and conditioned pain modulation (CPM) in healthy subjects and in patients with chronic musculoskeletal pain. The thesis is based on the four peer-reviewed papers, introduced below, which are referred to in the text as I-IV. The papers are based on three separate experiments, which have been conducted in the period 2011-2014 at Pain Center South, Department of Anesthesiology and Intensive Care Medicine, University Hospital Odense (OUH), Denmark. This PhD has been a collaboration between Pain Center South and Center for Sensory-Motor Interaction (SMI), Faculty of Medicine, Aalborg University. I: Vaegter, H. B., Handberg, G., Graven-Nielsen, T. (2014). Similarities between exercise-induced hypoalgesia and conditioned pain modulation in humans. Pain 155:158-167. II: Vaegter, H. B., Handberg, G., Jørgensen, M. N., Kinly, A., Graven-Nielsen, T. (2014). Aerobic exercise and cold pressor test induce hypoalgesia in active and inactive men and women. Pain Med: III: Vaegter, H. B., Handberg, G., Graven-Nielsen, T. (2014). Isometric exercises reduce temporal summation of pressure pain in humans. Eur J Pain: In Press IV: Vaegter, H. B., Handberg, G., Graven-Nielsen, T. (2014). Hypoalgesia after exercise and cold pressor test are reduced in chronic musculoskeletal pain patients with high pain sensitivity. Submitted ACKNOWLEDGEMENTS First of all, I wish to express my gratitude to my main supervisor Professor Thomas Graven-Nielsen, Dr.Med.Sci., PhD, Aalborg University, for his support, constructive criticism and discussions during the last three years, always providing clarity on difficult scientific issues. I would also like to thank my supervisor Gitte Handberg, MD, head of Pain Center South, for practical assistance, personal encouragement and for believing in me. A special thank you to all the volunteers and patients, who participated in the experiments. Without you, this thesis would not have been possible. I have benefitted from the input from several people to whom I wish to express my gratitude: Maria Nøregård Jørgensen and Anna Kinly for their collaboration on paper II. Wicky Jøhnk Lund, Henriette Thomsen, Benedikte Jørgensen and Sofie Marie Vægter for assistance with data entry. Sara Finocchieti, PhD, Kristian Kjær Petersen, PhD, and Julie Gade for technical assistance with data extraction. Ann Vægter for reviewing my spelling, punctuation and use of the English language. The inspiring clinical staff at Pain Center South, who has helped create a research friendly atmosphere. I appreciate the great scientific and social time spent with my fellow PhD-students, especially Thorvaldur Skuli Palson, PhD, Kristian Kjær Petersen, PhD, and Steffan Wittrup Christensen at the Center for Sensory Motor Interaction, Aalborg University. Finally, but not least, I would like to give a special thank you to my lovely, patient and very supportive wife, Sofie Marie Vægter, and my two fantastic girls, Aprilia and Aya-Mai. I owe you big time. The experiments in this thesis have in part been supported by grants from the philanthropic foundation TrygFonden, The Danish Rheumatism Association, The Fund for Physiotherapy in Private Practice and The Research Foundation of the Danish Physiotherapy Association. ABBREVIATIONS AND ACRONYMS CPM Conditioned pain modulation
Exercise-induced hypoalgesia QST Quantitative sensory testing
CONDITIONED PAIN MODULATION: The term ‘conditioned pain modulation' is not defined in the IASP terminology. It has been used throughout this thesis to denote the effect (i.e. inhibitory or facilitatory) on the pain test stimulus (i.e. pressure pain) after applying a painful conditioning stimulus (i.e. cold pressor test). HYPOALGESIA: The term ‘hypoalgesia' has been used throughout this thesis in agreement with the IASP taxonomy to denote Diminished pain in response to a normally painful stimulus. PAIN THRESHOLD: The term ‘pain threshold' has been used throughout this thesis in agreement with the IASP taxonomy to denote The minimum intensity of a stimulus that is perceived as painful. PAIN TOLERANCE: The term ‘pain tolerance' has been used throughout this thesis in agreement with the IASP taxonomy to denote The maximum intensity of a pain-producing stimulus that a subject is willing to accept in a given situation. TEMPORAL SUMMATION OF PAIN: The term ‘temporal summation of pain' is not defined in the IASP terminology. It has been used throughout this thesis to denote an increase in subjective pain ratings during application of repetitive painful pressure stimulations. 1. INTRODUCTION . 6 1.1 Aims of the PhD thesis. 8 1.2 Hypothesis . 9 2. ASSESSMENT OF PAIN SENSITIVITY AND PAIN MODULATION . 11 2.1 Assessment of pain sensitivity . 11 2.2 Assessment of pain modulation . 15 2.2.1 Conditioned pain modulation – methodological parameters . 15 2.2.2 Exercise-induced hypoalgesia – methodological parameters . 16 2.2.3 Subgrouping of patients with chronic musculoskeletal pain . 18 3. CURRENT PERSPECTIVES ON EXERCISE-INDUCED HYPOALGESIA. 19 3.1 Temporal and spatial manifestations of EIH in healthy subjects . 19 3.1.1 Aerobic exercise and EIH . 19 3.1.2 Isometric exercise and EIH . 21 3.2 Influence of exercise intensity and exercise duration on EIH . 24 3.3 Gender and age related differences in EIH . 25 3.4 Influence of regular physical activity on EIH . 26 3.5 EIH in patients with chronic pain . 28 3.6 Mechanisms of EIH . 31 4. CURRENT PERSPECTIVES ON CONDITIONED PAIN MODULATION . 34 4.1 Temporal and spatial manifestations of CPM in healthy subjects . 34 4.2 Gender and age related differences in CPM . 37 4.3 Influence of regular physical activity on CPM . 38 4.4 CPM in patients with chronic pain . 40 4.5 Mechanisms of CPM . 42 5. SIMILARITIES IN MANIFESTATIONS OF CPM AND EIH . 44 6. CONCLUSIONS AND FUTURE PERSPECTIVES . 47 SAMMENDRAG (Danish summary) . 52 Appendix 1 (summary of experimental studies on CPM in humans) . 72 Appendix 2 (summary of clinical studies on CPM in humans) . 80 Appendix 3 (summary of experimental studies on EIH in humans) . 87 Appendix 4 (summary of clinical studies on EIH in humans) . 93 Pain is defined by the International Association for the Study of Pain (IASP) as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage' (Merskey and Bogduk, 1994). However, the experience of pain is not static, and a variety of conditioning stimuli can modulate the way pain is perceived. This phenomenon has for instance been observed during combat in wounded soldiers reporting little or no pain (Beecher, 1956). Similarly, there are anecdotes about absence of pain associated with injuries sustained during running (Egger, 1979). Thus, pain is a complex and highly subjective phenomenon that can be influenced by several factors, which can modulate the experience of pain. Previous pain research has demonstrated that modulation of pain is an important determinant of the pain experience (Yarnitsky, 2010) and may therefore be an important factor in understanding pain conditions and potentially improving treatment strategies. Furthermore, reduced pain inhibition has been associated with several chronic pain conditions (Lewis et al., 2012b) and may predict who develop chronic pain (Yarnitsky et al., 2008; Wilder-Smith et al., 2010), and who will benefit from pharmacological pain treatment (Yarnitsky et al., 2012). In humans, assessment of the pain inhibitory pathways is recommended through the paradigm known as conditioned pain modulation (CPM) (Yarnitsky et al., 2014), frequently demonstrated as a reduction in pain sensitivity by a painful conditioning stimulus (e.g. cold pressor test). Recently, the paradigm of exercise-induced hypoalgesia (EIH) has also been proposed to reflect the efficiency of the pain inhibitory pathways (Lannersten and Kosek, 2010). EIH is also frequently demonstrated as a reduction in pain sensitivity after aerobic or isometric exercises (Koltyn, 2000; Naugle et al., 2012). Similarities between CPM and EIH in their interaction with the opioid system after noxious thermal stimuli (Le Bars et al., 1981c; Willer et al., 1990) and after exercise (Janal et al., 1984; Bertolini et al., 2012) indicate similar mechanisms underlying CPM and EIH, and the paradigms may reflect somewhat similar aspects of pain inhibition. This hypothesis is furthermore supported by a recent study demonstrating that the EIH response was predictive of pain severity following nerve injury in rats (Khan et al., 2014). Yet, the spatial and temporal manifestations of the two paradigms have never been directly compared, and it is currently unknown whether they provide equivalent data on the pain inhibitory systems. A comparison of the two paradigms will clarify whether they represent similar or different aspects of pain inhibition, which is necessary if the two phenomenons are to be used interchangeably as a method to evaluate the efficiency of the pain inhibitory systems. Additionally, similarities between CPM and EIH may also be related with the influence of gender and age on the CPM and EIH responses. Recent studies have shown significant differences in both CPM and EIH in relation to gender (Sternberg et al., 2001; Popescu et al., 2010) and age (Edwards et al., 2003a; Lariviere et al., 2007; Hoeger Bement et al., 2011). However, other studies showed no differences (Baad-Hansen et al., 2005; Umeda et al., 2010; Oono et al., 2011; Lemley et al., 2014b), and the gender and age effects on the CPM and EIH responses in healthy subjects are still unclear. Physical exercise is, besides its potential ability to assess pain inhibition, an important component in the treatment and rehabilitation of many patients with chronic musculoskeletal pain (Mannerkorpi and Henriksson, 2007; Hassett and Williams, 2011). A comprehensive understanding of how exercise influences pain perception is necessary to optimize the clinical utility of exercise as a method of pain management. Nevertheless, very little research has compared whether acute aerobic or isometric exercise has a greater effect on reducing pain sensitivity (Drury et al., 2004). Furthermore, the exercise intensity and duration to best inhibit pain are not clear. In addition, research on the effect of exercise on central pain mechanisms, like temporal summation of pressure pain, is sparse (Meeus et Regular exercise has been linked to alterations in pain perception with athletes demonstrating significantly higher pain tolerance compared with normally active controls (Tesarz et al., 2012). Current research comparing the CPM response in athletes and normally active controls during a cold pressor test showed equivocal results, with one study showing increased CPM (Geva and Defrin, 2013), and one study showing decreased CPM (Tesarz et al., 2013) in athletes compared to controls. A recent study found that greater amount of self-reported physical activity, as well as greater amount of vigorous physical activity, predicted a greater CPM response, assessed as change in thermal pain sensitivity during cold pressor test (Naugle and Riley, 2014). So far, two small studies have investigated the relationship between physical activity and EIH (Øktedalen et al., 2001; Sternberg et al., 2001), but no studies have investigated CPM and EIH responses between active and inactive subjects. In patients with chronic pain, studies have indicated that a large subset of patients demonstrate impaired CPM and EIH responses compared with asymptomatic controls (Lewis et al., 2012b; Naugle et al., 2012). It has been hypothesized that an impaired CPM response or an impaired EIH response may indicate a dysfunction of the pain inhibitory systems (Yarnitsky et al., 2014; Lannersten and Kosek, 2010). In patients, the degree of CPM has been linked with clinical pain (Nahman-Averbuch et al., 2011; Pickering et al., 2014) and psychological factors (Goodin et al., 2009), with both factors having a negative impact on the degree of pain inhibition. In addition to impaired pain inhibition, increased pain sensitivity has also been demonstrated in patients with chronic pain compared with asymptomatic controls (Staud et al., 2003a; Arendt-Nielsen et al., 2010; Kosek et al., 2013). Still, no studies have compared the degree of pain inhibition in chronic musculoskeletal pain patients with high and low pain sensitivity. It may be hypothesized that low pain sensitivity in sub-groups of patients could be due to adequate pain inhibitory pathways. Improving knowledge about the efficiency of the pain inhibitory pathways in patients with chronic pain is important for optimal treatment. As mentioned earlier, reduced pain inhibition may be predictive of acute and chronic postoperative pain and drug efficacy, which highlights the importance of pain mechanisms in clinical decision-making. In the current PhD study (Fig. 1.1), CPM and EIH responses were investigated in healthy subjects (experiment 1 and 2) and in patients with chronic musculoskeletal pain (experiment 3), to characterize the temporal and spatial manifestations of the two phenomenons and to study the influence of age, gender, regular physical activity, exercise modality, intensity and duration as well as experimental pain sensitivity on the CPM and EIH responses. Standardized quantitative sensory testing (QST) was used to assess pressure pain sensitivity (pain thresholds, pain tolerance, pain ratings and temporal summation of pain) in the deeper musculoskeletal structures in relation to cold pressor tests (CPM paradigm) and different exercise protocols (EIH paradigms). 1.1 Aims of the PhD thesis The aims of this PhD thesis were (Fig. 1.1): To compare the temporal and spatial manifestations of conditioned pain modulation and exercise-induced hypoalgesia in healthy subjects. To investigate the influence of age, gender and level of regular physical activity on conditioned pain modulation and exercise-induced hypoalgesia in healthy subjects. To investigate dose-response of exercise-induced hypoalgesia after different exercise modalities, intensities and durations in healthy subjects. To investigate the effect of exercise on central mechanisms of pain in healthy subjects and patients with chronic musculoskeletal pain. To investigate the influence of pain sensitivity, clinical pain intensity and psychological distress on conditioned pain modulation and exercise-induced hypoalgesia in patients with chronic musculoskeletal pain. The hypotheses in relation to the CPM and EIH responses in healthy subjects were that cold pressor tests, as well as aerobic and isometric exercises would cause a multisegmental decrease in pain sensitivity and the CPM and EIH responses would be correlated. It was also hypothesized that the CPM and EIH responses would be influenced by age, gender and level of regular physical activity. For the exercise conditions in healthy subjects, it was hypothesized that greater reduction of pain sensitivity would be observed after higher intensity exercise, compared with lower intensity exercise, and that aerobic and isometric exercise would reduce central mechanisms of pain. In the clinical experiment, it was hypothesized that the CPM and EIH responses would be reduced in chronic musculoskeletal pain patients with high pain sensitivity compared with pain patients with low pain sensitivity, and that the CPM and EIH responses would be correlated, as well as influenced by, clinical pain sensitivity and psychological distress. 80 healthy subjects: 56 healthy subjects: 61 chronic pain patients: 40 men and 40 women 28 active and 28 inactive 31 high with pain sensitivity and 30 with Subjects
low pain sensitivity CPM: Cold pressor test,
CPM: Cold pressor test,
CPM: Cold pressor test, foot
EIH: High intensity aerobic exercise and
CPM and EIH
EIH: Low and high
EIH: High intensity aerobic
low intensity isometric exercise paradigms
intensity aerobic and Control: Quiet rest
isometric exercises Control: Quiet rest
Manual pressure pain thresholds on leg, arm and shoulder
Manual pressure pain thresholds on
sensitivity
Cuff pressure pain thresholds, pain tolerances, pain tolerance
legs, arm and shoulder assessment
levels and temporal summation of pain on the leg and arm Cuff pressure pain threshold, pain
tolerance, pain tolerance level and
temporal summation of pain on the leg
1. Compare temporal and 1. Compare CPM and EIH 1. Compare CPM and EIH between spatial manifestations of between active and inactive patients with high and low pain 2. Investigate gender and 2. Investigate gender effect 2. Investigate the effect of clinical pain age effect on CPM and EIH intensity and psychological distress on 3. Investigate dose-response 3. Investigate the effect of exercise on central 3. Investigate the effect of exercise on 4. Investigate the effect of mechanisms of pain central mechanisms of pain exercise on central mechanisms of pain Fig. 1.1: Illustration of the methodologies and aims of the experiments.
‘MSK': Musculoskeletal. ‘CPM': Conditioned Pain Modulation. ‘EIH': Exercise-induced Hypoalgesia. 2. ASSESSMENT OF PAIN SENSITIVITY AND PAIN MODULATION In the current PhD study, QST was used to assess experimental pressure pain sensitivity in relation to paradigms of CPM and EIH in healthy subjects and in patients with chronic musculoskeletal pain. An overview of the options available for assessment of pain sensitivity and pain modulation is presented in this chapter. Procedures used in experiment 1-3 are summarized in Table 2.1. 2.1 Assessment of pain sensitivity Different methodologies for assessment of pain sensitivity have been used before and after CPM and EIH paradigms in humans, including assessment of pressure pain thresholds (Goodin et al., 2009; Hoeger Bement et al., 2009), pressure pain ratings (Rezaii et al., 2012; Lemley et al., 2014a), pressure pain tolerance (Gurevich et al., 1994; Sowman et al., 2011), temporal summation of pressure pain (Cathcart et al., 2009; Meeus et al., 2014), electrical pain thresholds (Drury et al., 2005; Rosen et al., 2008), heat pain thresholds (Talbot et al., 1987; Kodesh and Weissman-Fogel, 2014), heat pain ratings (Lariviere et al., 2007; Ellingson et al., 2014), temporal summation of heat pain (Edwards et al., 2003a; Koltyn et al., 2013), and the spinal nociceptive flexion reflex (RIII reflex) (Guieu et al., 1992; France and Suchowiecki, 1999). A standardized battery of pressure pain tests was used in experiment 1-3 to assess deep tissue pain sensitivity (I, II, III, and IV). Assessment of deep tissue pain sensitivity was chosen for three reasons. 1) The deeper tissues play an important role in many musculoskeletal pain conditions (Arendt- Nielsen and Graven-Nielsen, 2002), 2) pressure pain tends to give large and robust CPM responses (Ge et al., 2004; Arendt-Nielsen et al., 2008; Wang et al., 2010) and EIH responses (Koltyn, 2000), and 3) assessment of pressure pain sensitivity is a reliable method (Brennum et al., 1989). Though pressure stimulation applied on the skin could reflect the pain sensitivity of both the superficial and deep structures, deep-tissue nociceptors mediate a major component of the pressure-induced pain during pressure algometry (Kosek et al., 1995; Graven-Nielsen et al., 2004). Assessment of deep tissue pain sensitivity included assessment with manual pressure algometry and computer-controlled cuff algometry. Manual algometry (Somedic Sales AB, Sweden) was used for assessment of pressure pain thresholds with a standardized rate of pressure increase (30 kPa/s), applied at each assessment site with a stimulation probe of 1 cm2. Pressure pain thresholds were assessed at standardized anatomical muscular sites (leg, arm and shoulder). Manual pressure algometry has been extensively used and validated in clinical and experimental research as a quantitative method of assessing deep tissue pain sensitivity (Jensen et al., 1986a). Previous studies (Reeves et al., 1986; Brennum et al., 1989; Delaney and McKee, 1993; Nussbaum and Downes, 1998; Geber et al., 2011; Walton et al., 2011) on manual pressure algometry have demonstrated high levels of reliability with ICC values above 0.7 for test-retest data. These findings were supported by the current experiments, which showed substantial ICC values above 0.8 in healthy subjects (Table 2.2) and in patients with chronic musculoskeletal pain (IV). Cuff algometry (Nocitech, Denmark and Aalborg University, Denmark) was used for assessment of pressure pain thresholds, pressure pain tolerance, pain tolerance level (pain rating when pain tolerance was reached), and pain ratings during repeated pressure stimulations as a measure of temporal summation of pain. Assessment with cuff algometry was performed at standardized anatomical muscular sites (lower leg and upper arm) with a 13-cm wide silicone tourniquet cuff (VBM, Sulz, Germany). A 10 cm electronic visual analogue scale (VAS) anchored ‘no' pain at the left hand end and ‘maximal pain' at the right hand end was used to record pain during cuff inflation. VAS ratings have been shown to provide useful information in pain research (Jensen et al., 1986b; Staud et al., 2003b). In contrast to manual pressure algometry, a larger tissue volume can be assessed by computer- controlled cuff algometry (Polianskis et al., 2001). In cuff algometry, the pain intensity related to inflation of a tourniquet cuff applied around an extremity is used to establish stimulus-response curves, allowing assessment of deep-tissue pain sensitivity. Moreover, cuff algometry is less likely to be influenced by local variations in pain sensitivity and is also an examiner-independent technique reducing the potential measurement bias. Cuff algometry has shown less variability compared with manual algometry (Polianskis et al., 2001) and is sensitive to hypoalgesia and hyperalgesia in the deep tissues (Polianskis et al., 2002b). Furthermore, cuff algometry has been used previously to assess pain sensitivity in healthy subjects (Polianskis et al., 2001, 2002a, b, c), in patients with regional pain conditions (Lemming et al., 2012; Jespersen et al., 2013; Skou et al., 2013, 2014), and widespread pain conditions (Jespersen et al., 2007). In the current experiments, moderate to high ICC values (0.65 - 0.90) for test-retest data were found with cuff algometry in healthy subjects (Table 2.2) and in patients with chronic musculoskeletal pain (IV). Test-retest reliability for cuff algometry has not previously been determined.
Table 2.1. Experimental methods and standardization procedures used in the current studies on CPM
and EIH.
Experimental parameters
Standardization procedures
Deep tissue sensitivity 1. Pain threshold, pain tolerance, 1. Stimulation area: 13-cm wide pain tolerance level and pain silicone tourniquet cuff ratings during repeated Rate of application: 1 kPa/s and stimulations measured at the the maximal pressure limit was lower leg and upper arm (experiment 1 and 2) and lower leg (experiment 3) with computer-controlled pressure algometry (Nocitech, Denmark and Aalborg University, 2. Pain thresholds measured at 2. Stimulation area: 1.0 cm2 the thigh, upper arm and Rate of application: 30 kPa/s shoulder (experiment 1 and 2) Peak value: Average of 2 and thighs, upper arm and measurements per site shoulder (experiment 3) with manual pressure algometry (Somedic Sales AB, Sweden) Pain intensity during cuff Computer-controlled data Cold pressor test Tank containing circulating cold Standardized temperature, time water and immersion depth Aerobic exercise Stationary ergometric bicycle Standardized pedal frequency (Ergomedic 928E) and time of bicycling Intensity of aerobic exercise Electronic digital heat rate belt Standardized determination of (Monark Heart Rate Monitor) age-related heart rate Standardized increase and adjustment of resistance Maximal knee extension and Electronic digital hand Standardized body positions elbow flexion force dynamometer (Commander Peak values: Average of two Muscle Tester, Powertrack II) Sub-maximal knee extension Electronic digital hand Standardized body positions and and elbow flexion force dynamometer (Commander time of contractions Muscle Tester, Powertrack II) Visual feedback during contractions Assessment
Pain sensitivity parameter
1st session
2nd session
Mean ± SD
Mean ± SD
Manual pressure pain threshold 0.89 (0.84-0.92) Cuff pressure pain threshold 26.7 ± 12.9 kPa 27.4 ± 11.8 kPa 0.79 (0.70-0.85) Cuff pressure pain tolerance 58.4 ± 18.4 kPa 60.6 ± 19.5 kPa 0.87 (0.81-0.91) Cuff pain tolerance level 0.74 (0.63-0.82) Cuff pain ratings during repeated 0.73 (0.62-0.81) stimulations (VAS-I) Cuff pain ratings during repeated 0.70 (0.58-0.79) stimulations (VAS-II) Cuff pain ratings during repeated 0.71 (0.59-0.80) stimulations (VAS-III) Manual pressure pain threshold 0.87 (0.82-0.91) Cuff pressure pain threshold 30.4 ± 15.1 kPa 34.5 ± 15.8 kPa 0.85 (0.79-0.90) Cuff pressure pain tolerance 69.1 ± 16.1 kPa 70.6 ± 15.4 kPa 0.90 (0.87-0.93) Cuff pain tolerance level 0.82 (0.75-0.87) Cuff pain ratings during repeated 0.65 (0.51-0.75) stimulations (VAS-I) Cuff pain ratings during repeated 0.66 (0.52-0.76) stimulations (VAS-II) Cuff pain ratings during repeated 0.65 (0.51-0.75) stimulations (VAS-III) Table 2.2: Test-retest reliability of manual pressure algometry and computer-controlled cuff algometry
in healthy men and women. The mean and standard deviation (SD) at baseline for each of the two sessions were calculated for the leg and arm. Intraclass correlations (ICCs) and 95 % confidence intervals (CI) based on a single rating, consistency and 2-way mixed effect model (ICC3,1) was used for analysis of reliability. VAS scores during repeated pressure stimulations are presented as mean values from stimulations 1-4 (VAS-I), 5-7 (VAS-II), and 8-10 (VAS-III). (Unpublished data from experiment 1 and 2). 2.2 Assessment of pain modulation Efficiency of the pain inhibitory pathways is typically assessed by paradigms of CPM (Yarnitsky et al., 2008; Pud et al., 2009; Yarnitsky, 2010; Wilder-Smith et al., 2010) or EIH (Koltyn et al., 1996; Cook et al., 2010; Meeus et al., 2014) with recordings of pain sensitivity before and during a painful conditioning stimulus or before and after an exercise condition. 2.2.1 Conditioned pain modulation – methodological parameters The clinical observation that pain in one area of the body can be reduced by painful stimuli, applied to distant parts of the body has been known for centuries (Wand-Tetley, 1956; Melzack, 1975). Le Bars et al. (1979a, 1979b) first investigated the phenomenon of ‘pain inhibits pain', and they observed that the electrophysiological responses of dorsal horn neurons to somatic noxious stimuli were inhibited when a second noxious stimulus was applied to an extrasegmental site. These observations led to a formulation of the concept of diffuse noxious inhibitory control (DNIC) (Le Bars et al., 1979b, a). Various other terms have been used including ‘counterirritation' (Le Bars et al., 1979a; Michaux et al., 2010), ‘endogenous analgesia' (Pud et al., 2005; Granot et al., 2008), and ‘heterotopic noxious conditioning stimulation' (Kosek and Ordeberg, 2000b; Tuveson et al., 2007). Recently, the term ‘conditioned pain modulation' (CPM) has been recommended (Yarnitsky et al., 2010). In humans, CPM is typically assessed by recordings of a pain test stimulus (e.g. pain thresholds) before, during or after applying a conditioning painful stimulus (e.g. cold pressor test). To demonstrate CPM, various modes of conditioning stimulus have been used, including painful cold (Chalaye et al., 2013), painful hot (Nir et al., 2011), painful ischemic (Cathcart et al., 2009), chemical (Graven-Nielsen et al., 1998), and electrical (Vo and Drummond, 2014). CPM can be either inhibitory (iCPM) or facilitatory (fCPM) (Yarnitsky et al., 2010). As illustrated in Appendix 1, the experimental phenomenology of CPM is well established in healthy subjects and typically reported as reduced pain sensitivity in response to a painful conditioning stimulus. CPM causes an acute heterotopic decrease in the pain sensitivity (Graven-Nielsen et al., 1998), although homotopic hypoalgesia have been reported (Pud et al., 2005). As illustrated in Appendix 2, several studies have demonstrated impaired CPM responses in patients with chronic pain. A recent systematic review and meta-analysis concluded that reduced CPM is common in patients with chronic pain. In 29 out of 42 included studies, patients with chronic pain demonstrated reduced CPM compared to asymptomatic controls and a reduced CPM response was a common feature across different pain conditions (Lewis et al., 2012b). Nonetheless, CPM response similar to asymptomatic controls (Chua et al., 2011; Garrett et al., 2013) has also been reported, indicating that a subgroup of patients may have preserved inhibitory pain modulation. CPM responses may be impaired at painful body sites, but not at non-painful body sites (Oono et al., 2014). This indicates systemic effects of CPM and highlights the importance of several pain assessment sites when assessing the CPM response, but it also illustrates the influence of clinical pain on the CPM response. In the current experiments, circulating cold water at 1-2ºC (cold pressor test) was chosen as conditioning stimulus (I, II, and IV). Cold pressor test is often used for investigation of CPM in healthy subjects (Appendix 1) and in patients with chronic pain (Appendix 2) and produced the greatest inhibitory effect when compared with muscle pain (Arendt-Nielsen et al., 2008). Several standardized assessment sites including the body part immersed in cold water and distant body sites were used in the experiments (I, II, and IV). 2.2.2 Exercise-induced hypoalgesia – methodological parameters Black and colleagues (1979) investigated the phenomenon of pain relief in response to exercise. Yet, the term ‘exercise-induced hypoalgesia' was coined more than twenty years later (Koltyn, 2002). Various other terms have been used including ‘exercise analgesia' (Fuller and Robinson, 1993) and ‘exercise-induced analgesia' (Kemppainen et al., 1990). Exercise rarely causes complete analgesia and the term ‘exercise-induced hypoalgesia' is preferred, as it avoids the implication of complete pain Early research in this area was limited by significant methodological flaws (e.g. no control condition), leading some to conclude that reduced pain sensitivity following exercise was simply a phenomenon of pre-exposure to painful stimuli (Padawer and Levine, 1992). Subsequent research has clearly demonstrated that reduced pain sensitivity occurs following acute exercise when compared to non-exercise control conditions (Gurevich et al., 1994; Koltyn et al., 1996). The experimental phenomenology of EIH is now well established in healthy subjects and typically reported as ‘reduced pain sensitivity in response to an exercise condition' (Koltyn, 2002; Naugle et al., 2012), but no hypoalgesic effect (Dannecker et al., 2001; Ruble et al., 2005) and hyperalgesia following exercise have been demonstrated (Vecchiet et al., 1984; Sternberg et al., 2001). A summary of experimental studies on EIH in healthy subjects are presented in Appendix 3. The effect of exercise on pain sensitivity in subjects with chronic pain is still controversial, since both hyperalgesia (Cook et al., 2010) and hypoalgesia (Lannersten and Kosek, 2010) have been reported. A summary of experimental studies on EIH in patients with chronic pain are presented in Appendix 4. To demonstrate EIH, various modes of exercise have been used, including aerobic exercises (e.g. cycling and running) (Dannecker et al., 2002; Hoffman et al., 2007), isometric exercises (i.e. a muscle contractions without joint movement) (Kosek and Lundberg, 2003) and resistance exercises (i.e. a muscle contractions with joint movement) (Focht and Koltyn, 2009). Changes in pain sensitivity occur not only in the exercising body part or within a few segmental levels, but also at distant sites, which indicate systemic effects, which further highlights the importance of several pain assessment sites when assessing EIH. In the current experiments, aerobic exercise (I, II, III, and IV) and isometric exercises (I, III, IV) were used to investigate EIH. Bicycling was performed on a stationary bicycle (Ergomedic 928E, Monark Exercise AB, Vansbro, Sweden) at age-related target heart rate corresponding to 75 % VO2max and 50 % VO2max (Swain et al., 1994), which has previously demonstrated robust EIH responses (Naugle et al., 2014). Isometric muscle contractions were performed against a force transducer on a handheld dynamometer (Commander Muscle Tester, Powertrack II, JTECH Medical, Utah, USA) at intensities of 30 % and 60 % of maximal voluntary contraction (MVC). During the sustained sub-maximal isometric contractions, each subject was required to match the target force as displayed on the monitor of the force transducer. Handheld dynamometry has demonstrated high inter-rater reliability (Whiteley et al., 2012), good construct validity (Roy et al., 2009) and showed medium to high correlation with isokinetic measures of isometric muscle strength for isometric knee extension and elbow flexion (Stark et al., 2011). Several standardized assessment sites including the exercising body part and distant body sites were used for evaluation of the EIH response (I, II, III, and IV). 2.2.3 Subgrouping of patients with chronic musculoskeletal pain 61 patients with chronic musculoskeletal pain participated in experiment 3: 37 patients presented with low back pain as their primary complaint, 16 with neck pain, 7 with shoulder pain, and 1 with elbow pain. Based on widespread manual pressure pain thresholds assessed at the legs, arm and shoulder at baseline, patients were sub-grouped into patients with high pain sensitivity (HPS) and low pain sensitivity (LPS), respectively. The median of the averaged pressure pain thresholds for men and women, respectively were used for subgrouping. The median pressure pain threshold was chosen as the cut-off point, since this divides the groups in equally sized subgroups with distinguishable degrees of pain sensitivity. A similar approach has recently been demonstrated useful (Skou et al., 2014). Patients with high pain sensitivity demonstrated decreased cuff pain threshold and tolerance as well as facilitated temporal summation of pain. They also reported more pain during cold pressor test compared with patients with low pain sensitivity, indicating that subgrouping, based on widespread pain sensitivity, was relevant (IV). The difference in pain sensitivity between subgroups of patients is in agreement with a previous study on lateral epicondyalgia, which also found subgroups of patients with more or less temporal summation of pain (Jespersen et al., 2013). The relevance of the subgrouping is furthermore supported by previous research, demonstrating differences in pain reporting during cold pressor test between subgroups (Chen et al., 1989; Zheng et al., 2014). 3. CURRENT PERSPECTIVES ON EXERCISE-INDUCED HYPOALGESIA This chapter describes the current perspectives on exercise-induced hypoalgesia in healthy subjects and in patients with chronic pain. 3.1 Temporal and spatial manifestations of EIH in healthy subjects The first part of the chapter describes the current perspectives on EIH in healthy subjects. 3.1.1 Aerobic exercise and EIH In agreement with previous research (Koltyn et al., 1996; Hoffman et al., 2004; Naugle et al., 2014) the current experiments demonstrated multisegmental increases in manual pressure pain thresholds immediately after high intensity aerobic exercise (I and II; Fig. 3.1). In contrast with these findings, earlier studies have also demonstrated a lack of EIH response after high intensity aerobic exercise (Padawer and Levine, 1992; Ruble et al., 2005). However, these studies used heat and cold pain thresholds to assess pain sensitivity on the skin, which may not be subject to as strong pain inhibition as input from deep structure nociceptors (Yu and Mense, 1990). The duration of the EIH response differed between experiments, with one experiment demonstrating short-lasting (< 15 min) effects (I), and one demonstrating significant increases in pain thresholds immediately after and 15 min after exercise (II). The duration of the EIH response is in agreement with previous research demonstrating hypoalgesia for a maximum of 10-15 min following aerobic exercise, but results on the duration of the EIH response are inconsistent. A previous study found a significant decrease in pressure pain sensitivity 5 min after high intensity aerobic exercise, which was not sustained after 10 min (Hoffman et al., 2004), while hypoalgesic effects on ischemic pain test 20 min after high intensity aerobic exercise in runners (Janal et al., 1984) and hypoalgesic effects on electrical dental pain thresholds 30 min after high intensity aerobic exercise (Kemppainen et al., 1990) have been reported. The increase in manual pressure pain thresholds was significantly larger in the exercising body part compared with non-exercising body parts (I). This indicates that local or segmental mechanisms play an important role in the EIH response after aerobic exercise. The effect of aerobic exercise on the EIH response in exercising and non-exercising body parts has not previously been investigated. Low intensity exercise High intensity exercise Fig. 3.1: Mean (+SEM) manual pressure pain threshold at the quadriceps muscle, biceps muscle
and trapezius muscle before, immediately after 1st bout, immediately after 2nd bout, and 15 min
after low and high intensity aerobic exercises (*, significant difference compared with baseline. †,
significant difference between low and high intensity exercise conditions; NK: P < 0.05; Raw data from I). In the current experiments, the effect of aerobic exercise on pain tolerance was mixed. When compared with a control condition, high intensity exercise increased pain tolerance in subjects aged 18- 30 years compared with baseline and quiet rest (III). However, when high and low intensity aerobic exercises were compared in subjects aged 18-65, pain tolerance was not significantly different after exercise compared with baseline (III). The increase in pain tolerance, which was found in the younger subjects, is in agreement with previous findings of the effect of aerobic exercise on pain tolerance (Gurevich et al., 1994; Bartholomew et al., 1996). The mixed results in the current experiments were somewhat unexpected. The same protocol for the aerobic exercises, as well as for the assessment of pain tolerance, was used in both experiments. One possible reason for the mixed results may be related with the different age groups included in the experiments. This is supported by the negative correlation between age and the EIH response after aerobic exercise, indicating that older subjects may have less EIH response after aerobic exercise (III). This hypothesis is also supported by a study in pain patients (Bement et al., 2011) demonstrating increased EIH responses after isometric exercise in younger patients. Nevertheless, a recent study in healthy subjects found no difference in the EIH response after isometric exercise between younger and older healthy subjects (Lemley et al., 2014b). Temporal summation of pain was reduced after aerobic exercise compared with baseline in subjects aged 18-30 years, but when compared with the quiet rest condition, the reduction in temporal summation of pain failed to reach significance. When high and low intensity aerobic exercises were compared in subjects aged 18-65, temporal summation of pain was not significantly influenced (III). This indicates that the aerobic exercises used in these experiments did not target the central mechanisms of pain summation. Recently, low and high intensity aerobic exercises were found to reduce temporal summation of heat pain in 27 healthy subjects (Naugle et al., 2014b), however pain ratings to suprathreshold pressure stimuli were not affected, highlighting the importance of pain sensitivity assessment methodology. 3.1.2 Isometric exercise and EIH Previous findings of increased pressure pain thresholds after isometric exercises (Kosek and Ekholm, 1995; Koltyn et al., 2001; Kosek and Lundberg, 2003; Koltyn and Umeda, 2007; Bement et al., 2008; Bement et al., 2009; Umeda et al., 2010; Naugle et al., 2013; Bement et al., 2014; Lemley et al., 2014a; Koltyn et al., 2014) were supported by the findings in the current experiments (I). Low and high intensity isometric exercises induced short-lasting (< 15 min) multisegmental increases in manual pressure pain thresholds immediately after exercise. The increase in pressure pain thresholds was larger in the exercising body part compared with non-exercising body parts (I; Fig. 3.2). This indicates that local or segmental mechanisms also play an important role in the EIH response after isometric exercise. The multisegmental pain inhibitory effects after isometric exercise are also in agreement with previous findings on EIH (Kosek and Lundberg, 2003; Koltyn and Umeda, 2007; Bement et al., 2008). More pronounced EIH responses at the contracting thigh muscle compared with the contralateral non- contracting thigh muscle has previously been demonstrated (Kosek and Lundberg, 2003). The duration of EIH after isometric exercise is in agreement with previous research demonstrating hypoalgesia immediately after isometric exercise (Kosek and Ekholm, 1995). Low and high intensity isometric arm and leg exercises produced multisegmental increases in pain tolerance immediately after and also 15 min after exercise, without significant difference between assessment sites (III). Low and high intensity isometric leg exercises reduced temporal summation of pain, whereas only high intensity isometric arm exercise reduced temporal summation of pain immediately after and 15 min after exercise (III). This indicates that isometric exercise, in contrast to aerobic exercise, also target the central mechanisms of pain summation. Previous research have demonstrated that isometric exercise reduce temporal summation of heat pain in healthy subjects (Koltyn et al., 2013; Koltyn et al., 2014; Naugle et al., 2014), but the effect of isometric exercises on pressure pain tolerance and temporal summation of pressure pain has not previously been investigated. Low intensity exercise High intensity exercise Low intensity exercise High intensity exercise Fig. 3.2: Mean (+SEM) manual pressure pain threshold at the quadriceps muscle, biceps muscle and
trapezius muscle before, immediately after 1st bout, immediately after 2nd bout, and 15 min after low and high in tensity isometric arm (A) and isometric leg (B) exercises (*, significant difference compared with baseline. †, significant difference between low and high intensity exercise conditions; NK: P < 0.05; Raw data from I). Few studies have previously compared the effect of different exercise modalities on the EIH response. A small study including 12 healthy men compared the effect of high intensity aerobic exercise and repeated maximal isometric exercise on pressure pain threshold. Both exercise conditions caused hypoalgesia with aerobic exercise, resulting in greater hypoalgesia compared with isometric exercise (Drury et al., 2004). A recent meta-analysis by Naugle et al. (2012) examined the effect of aerobic, isometric, and resistance exercise on pain threshold and pain intensity, suggesting that all included exercise modalities reduced pain sensitivity. The mean effect size for aerobic exercise was moderate, while the mean effect sizes for isometric and resistance exercises were large. In the current experiment, no significant difference in the EIH responses was found between aerobic and isometric exercises (I), yet only isometric exercises reduced temporal summation of pain (III), and it appears that isometric exercises can be performed at lower intensities than aerobic exercises to produce an EIH response (I and III). A possible reason for this discrepancy is that the EIH responses after aerobic and isometric exercise are due to partly different mechanisms (See section 3.6). 3.2 Influence of exercise intensity and exercise duration on EIH Previous research investigating the influence of aerobic exercise intensity on pressure pain sensitivity has demonstrated larger effects after high intensity exercise compared with low intensity exercise (Hoffman et al., 2004; Naugle et al., 2014b), which is supported by the current findings (I). Naugle et al. (2014b) assessed pain thresholds before and after low and high intensity exercises and found that pain thresholds increased after high intensity exercise only. An interaction between intensity and duration after aerobic exercise has been demonstrated. Hoffman et al. (2004) assessed pressure pain sensitivity in healthy subjects before and after aerobic exercise and discovered that pain sensitivity only decreased after exercise at high intensity (75 % VO2max) and longer duration (30 min) and not after shorter time (10 min) at same intensity or same duration at a reduced exercise intensity. This is in contrast with the current findings on manual pressure pain thresholds, where no difference in the EIH response after 10 min of high intensity aerobic exercise compared with 2 x 10 min of high intensity aerobic exercise was observed (I). No systematic differences in pain tolerance and temporal summation of pain after aerobic exercise were found between low and high intensity exercises. Bement et al. (2008) investigated the influence of isometric exercise intensity on pressure pain sensitivity and demonstrated that isometric contractions at lower intensity and longer duration caused greater decrease in pain sensitivity compared with contractions at low and high intensity and shorter duration. This is in contrast to the current findings, which showed that high intensity isometric exercise had larger effects on manual pressure pain thresholds compared with low intensity isometric exercise (I). However, the larger EIH response after high intensity isometric exercises was only in the exercising body part (I). Bement et al. (2008) assessed pain sensitivity at the finger in relation to elbow exercises, not at the exercising body part, which may explain the equivocal results. Earlier research investigating the influence of isometric exercise intensity on heat pain sensitivity and electrical pain stimulation has demonstrated larger effects after high intensity exercises compared with low intensity exercise (Ring et al., 2008; Misra et al., 2014). No systematic differences in pain tolerance and temporal summation of pain after isometric exercise were found between low and high intensity exercises, although only high intensity isometric biceps contractions reduced temporal summation of pain (III). EIH occurred after low and high intensity isometric exercises performed for duration of both 90 s and 2 x 90 s, but in general without significant difference in the EIH response between the first and second bout of exercises. This is in agreement with a previous study, failing to find a dose-response relationship for the EIH response after isometric handgrip exercises performed at 25 % MVC for 1, 3 and 5 min (Umeda et al., 2010). 3.3 Gender and age related differences in EIH
Recent studies on the influence of gender on the EIH response have demonstrated mixed results. Some studies have shown comparable EIH responses in men and women (Kosek and Lundberg, 2003; Hoffman et al., 2004; Umeda et al., 2010; Koltyn et al., 2014), while other studies have shown larger effects in women (Koltyn et al., 2001; Sternberg et al., 2001). Mixed results were also found in the current experiments. No gender differences were found after isometric exercises (I). The increase in manual pressure pain thresholds after aerobic exercise was increased in women compared with men (I), but no gender differences were found after aerobic exercise in younger subjects (II). Limitations regarding the gender effects should be considered. Although different phases of the menstrual cycle do not appear to influence the magnitude of the EIH response in women (Bement et al., 2009), data were not collected in the current experiments on the use of contraceptives, status of menopause or menstrual cycle, which may affect the pain perception in the female participants (Riley et al., 1999), and the complexity of the gender, pain and exercise relationship deserves more systematic study. In the current experiment (I), the increase in manual pressure pain thresholds after isometric exercises were not affected by age, which is in agreement with previous research on age and EIH after isometric exercise (Lemley et al., 2014b; Burrows et al. 2014). Nonetheless, a negative correlation between age and the EIH response after aerobic exercise was found (III), indicating that older subjects may have less EIH response after aerobic exercise. This hypothesis is also supported by the mixed effects of aerobic exercise on pain tolerance (III) as previously mentioned. 3.4 Influence of regular physical activity on EIH Regular exercise has been linked with alterations in pain sensitivity and athletes have significantly higher pain tolerance (Tesarz et al., 2012), report less pain intensity during experimental pain (Sternberg et al., 2001), and demonstrate higher nociceptive withdrawal reflex threshold compared with normally active controls (Guieu et al., 1992). The influence of regular exercise on EIH has previously been investigated in two small studies with 20 active subjects and 9 inactive subjects (Øktedalen et al., 2001) and 10 athletes and 10 nonathletes (Sternberg et al., 2001). Pressure pain ratings during an ischemic tourniquet test were assessed before and after maximal treadmill exercise and no difference in the EIH response between active and inactive subjects were found (Øktedalen et al., 2001). Pain ratings during cold pressor test were assessed before and after a submaximal running exercise and no difference in the EIH response between athletes and nonathletes were discovered (Sternberg et al., 2001). These findings are supported by the current experiment (II), which demonstrated a robust increase in manual pressure pain thresholds after aerobic exercise in both active and inactive subjects, with no significant difference between the groups (Fig. 3.3). Inactive subjects
Fig. 3.3: Mean (+SEM) manual pressure pain threshold at the quadriceps and biceps muscles before,
immediately after, and 15 min after high intensity aerobic exercise in active and inactive men and
women (*, significant diffe rence compared with baseline; NK: P < 0.05; Raw data from II).
3.5 EIH in patients with chronic pain The results from a recent meta-analysis indicate that a subset of patients with chronic pain demonstrates impaired EIH responses compared with asymptomatic controls (Naugle et al., 2012). A hyperalgesic response after submaximal isometric exercise and vigorous aerobic exercise have also been demonstrated in patients with fibromyalgia (Vierck et al., 2001; Staud et al., 2005; Lannersten and Kosek, 2010) and after vigorous aerobic exercise in patients with widespread chronic pain (Cook et al., 2010; Meeus et al., 2010). Even so, a hypoalgesic response was elicited at multiple body sites after aerobic exercise in patients with chronic low back pain similar to healthy controls (Hoffman et al., 2005; Meeus et al., 2010) and after isometric contractions at non-painful muscles in patients with shoulder myalgia (Lannersten and Kosek, 2010). An EIH response was also elicited in patients with fibromyalgia after aerobic exercise performed at moderate intensity (Newcomb et al., 2011) and after isometric contractions performed at low intensity (Kadetoff and Kosek, 2007). The current clinical experiment on patients with chronic musculoskeletal pain (IV) showed that the EIH response was partly impaired in patients with high pain sensitivity compared with patients with low pain sensitivity. Only patients with low pain sensitivity demonstrated an increase in cuff pressure pain threshold and a decrease in pain ratings after aerobic and isometric exercises (IV; Fig. 3.4). Furthermore, patients with high pain sensitivity showed facilitated temporal summation of pain following high intensity aerobic exercise (IV; Fig. 3.5). Clinically, it is well known that some chronic pain patients report increasing pain after exercise and this finding is in agreement with previous studies demonstrating a hyperalgesic response after aerobic exercise (Vierck et al., 2001; Whiteside et al., 2004; Cook et al., 2010; Meeus et al., 2010). These findings support the hypothesis that low pain sensitivity in subgroups of patients could be due to adequate pain inhibitory pathways. Change in cuff pain threshold after cold pressor test (CPM response) predicted the change in cuff pain threshold after aerobic exercise (EIH response), and change in pain tolerance level after cold pressor test (CPM response) predicted the change in pain tolerance level after aerobic (EIH response) exercise, suggesting that individuals who demonstrated a greater ability to activate the descending inhibitory systems reported greater hypoalgesia following aerobic exercise (IV). Fig. 3.4: Mean (± SEM) cuff pressure pain threshold at the non-dominant lower leg before, immediately
after, and 15 min after high intensity aerobic exercise (A) and low intensity isometric leg exercise (B) in c hronic musculoskeletal pain patients with high pain sensitivity (HPS, n = 30) and low pain sensitivity (LPS, n = 30) (*, significant difference compared with baseline; NK: P < 0.05; Raw data from IV). Fig. 3.5: Mean (±SEM) VAS scores during 10 repeated cuff stimulations at PTT level at the non-
dominant lower leg indicating temporal summation of pain in chronic pain patients with high pain sensitivity (A) and low pain sensitivity (B) before and immediately after aerobic exercise. VAS scores are presented as mean values from stimulations 1-4 (VAS-I), 5-7 (VAS-II), and 8-10 (VAS-III) (*, significant difference from baseline; NK: P < 0.05; Raw data from IV). 3.6 Mechanisms of EIH
The most studied mechanism of the EIH response involves the endogenous opioid system, which may account for the multisegmental manifestations of EIH. Aerobic exercise results in an increased level of systemic β-endorphin (Janal et al., 1984; McMurray et al., 1987) although not directly correlated to the reduction in pain sensitivity (Janal et al., 1984; Droste et al., 1991). Several studies have investigated the contribution of an opioid mechanism by administering naloxone, an opioid antagonist prior to aerobic exercise (Black et al., 1979; Haier et al., 1981; Janal et al., 1984; Droste et al., 1991). In two studies (Black et al., 1979; Droste et al., 1991) naloxone did not affect hypoalgesia. In one study (Haier et al., 1981), a dose-dependent effect of naloxone was found with only high dose (10 mg) naloxone blocking the hypoalgesic response. In another study (Janal et al., 1984), naloxone blocked hypoalgesia to ischemic pain but not thermal pain. These findings implicate that the endogenous opioid system is involved in some of the hypoalgesic response after aerobic exercise, but not all of the exercise-induced alterations in pain sensitivity. In addition to an opioid mechanism, it has been suggested that non-opioid mechanisms may also be involved in the hypoalgesic response produced by exercise, and several non-opioid mechanisms have been proposed. A non-opioid mechanism potentially contributing to EIH after aerobic exercise is the Gate Control Theory (Melzack and Wall, 1965), where limb movement during exercise may excite large diameter afferent nerve fibers inhibiting nociceptive processes in the dorsal horn. Interestingly, in healthy subjects, passive movements induced hypoalgesia compared with a control condition, indicating a potential role of joint movement or proprioception in EIH (Nielsen et al., 2009). Still, if this was a main mechanism, low intensity aerobic exercise should have produced an EIH response in the exercising body parts, which was not the case (I). The Gate Control Theory does not explain the distant effects on pain sensitivity demonstrated in the current experiments (I, II, III, and IV), but could account for part of the hypoalgesic response in the exercising body part. Vigorous aerobic exercise has been shown to increase circulating plasma levels of catecholamines, particularly norepinephrine, which can remain elevated for hours after exercise (Bahr et al., 1991). Similarly, serotonin has been shown to be affected by exercise with increased levels of serotonin in active subjects (Soares et al., 1994), and with an increase in serotonin after aerobic exercise in active subjects, compared with inactive subjects (Steinberg et al., 1998). Aerobic exercise of moderate intensity activates the endocannabinoid system (Sparling et al., 2003), and antinociception after aerobic exercise is partly mediated by the endocannabinoid system in rats (Galdino et al., 2014). The hypothesis of involvement of the endocannabinoid system in the EIH response is futher supporteed by a recent study in humans, demonstrating a significant decrease in temporal summation of heat pain after isometric exercise in conjunction with a significant increase in circulating endocannabinoids (Koltyn et al., 2014). Exercise causes changes in the cardiovascular response and changes in blood pressure, which have been suggested as a possible mechanism (Koltyn and Umeda, 2006). Even so, there is no consistent dose-response correlation between changes in blood pressure and pain perception following isometric exercise (Umeda et al., 2009; Umeda et al., 2010). The EIH response has also been linked to the CPM response. Recently, a study in 39 healthy subjects found that subjects with a greater CPM response were more likely to report a greater EIH response after isometric exercise (Lemley et al., 2014b). To support the link between EIH and CPM, another study including 16 healthy women found that the hypoalgesic response after aerobic exercise was greater following painful exercise than non-painful exercise (Ellingson et al., 2014). Although the relation between the CPM and EIH responses was not strong, the EIH response after aerobic exercise was predicted by the CPM response after cold pressor test (IV), suggesting that patients who demonstrated a greater ability to activate the descending inhibitory systems, reported greater hypoalgesia following aerobic exercise. This relationship could also indicate that the increase in temporal summation of pain after aerobic exercise in patients with high pain sensitivity may be due to impaired descending inhibition. The connection between the CPM and EIH responses could indicate similar mechanisms underlying the hypoalgesic response; yet, hypoalgesia has also been demonstrated after non-painful aerobic exercise (Ellingson et al., 2014), indicating that the CPM response may work as an additive effect after painful exercise. Pain during exercise was not assessed in the current experiments to confirm this. In summary, high intensity aerobic exercise as well as low and high intensity isometric exercises produced short-lasting, multisegmental increases in manual pressure pain thresholds in healthy subjects, with significantly larger effects in the exercising body part compared with non- exercising body parts. Exercise intensity influences the magnitude of the EIH response, but the duration of exercise appears to be of less importance. Isometric exercises also increased cuff pain tolerance and reduced temporal summation of pain, illustrating the potential for isometric exercise as a rehabilitation procedure, also targeting the central mechanisms of pain. The effect of aerobic exercise on pain tolerance was less consistent and no effect was demonstrated on temporal summation of pain. The EIH response after aerobic exercise was increased in women and negatively correlated with age, however no influence of level of regular physical activity was found. The EIH response after isometric exercise was not influenced by age or gender. Patients with high pain sensitivity demonstrated reduced EIH responses after aerobic and isometric exercises and facilitated temporal summation of pain following high intensity aerobic exercise compared with patients with low pain sensitivity. Differences in mechanisms for the EIH responses after aerobic and isometric exercises may explain the different effect on central mechanisms of pain summation as well, as the difference in the EIH response after low intensity exercises demonstrated (I and III). 4. CURRENT PERSPECTIVES ON CONDITIONED PAIN MODULATION This chapter describes the current perspectives on conditioned pain modulation in healthy subjects and in patients with chronic pain. 4.1 Temporal and spatial manifestations of CPM in healthy subjects In the current experiments, cold pressor test induced heterotopic and homotopic increases in manual pressure pain thresholds during immersion of the hand and foot (I and II; Fig. 4.1) in agreement with previous studies (Pud et al., 2005; Oono et al., 2011). Cold pressor test hand Cold pressor test foot Fig. 4.1: Mean (+SEM) manual pressure pain threshold at the quadriceps muscle, biceps muscle and
trapezius muscle before, during, immediately after, and 15 min after cold pressor test at the dominant hand and foot (*, significant difference compared with baseline; NK: P < 0.05; Raw data from I). Pain tolerance increased (Fig. 4.2), and temporal summation of pain decreased significantly in both the arm and leg after cold pressor test on the hand (Fig. 4.3). A previous study reported similar findings in decreased cuff pain sensitivity assessed on the leg when conditioning stimulus was applied on the arm (Graven-Nielsen et al., 2012). Reduction in temporal summation of mechanical pain (Cathcart et al., 2009; Streff et al., 2011) and heat pain (Edwards et al., 2003a; Edwards et al., 2003b) has previously been demonstrated after CPM paradigms. However, in the current experiments, the stimulation intensity used for the temporal pain summation was increased after the cold pressor test, as an attempt to account for the pain sensitivity changes, and still the temporal summation effect was The cold pressor tests used in the current experiments were perceived as painful by all subjects, with most subjects reporting moderate to severe pain during cold water immersion (I and II). A significant positive correlation between the intensity of pain during cold pressor test on the foot and increase in heterotopic pressure pain threshold was found (I), but no association was found between the intensity of pain during cold pressor test on the hand and increase in pressure pain thresholds (I and II). This difference between cold pressor test on the hand and foot was unexpected. Having said that, this is the first study to compare cold pressor test on different limbs and further research is warranted. Although a clear relationship between the intensity of the conditioning stimulus and the strength of the resultant CPM has been reported (Villanueva and Le Bars, 1995), the influence of the intensity of perceived pain induced by a conditioning stimulus has been mixed. Some studies demonstrated a correlation with the magnitude of the CPM response (Treister et al., 2010; Nir et al., 2012) and some demonstrated no correlation with the magnitude of the CPM effect (Granot et al., 2008; Weissman- Fogel et al., 2008; Nir et al., 2011). A significant increase in manual pressure pain thresholds was in general only observed during the cold pressor stimulation. This is in agreement with previous studies, reporting an increase in pressure pain thresholds during noxious thermal stimulation, but not after (Kosek and Ordeberg, 2000b; Leffler et al., 2002a; Oono et al., 2011). Other investigators have, however, found a significant CPM response immediately after noxious stimulation (Pud et al., 2005) and up to 60 min after cold pressor test (Washington et al., 2000), indicating longer-lasting effects. Fig. 4.2:
Mean (+SEM) pain tolerance at the arm and leg before, immediately after, and 15 min after after cold pres sor test on the hand (*, significant difference from baseline; NK: P < 0.05; Unpublished data from experime nt 1 and 2). Fig. 4.3: Mean (±SEM) VAS scores during 10 repeated cuff stimulations at PTT level before,
imme diately after, and 15 min after cold pressor test on the hand. VAS scores are presented as mean
values from stimulations 1-4 (VAS-I), 5-7 (VAS-II), and 8-10 (VAS-III) (*, significant difference from
baseline; NK: P < 0.05; Unpublished data from e 3x6p eriment 1 and 2). The increase in manual pressure pain thresholds was only observed during the cold pressor stimulation (I and II), whereas the increase in pain tolerance and decrease in temporal summation of pain was also observed after cold pressor test (Fig. 4.2 and 4.3). The equivocal results on the temporal manifestations of the CPM response between manual algometry and cuff algometry may be due to the different temporal and spatial aspects of assessment. First of all, cuff algometry was performed after cold pressor test and not during, as was the case with manual algometry. Secondly, the equivocal results suggest either that spatial integration is a major determinant in pain modulation, or that the integration between spatial summation and temporal summation of pain is more sensitive to pain modulation after cold pressor test. Finally, the CPM response may influence pain thresholds, pain tolerance and temporal summation differently and a difference in the response on pain threshold, and pain tolerance after a CPM paradigm has previously been demonstrated (Sowman et al., 2011). 4.2 Gender and age related differences in CPM
Recent human studies have shown significant gender differences in CPM response (Staud et al., 2003c; Ge et al., 2004; Serrao et al., 2004; Arendt-Nielsen et al., 2008, Granot et al., 2008; Goodin et al. 2009; Honigman et al., 2013) and, according to a recent review (Popescu et al., 2010), the majority of the studies report significantly more efficient CPM in men compared with women. However, several other studies (France and Suchowiecki, 1999; Baad-Hansen et al., 2005; Pud et al., 2005; Quiton and Greenspan, 2007; Tousignant-Laflamme et al., 2008; Rosen et al., 2008; Cathcart et al., 2009; Wang et al., 2010; Grashorn et al., 2013; Nahman-Averbuch et al., 2014; Zheng et al., 2014), as well as the current experiments (I and II) demonstrated no influence of gender on the magnitude of the CPM response. Yet, a gender difference in the temporal manifestation of the CPM response was demonstrated. Young women demonstrated increased manual pressure pain thresholds during and immediately after cold pressor test compared with men who only demonstrated increases in manual pressure pain thresholds during cold pressor stimulation (II). Age was not significantly correlated with the CPM response (I), which is in agreement with a previous study (Nahman-Averbuch et al., 2014). Earlier studies using manual pressure pain (Lemly et al., 2014) or heat pain (Washington et al., 2000; Edwards et al., 2003a; Lariviere et al., 2007; Riley et al., 2010) as test stimuli, have established reduced CPM responses associated with ageing. The conflicting results may be related to different pain sensitivity assessment methodology or due to the different age groups included in the studies. The study by Lemley et al. (2014) assessed pressure pain thresholds and pain ratings before and after cold pressor test in two groups of subjects with a mean age of 21.9 and 72.0 years, respectively, with only young subjects demonstrating a CPM response. 4.3 Influence of regular physical activity on CPM Few studies have examined the relationship between regular physical activity and CPM response. In this PhD study, the manifestations of the CPM response between normally active and inactive healthy subjects were compared, and a robust increase in manual pressure pain thresholds was found in both active and inactive subjects (II; Fig. 4.4). Although the effect size indicated that the inactive subjects had a larger CPM response compared with active subjects, there was no significant difference in the CPM response between groups. This was further supported by the lack of association between times spent on physical activity and the CPM response during cold pressor test (II). A similar trend has previously been demonstrated in endurance athletes demonstrating less reduction in heat pain after a cold pressor test compared with healthy controls (Tesarz et al., 2013). Chronic pain has been associated with an impaired CPM response (Lewis et al., 2012b, Appendix 2) and a reduced CPM response in athletes could be due to regular pain during training and due to exercise-induced injuries as an additional source of pain. In contrast, Geva and Defrin (2013) demonstrated an increased CPM response in triathletes compared with controls. This study also showed that triathletes demonstrated significantly less fear of pain compared with controls and that the CPM response was significantly correlated with fear of pain and mental stress during training. This indicates that the more efficient pain inhibition in triathletes may also relate to psychological factors. The relation between increased physical activity and a greater CPM response was supported by Naugle and Riley (2014), who showed that greater amount of self-reported physical activity, as well as greater amount of vigorous physical activity, predicted a greater CPM response during cold pressor test. The conflicting results may be due to different pain sensitivity assessment methodologies, with pressure pain used to evaluate the CPM response in the current experiment (II) and heat pain used in the previous studies (Geva and Defrin, 2013; Tesarz er al., 2013; Naugle and Riley, 2013). Inactive subjects Fig. 4.4: Mean (+SEM) manual pressure pain threshold at the quadriceps muscle and biceps muscle
before, during, immediately after, and 15 min after cold pressor test at the dominant hand in active and inactive subjects (*, significant difference compared with baseline; NK: P < 0.05; Raw data from II). 4.4 CPM in patients with chronic pain The assessment of the CPM response in clinical studies has provided insights into the function of the pain inhibitory systems in chronic pain. Impaired CPM responses have previously been shown in long- lasting pain conditions such as chronic pancreatitis (Olesen et al., 2010; Bouwense et al., 2013), irritable bowel syndrome (Heymen et al., 2010), tension-type headache (Pielsticker et al., 2005; Sandrini et al., 2006; Cathcart et al., 2010), fibromyalgia (Kosek and Hansson, 1997; Lautenbacher and Rollman, 1997; de Souza et al., 2009; Normand et al., 2011; Paul-Savoie et al., 2012), temporomandibular disorder (King et al., 2009), chronic whiplash associated disorder (Daenen et al., 2013; Ng et al., 2014), and osteoarthritis (Kosek and Ordeberg, 2000a; Graven-Nielsen et al., 2012) compared with asymptomatic controls. The present experiment extends these findings by showing a reduced CPM response in chronic musculoskeletal pain patients with high pain sensitivity, compared with patients with less pain sensitivity (IV; Fig. 4.5). Only patients with low pain sensitivity demonstrated an increase in cuff pressure pain threshold and a decrease in pain ratings after cold pressor test (IV; Fig. 4.5). Cold pressor test did not affect temporal summation of pain in any of the pain sensitivity groups, highlighting potential differences in the effect of cold pressor test on central mechanisms of pain summation between healthy subjects (Fig. 4.3) and patients with chronic pain (IV). This finding is in agreement with a previous study on pain patients with chronic widespread pain (Staud et al., 2003a). A possible explanation is that patients with chronic musculoskeletal pain demonstrate facilitated temporal summation of pain making central mechanisms of pain summation less likely to be reduced by the competing mechanism of CPM. High pain sensitivity has recently been associated with impaired pain inhibition in 29 women subjects demonstrating a significant negative correlation between pain sensitivity assessed with the pain sensitivity questionnaire and pain modulation assessed by the offset analgesia paradigm (Honigman et al., 2013). Furthermore, the CPM response was negatively correlated with clinical peak pain intensity highlighting the importance of ongoing pain in the process of reduced CPM in chronic musculoskeletal pain (IV). The association between clinical pain intensity and the CPM response has previously been demonstrated in subjects with neuropathy (Nahman-Averbuch et al., 2011; Pickering et al., 2014) but not in temporomandibular disorder (Oono et al., 2014).
Fig. 4.5: Mean (± SEM) pressure pain threshold at the non-dominant lower leg before,
immediately after, and 15 min after cold pressor test at the dominant foot in chronic
musculoskeletal pain patients with high pain sensitivity (HPS, n = 30) and low pain sensitivity (LPS, n = 30) (*, significant difference compared with baseline. NK: P < 0.05; Raw data from IV). 4.5 Mechanisms of CPM The specific mechanisms involved in the CPM response in humans are largely unknown, but is believed to represent the net outcome of multiple descending pain inhibitory mechanisms. The most commonly used hypothesis to explain the CPM response to a painful condition stimulus, is the activation of a spino-bulbo-spinal loop through the subnucleus reticularis dorsalis (SRD) in the medulla (Villanueva et al., 1988), leading to an inhibition of wide-dynamic-range neurons in the dorsal horn (Le Bars et al., 1979a; Le Bars et al., 1981a; Willer et al., 1984; Talbot et al., 1987; Price and McHaffie, 1988; De Broucker et al., 1990; Bouhassira et al., 1993). Activation of the opioid system has also been linked with the CPM response (Le Bars et al., 1981b; Le Bars et al., 1981c; Bouhassira et al., 1992; Le Bars et al., 1992) and injection of naloxone, in both animals and humans caused a reduction in the inhibitory response after noxious thermal stimuli (Le Bars et al., 1981c; Willer et al., 1990; Sprenger et al., 2011). A reduced CPM response has also been reported in patients treated with opioids (Ram et al., 2008). These findings indicate involvement of an opioidergic mechanism in CPM, which could explain the heterotopic and homotopic hypoalgesic response during cold water immersion (I, II, and IV). However, naloxone does not completely abolish the CPM response (Sprenger et al., 2011) providing evidence for a non-opioid mechanism. Immersion of a body part in cold water produces sympathetically mediated heart rate and blood pressure increases (Weise et al., 1993; Chalaye et al., 2013). Interestingly, recent studies demonstrated a significant positive association between magnitude of the CPM response and increase in blood pressure during a cold pressor test in healthy subjects (Chalaye et al., 2013) and in patients with fibromyalgia (Chalaye et al., 2014), indicating that activation of a baroreceptor mechanism could be involved in the CPM response. Recent animal studies have also shown that systemic or local administration of a α1- adrenoceptor agonist and systemic administration of a selective α2-adrenoceptor agonist inhibit the painful CPM response (Sanada et al., 2009, Makino et al., 2010) suggesting the involvement of adrenergic neurons in the CPM response. Involvement of a baroreceptor mechanism and adrenergic neurons could also explain the heterotopic and homotopic hypoalgesic response during cold water immersion (I, II, and IV). In summary, cold pressor test applied to the hand and foot produced multisegmental increases in manual pressure pain thresholds during water immersion, as well as an increase in pain tolerance and a decrease in temporal summation of pain after water immersion. A significant association between the CPM response and the perceived pain during water immersion was only found for cold pressor test on the foot. The CPM response was not affected by age or level of physical activity, and the CPM response during water immersion was comparable between men and women. Patients with high pain sensitivity demonstrated a reduced CPM response after cold pressor test compared with patients with low pain sensitivity. The CPM response was negatively correlated with the clinical peak pain intensity, highlighting the importance of ongoing pain in the reduced CPM response. 5. SIMILARITIES IN MANIFESTATIONS OF CPM AND EIH Several similar manifestations between CPM and EIH were found in the current experiments (Table 5.1). Although the increase in manual pressure pain thresholds was larger during cold pressor tests, compared with exercise conditions (I and II), robust multisegmental increases in manual pressure pain thresholds were found in healthy men and women in relation to both paradigms (I and II). The CPM response and the EIH response after aerobic exercise were not affected by level of physical activity (II). The CPM response and the EIH response after isometric exercise were not affected by age and gender (I), and reduction in central mechanisms of pain summation was found after both paradigms (III, Fig. 4.3). Impaired CPM and EIH responses were found in patients with high pain sensitivity (IV). The similar manifestations between the CPM and EIH responses indicate a potential commonality in their underlying mechanisms. The CPM response may be involved in the EIH response after both isometric exercise (Lemley et al., 2014b) and aerobic exercise (Ellingson et al., 2013). To support this hypothesis, the clinical experiment (IV) demonstrated that the EIH response after aerobic exercise was predicted by the CPM response after cold pressor test, suggesting that individuals who demonstrated a greater ability to activate the descending inhibitory systems reported greater hypoalgesia following aerobic exercise. This relationship could also indicate that the increase in temporal summation of pain after aerobic exercise in patients with high pain sensitivity may be due to impaired descending inhibition. Ellingson et al. (2014) demonstrated a greater hypoalgesic response in 16 healthy women after painful aerobic exercise compared with non-painful aerobic exercise, supporting the link between the CPM and EIH responses. The relation between CPM and EIH could indicate similar mechanisms underlying the hypoalgesic response. However, hypoalgesia has also been demonstrated after non- painful aerobic exercise (Ellingson et al., 2014) indicating that the CPM response may work as an additive effect after painful exercise. Lemley et al. (2014) demonstrated that the CPM response predicted the EIH response after isometric exercise in healthy subjects, however this was not found in the current clinical experiment (IV). In the experiments on healthy subjects (I and II), a weak but significant correlation between the CPM and the EIH responses was demonstrated (II), supporting the hypothesis of similar mechanisms. This correlation was not demonstrated in a larger sample size (I), questioning the commonality of mechanisms underlying the CPM and EIH responses. These findings are in agreement with previous studies, comparing the CPM response with the response to the offset analgesia (OA) paradigm (Honigman et al., 2013; Nahman-Averbuch et al., 2014). Honigman et al. (2013) demonstrated a significant correlation between the maximal inhibitory responses in relation to the CPM and OA paradigms. Interestingly, the study by Nahman-Averbuch et al. (2014) found no significant correlation between the pain inhibitory responses, although similar methodology was used. Although several similar manifestations between the CPM and EIH responses were found in the current experiments, differences in temporal and spatial manifestations were also established (Table 5.1). First of all, a significant increase in manual pressure pain thresholds was only observed during the cold pressor stimulation (I, II), whereas eloquent increases were also found following exercise conditions (I and II), signifying differences in the temporal manifestations. Secondly, a notable larger effect on manual pressure pain thresholds at the remote sites, compared with the local site, was found during cold pressor test on the foot, whereas the increase in manual pressure pain thresholds was significantly larger in the exercising body part compared with remote sites after exercise conditions (I), showing differences in the spatial manifestations. These differences in temporal and spatial manifestations of the CPM and EIH responses indicate that partially different mechanisms may be involved.
Table 5.1: A comparison of the temporal and spatial manifestations of CPM and EIH in healthy subjects and in patients with chronic
musculoskeletal pain (cold pressor test)
(aerobic exercise)
(isometric exercise)
Pain thresholds: Pain thresholds: Pain thresholds: Multisegmental ↑ during Multisegmental ↑ after Multisegmental ↑ after Larger effects in heterotopic Larger effects in exercising body Larger effects in exercising body areas compared with homotopic part compared with remote areas part compared with remote areas Multisegmental ↑ after Multisegmental ↑ after Multisegmental ↑ after Temporal summation: Temporal summation: Temporal summation: subjects
Multisegmental ↓ after Multisegmental ↓ after Age: No influence Age: ↓ EIH with ↑ age Age: No influence Gender: No influence during Gender: ↑ in women Gender: No influence conditioning stimuli, but ↑ duration in women Physical activity: No influence Physical activity: No influence Physical activity: Unknown Manual pain thresholds: Manual pain thresholds: Manual pain thresholds: Multisegmental ↑ during Multisegmental ↑ after Multisegmental ↑ after Cuff pain threshold: Cuff pain threshold: Cuff pain threshold: Increase in patients with low Increase in patients with low pain Increase in patients with low pain pain sensitivity. No effect in sensitivity. No effect in patients sensitivity. No effect in patients patients with high pain with high pain sensitivity with high pain sensitivity Segmental ↑ after Segmental ↑ after Segmental ↑ after Temporal summation: No effect Temporal summation: Increase in Temporal summation: No effect patients with high pain sensitivity. No effect in patients with low pain Predicted by clinical peak pain No significant relation was found No significant relation was found The CPM response predicted the EIH response after aerobic exercise 6. CONCLUSIONS AND FUTURE PERSPECTIVES Based on the results of the current PhD study, the following conclusions can be made (Fig. 6.1): 1. Cold pressor test (CPM response) as well as aerobic and isometric exercises (EIH responses) produced multisegmental increases in manual pressure pain thresholds in healthy men and women (I 2. The CPM response and the EIH response after isometric exercise were not affected by age and gender. The EIH response after aerobic exercise was increased in women (I) and decreased with increasing age (III). 3. The increase in manual pressure pain thresholds was comparable between active and inactive men and women during cold pressor tests and after aerobic exercise (II). 4. The temporal and spatial manifestations of hypoalgesia were partly different for the EIH and CPM paradigms, and there was no consistent correlation between the maximal EIH response and the maximal CPM response in healthy subjects (I and II). 5. High intensity exercise produced larger increases in manual pressure pain thresholds than low intensity exercise (I). 6. Aerobic and isometric exercises increased pain tolerance, but only isometric exercises reduced temporal summation of pain, illustrating the potential for isometric exercise as a rehabilitation procedure, also targeting the central mechanisms of pain summation (III). 7. The EIH and CPM responses were partly impaired in chronic musculoskeletal pain patients with high pain sensitivity compared with patients with low pain sensitivity (IV). 8. Aerobic exercise further facilitated temporal summation of pain in chronic musculoskeletal pain patients with high pain sensitivity (IV). 9. The CPM response was predicted by clinical peak pain intensity, and the CPM response predicted the EIH response after aerobic exercise (IV). These findings have implications for future evaluation of the pain inhibitory systems as well as for clinical practice. An impaired CPM response is commonly observed in clinical pain populations with chronic pain of musculoskeletal (Normand et al., 2011; Graven-Nielsen et al., 2012), neuropathic (Pickering et al., 2014) or visceral origin (King et al., 2009; Heyman et al. 2010). An impaired EIH response has primarily been demonstrated in chronic pain of musculoskeletal origin, and it is currently unknown whether a reduced EIH response is also observed in other pain conditions. The evaluation of the pain inhibitory systems with multiple paradigms (e.g. CPM and EIH) may provide additional information about the pain inhibitory phenotype of the individual patient. For example, a patient may have an intact CPM response but a reduced EIH response and vice versa. The CPM paradigm alone may not be a sufficient paradigm to assess the wide scope of pain modulation, and multifaceted assessment might therefore have an important role in future pain assessment. In clinical practice, it may be recommended that clinicians evaluate pain sensitivity, as well as the CPM and EIH responses, in addition to clinical pain, when considering treatment options utilizing the descending inhibitory pain control. The current results imply that chronic musculoskeletal pain patients with high pain sensitivity demonstrated less efficient pain inhibition. In conclusion, the present work on EIH and CPM has provided new information on assessment of the pain inhibitory systems as well as on the effect of different exercise modalities on the pain system. The results might be helpful to improve assessment and treatment of chronic musculoskeletal pain disorders in the future. 1. Compare temporal and spatial 1. Compare CPM and EIH 1. Compare CPM and EIH between manifestations of CPM and EIH between active and inactive patients with high and low pain 2. Investigate gender and age effect 2. Investigate gender effect 2. Investigate the effect of clinical 3. Investigate dose-response on pain intensity and psychological 3. Investigate the effect of distress on CPM and EIH 4. Investigate the effect of exercise exercise on central 3. Investigate the effect of exercise on central mechanisms of pain mechanisms of pain on central mechanisms of pain 1. The temporal and spatial 1. The increase in pressure 1. The EIH and CPM responses were manifestations of hypoalgesia pain thresholds was partly impaired in patients with high were partly different for the EIH comparable between active versus less pain sensitivity and CPM paradigms, and no and inactive men and consistent significant correlation women during cold pressor 2. The CPM response predicted the between the EIH response and the tests and after aerobic EIH response after aerobic exercise CPM response was found The CPM response was predicted by clinical peak pain intensity 2. The CPM response and the EIH 2. The CPM response response after isometric exercise during cold pressor test and 3. Aerobic exercise facilitated were not affected by age and the EIH response after temporal summation of pain in gender. Part of the EIH response aerobic exercise were patients with high pain sensitivity after aerobic exercise was comparable in men and increased in women and Conclusions
negatively correlated with age 3. Aerobic exercise 3. High intensity exercise increased pain tolerance but produced larger increases in did not significantly reduce pressure pain thresholds than low temporal summation of pain intensity exercise. No dose- response pattern was found on the effect of exercise on pain tolerance and temporal summation of pain 4. Isometric exercises increased pain tolerance and reduced temporal summation of pain Fig. 6.1: Illustration of the aims and conclusions of the experiments.
‘CPM': Conditioned Pain Modulation. ‘EIH': Exercise-induced Hypoalgesia. Temporal and Spatial Manifestations of Exercise-induced Hypoalgesia and Conditioned Pain
Modulation
Introduction: Impaired pain inhibition is believed to be involved in several chronic pain conditions.
Efficiency of the pain inhibitory pathways is typically assessed by paradigms of conditioned pain modulation (CPM) or exercise-induced hypoalgesia (EIH). Still, the spatial and temporal manifestations of the two paradigms have never been directly compared, and it is unknown whether the paradigms provide equivalent data on pain inhibition. Furthermore, physical exercise is an important component in the treatment and rehabilitation of patients with chronic musculoskeletal pain and a comprehensive understanding of how exercise influences the nociceptive and pain inhibitory pathways is necessary to optimize the clinical utility of exercise. The aims of this PhD project were 1) to compare the temporal and spatial manifestation of EIH and CPM, 2) to investigate the influence of age, gender and level of regular physical activity on CPM and EIH, 3) to investigate the influence of exercise modality, intensity and duration on the EIH response in healthy subjects, 4) to investigate the effect of exercise on central mechanisms of pain, and 5) to investigate the influence of pain sensitivity and clinical pain characteristics on CPM and EIH in patients with chronic musculoskeletal pain. Methods: Three experiments were conducted. Experiment 1: 80 healthy subjects (40 women and 40
men) performed cold pressor tests on the hand and foot as well as aerobic and isometric exercises at the arm and leg with different intensities and durations. Experiment 2: 56 healthy subjects (30 active and 26 inactive) performed a cold pressor test, an aerobic exercise and a control condition. Experiment 3: 61 patients with chronic musculoskeletal pain (31 with high pain sensitivity and 30 with low pain sensitivity) performed cold pressor test, aerobic and isometric exercises and a control condition. In all three experiments, pressure pain thresholds, pressure pain tolerances and temporal summation of pain were assessed with manual algometry and computerized cuff algometry at local and distant body sites before and after conditions. Results: Manual algometry and cuff algometry demonstrated good test-retest reliability.
Experiment 1 demonstrated robust multisegmental increases in manual pressure pain thresholds in men and women during cold pressor tests and after high intensity aerobic and low and high intensity isometric exercise conditions. The CPM response and the EIH response after isometric exercises were not affected by age or gender. Part of the EIH response after aerobic exercise was increased in women and decreased with increasing age. Differences in temporal and spatial manifestations between the EIH response and the CPM response were found, and there was no significant correlation between the maximal EIH response and the maximal CPM response, indicating partly different mechanisms. The increase in pressure pain thresholds was larger in the exercising body part compared with non- exercising body parts, and high intensity exercise produced larger increases in pressure pain thresholds than low intensity exercise. Isometric exercises also increased cuff pain tolerance and reduced temporal summation of pain, illustrating the potential for isometric exercise as a rehabilitation procedure, also targeting the central mechanisms of pain. Experiment 2 demonstrated comparable multisegmental increases in manual pressure pain thresholds in active and inactive men and women during cold pressor tests and after aerobic exercise, indicating that physical inactivity does not alter the magnitude of the EIH and CPM responses compared to regular physical activity. Aerobic exercise also increased cuff pain tolerance, but did not affect temporal summation of pain. Experiment 3 demonstrated partly impaired EIH and CPM responses in chronic musculoskeletal pain patients with high versus less pain sensitivity. Aerobic exercise facilitated temporal summation of pain in patients with high pain sensitivity. The CPM response was predicted by clinical pain intensity and the EIH response after aerobic exercise was predicted by the CPM response. These findings have implications for future evaluation of the pain inhibitory systems as well as for clinical practice. The evaluation of pain inhibition with multiple paradigms (e.g. CPM and EIH) may provide additional information about the pain inhibitory phenotype of the patient. For example, a patient may have an intact CPM response but a reduced EIH response and vice versa. In clinical practice, clinicians should evaluate general pain sensitivity, as well as the CPM and EIH responses in addition to evaluating clinical pain when considering treatment options, utilizing the descending inhibitory pain control. In conclusion, the present work on EIH and CPM may help guiding the choice of exercise in future assessment and rehabilitation of chronic musculoskeletal pain patients. SAMMENDRAG (Danish summary) Tids- og Rummæssige Manifestationer af Træningsinduceret Smertelindring og Betinget
Indledning: Nedsat smertehæmning menes at være involveret i flere kroniske smertetilstande.
Effektiviteten af de smertehæmmende systemer vurderes typisk via den betingede smerte modulation (CPM) eller træningsinduceret smertelindring (EIH). De tids- og rummæssige manifestationer af CPM og EIH er aldrig tidligere blevet direkte sammenlignet, og det er fortsat uvist, om paradigmerne giver ækvivalent information om smertehæmning. Træning er desuden en vigtig komponent i behandlingen af patienter med kroniske smerter i bevægeapparatet, og en større forståelse af, hvordan træning påvirker smertesystemet og smertehæmning, er nødvendigt for at optimere den kliniske anvendelighed Formålene med dette ph.d.-projekt var 1) at sammenligne de tids- og rummæssige manifestationer af EIH og CPM, 2) at undersøge betydningen af alder, køn og graden af habituel fysisk aktivitet på EIH og CPM, 3) at undersøge betydningen at trænings-type, -intensitet og -varighed på graden af EIH, 4) at undersøge effekten af træning på de centrale smertemekanismer, og 5) at undersøge hvilken indflydelse smertesensitivitet og kliniske smerte karakteristika har på CPM og EIH responsen hos patienter med kroniske smerter i bevægeapparatet. Metoder: Tre eksperimenter blev udført. Eksperiment 1: 80 raske forsøgspersoner (40 kvinder og 40
mænd) udførte isvandstest på hånd og fod samt aerobe og isometriske træningsøvelser for arm og ben ved forskellige intensiteter og varigheder. Eksperiment 2: 56 raske forsøgspersoner (30 aktive og 26 inaktive) udførte isvandstest, aerob træning og en kontrolkondition. Eksperiment 3: 61 patienter med kroniske smerter i bevægeapparatet (31 med høj smertesensitivitet og 30 med lav smertesensitivitet) udførte isvandstest, aerob og isometrisk træning og en kontrolkondition. I alle tre eksperimenter blev tryksmertetærsklen, tryksmertetolerancen og tidsmæssig summation af smerte ved gentagne trykstimuli vurderet med håndholdt trykalgometri og computerstyret cuffalgometri på lokale og perifere steder på kroppen før og efter de forskellige konditioner. Resultater: Håndholdt trykalgometri og computerstyret cuffalgometri viste god test-retest
pålidelighed. Eksperiment 1 viste robuste, multisegmentalt øgede tryksmertetærskler hos mænd og kvinder under isvandstest samt efter højintensitets aerob og lav- og højintensitets isometrisk træning. CPM responsen og EIH responsen efter isometrisk træning var ikke påvirket af forsøgspersonernes alder eller køn. EIH responsen efter aerob træning var større hos kvinder, men aftagende med stigende alder. Forskelle i tids- og rummæssige manifestationer mellem EIH responsen og CPM responsen blev fundet, og der var ingen konsistent korrelation mellem den maksimale EIH respons og den maksimale CPM respons, hvilket indikerer forskellige mekanismer. Ændringen i tryksmertetærskel var størst på den kropsdel, hvor træningen blev udført sammenlignet med kropsdele, der ikke udførte træningen. Højintensitets træning resulterede i en større ændring i tryksmertetærsklen end lavintensitets træning. Isometrisk træning øgede også smertetolerancen og reducerede den tidsmæssige summation af smerte, hvilket illustrerer potentialet for at isometrisk træning kan reducere de centrale smertemekanismer. Eksperiment 2 viste sammenlignelige ændringer i tryksmertetærsklen hos aktive og inaktive mænd og kvinder under isvandstest og efter aerob træning, hvilket indikerer, at inaktivitet ikke reducerer smertehæmningen sammenlignet med regelmæssig fysisk aktivitet. Aerob træning øgede smertetolerancen, men påvirkede ikke den tidsmæssige summation af smerten. Eksperiment 3 viste delvist reduceret EIH og CPM i patienter med kroniske bevægeapparatssmerter og høj smertesensitivitet i forhold til patienter med lav smertesensitivitet. Aerob træning øgede den tidsmæssige summation af smerte hos patienter med høj smertesensitivitet. CPM responsen var prædikteret af den kliniske smerteintensitet, og EIH responsen efter aerob træning var prædikteret af Disse fund har implikationer for fremtidig undersøgelse af de smertehæmmende systemer og for klinisk praksis. Fremtidig undersøgelse af de smertehæmmende systemer med multiple paradigmer (ex. CPM og EIH) kan give yderligere information om det enkelte individs smertehæmmende fænotype. For eksempel kan en patient fremstå med en intakt CPM respons, men med en reduceret EIH respons eller omvendt. I klinisk praksis bør klinikere fremadrettet vurdere den generelle smertesensitivitet og CPM- og EIH-responsen i tillæg til vurdering af den kliniske smerteintensitet når behandlingsmuligheder, der påvirker de smertehæmmende systemer, overvejes. De indeværende studier om EIH og CPM har givet nye informationer om undersøgelse af de smertehæmmende systemer samt om effekten af forskellige træningstyper på smertesystemet. 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Temporal stability of conditioned pain modulation in healthy women over four menstrual cycles at the follicular and luteal phases. Pain 154:2633-38. Wonders, K. Y., Drury, D. G. (2011). Exercise Intensity as a Determinant of Exercise Induced Hypoalgesia. Journal of Exercise Physiology 14:134-44. Woodrow, K. M., Friedman, G. D., Siegelaub, A. B., Collen, M. F. (1972). Pain tolerance: differences according to age, sex and race. Psychosom Med 34:548-56. Yarnitsky, D., Crispel, Y., Eisenberg, E., Granovsky, Y., Ben-Nun, A., Sprecher, E., Best, L. A., Granot, M. (2008). Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk. Pain 138:22-28. Yarnitsky, D. (2010a). Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol 23:611-15. Yarnitsky, D., Arendt-Nielsen, L., Bouhassira, D., Edwards, R. R., Fillingim, R. B., Granot, M., Hansson, P., Lautenbacher, S., Marchand, S., Wilder-Smith, O. (2010b). Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 14:339. Yarnitsky, D., Granot, M., Nahman-Averbuch, H., Khamaisi, M., Granovsky, Y. (2012). Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain 153:1193-98. Yarnitsky, D., Granot, M., Granovsky, Y. (2014). Pain modulation profile and pain therapy: Between pro- and antinociception. Pain 155:663-65. Yarnitsky, D., Bouhassira, D., Drewes, A. M., Filingim, R. B., Granot, M., Hansson, P., Landau, R., Marchand, S., Matre, D., Nilsen, K. B., Stubhaug, A., Treede, R. D., Wilder-Smith, O. H. G. (2014). Recommendations on practice of conditioned pain modulation (CPM) testing. Eur J Pain: In Press. Yu, X. M., Mense, S. (1990). Response properties and descending control of rat dorsal horn neurons with deep receptive fields. Neuroscience 39:823-31. Zheng, Z., Wang, K., Yao, D., Xue, C. C., Arendt-Nielsen, L. (2014). Adaptability to pain is associated with potency of local pain inhibition, but not conditioned pain modulation: A healthy human study. Pain 155:968-76. Øktedalen, O., Solberg, E. E., Haugen, A. H., Opstad, P. K. (2001). The influence of physical and mental training on plasma beta-endorphin level and pain perception after intensive physical exercise. Stress and Health 17:121-27. Appendixes 1-4 are summaries of experimental and clinical studies on CPM and EIH in humans. Ongoing literature searches in the following databases: PubMed, Web of Science, Embase, CINAHL and PEDro, has been conducted throughout the study period. The following keywords were used for searches on CPM: ‘conditioned pain modulation', ‘CPM', ‘pain modulation', ‘endogenous pain modulation', ‘counterirritation', ‘endogenous analgesia', ‘heterotopic noxious conditioning stimulation', ‘diffuse noxious inhibitory controls', ‘DNIC'. The following keywords were used for searches on EIH: ‘exercise-induced hypoalgesia', ‘EIH', ‘exercise-induced analgesia', ‘EIA', ‘exercise analgesia' and ‘exercise hypoalgesia'. Furthermore, the reference list from each identified study and review was examined for studies that were not identified through the databases. However, the summaries are not part of a systematic literature review on CPM and EIH and thus may not be
Appendix 1: A summary of experimental studies investigating conditioned pain modulation in healthy human adults, primarily organized according to the
conditioning stimuli in the following order: ‘cold pressor test', ‘cold pack', 'hot water', ‘heat pain', ‘tourniquet test', ‘mechanical pressure', ‘electrical stimulation',
‘hypertonic saline', ‘more than one paradigm' and secondly after year of publication.
Reference
Healthy Subjects
Control condition
Conditioning stimulus
Pain sensitivity
Main findings
‘cold pressor test'
parameters
Intensity
Location

(Talbot et al., 1987) 10 healthy subjects Within-subject control Cold pressor test (5ºC) Heat pain threshold and Heat pain intensity was reduced during CPM. rating on the upper lip Heat pain tolerance was increased during and 19-36 years of age during and after CPM (Talbot et al., 1989) 10 healthy subjects Within-subject painful and Cold pressor test (5ºC) Noxious heat stimuli Heat detection latencies were increased during non-painful CPM paradigms detection changes on the the painful CPM paradigm 19-37 years of age (Edwards et al., 45 healthy young adults Different CPM paradigms Cold pressor test (5ºC or 22ºC) Temporal summation of Younger subjects: Temporal summation was
heat at the left forearm decreased during painful CPM paradigm on both Older subjects: Temporal summation was
48 healthy older adults increased during painful CPM paradigm on both (Edwards et al., 45 healthy young adults Different CPM paradigms Cold pressor test (5ºC or 22ºC) Temporal summation of CPM was not related to laboratory pain heat at the left forearm responses, psychological variables or physiological variables 48 healthy older adults (32/16) 63.1 (55-67) (Serrao et al., 2004) 36 healthy subjects Within-subject painful and Cold pressor test (2-4ºC) Nociceptive flexion Cold pressor test induced a significant reduction non-painful CPM paradigms reflex and pain rating of the NFR. The reduction was larger in men 24-39 years of age elicited by sural nerve compared with women stimulation during and after CPM (Baad-Hansen et al., 54 healthy subjects Control CPM paradigm with Cold pressor test (1-2ºC) Pain intensity and Pain intensity and unpleasantness decreased unpleasantness during Non-dominant hand capsaicin-evoked pain No gender differences intra orally during and after CPM (Pud et al., 2005) 40 healthy subjects Cold pressor test (1ºC) Both hands demonstrated CPM with no mechanical punctate difference between hands. No difference was Fingers at right hand stimuli on the thenar found between men and women eminence on both hands after cold pressor test (Lariviere et al., 20 healthy young adults Cold pressor test (7ºC) Heat pain ratings at the Young healthy adults: Significant CPM
Middle aged healthy adults: significant CPM
20 middle-aged adults Older healthy adults: No CPM response
(10/10) 47.0 (4.5) 20 older adults (10/10) 68.1 (3.8) (Smith et al., 2007) 32 healthy subjects Randomized to 3 different Cold pressor test (4ºC) Pressure pain threshold CPM was reduced in the forced awakening group on the trapezius, masseter and brachioradialis muscles during CPM (Rosen et al., 2008) 30 healthy subjects Cold pressor test (2-4ºC) Electrical pain thresholds Pressure pain thresholds increased during and at the orofacial region immediately after the CPM paradigm No difference was found between men and Pressure pain threshold at the masseter muscle Electrical pain threshold at the finger increased and the finger during and during and after the CPM paradigm after the CPM paradigm 35 healthy subjects Cold pressor test (4ºC) Pressure pain threshold Significant CPM response. Men had larger CPM left forearm and response compared with women. CPM and trapezius during CPM. catastrophizing was inversely correlated. 32 healthy subjects Within-subject different Cold pressor test (10ºC) for Pressure pain threshold Cold pressor tests at 2ºC and repeated cold and sharpness at the pressor tests at 4ºC produced CPM 17-51 years of age forehead after CPM Cold pressor test at 10ºC produced no CPM Cold pressor test (2ºC) 1 min Dominant hand Repeated cold pressor test (4ºC) 1 min Dominant hand (Riley et al., 2010) 27 younger healthy subjects Within-subject painful and Cold pressor test (8-16ºC) Heat pain rating on the Younger subjects: Heat pain ratings were
non-painful CPM paradigms. reduced during painful CPM paradigm Older subjects: Facilitation of heat pain rating
22 older healthy subjects during the painful CPM paradigm (18/4) 65.2 (6.9) (Treister et al., 191 healthy subjects Within-subject painful and Cold pressor test (12ºC) Heat pain rating on the Significant CPM effects during and immediately non-painful CPM paradigms thenar eminence of the after painful and non-painful cold pressor test. Non-dominant hand left hand during and after Repeated pain testing also decreased pain ratings. The CPM effect for painful cold pressor test was significantly larger than the other two paradigms. The CPM response was correlated to conditioning pain scores in men (Rezaii et al., 2012) 36 healthy subjects Different painful and non- Cold pressor test (3ºC) Pressure pain rating on Pain rating decreased during and immediately painful CPM paradigms the masseter muscles after painful CPM paradigm during and after CPM Subjects in ovulatory phase had larger CPM response compared with the early follicular phase 72 healthy subjects 1/3 of the subjects were told Cold pressor test (8ºC) Heat pain ratings at the In women: Decrease in pain rating in analgesic
that the CPM paradigm non-dominant hand group and increase in pain rating in hyperalgesic (19-33 years of age) would reduce pain, 1/3 that it would increase pain and 1/3 In men: No difference in any of the groups
were not giving any information (Grashorn et al., 22 healthy young adults Cold pressor test (0ºC) Heat pain ratings at the Younger subjects Significant CPM response
right forearm during and Middle aged subjects: No CPM response
Older subjects: No CPM response
No difference in CPM between men and women 17 middle-aged adults (9/8) 48.7 (5.3) 25 older adults (13/12) 70.3 (5.2) (King et al., 2013) 33 healthy subjects Within-subject placebo and Cold pressor test (avg.: 12.9±2.7ºC) Heat pain ratings on left CPM during placebo but not during naltroxen naltroxen conditions No difference in CPM based on catastrophizing (Geva and Defrin, 17 non- athletes Cold pressor test (12ºC) Heat pain rating and Athletes: Significant CPM response
temporal summation Non-athletes: Significant CPM response
The CPM effect on pain ratings was larger in the triathletes. A trend towards greater CPM with greater time spent on exercise (Chalaye et al., 26 healthy subjects Cold pressor test (7ºC) Heat pain rating on left Pain ratings decreased after CPM forearm after CPM Correlated with increase in blood pressure Right hand and forearm 149 healthy subjects Cold pressor test (4ºC) Pressure pain threshold Significant CPM response during cold pressor left forearm and trapezius during CPM Greater optimism was associated with greater CPM (Tesarz et al., 2013) 25 healthy endurance athletes No within-subject control Cold pressor test (12ºC) Heat pain rating on the Athletes: Significant CPM response
dorsum of the hand after Non-athletes: Significant CPM response
Non-dominant hand The CPM response was significantly larger in 26 normally active controls (0/26) 28.0 (4.5) (Riley et al., 2014) 89 middle-aged subjects Different painful and non- .Repeated cold pressor test (8ºC) Heat pain rating and No significant CPM responses in any group painful CPM paradigms temporal summation on 45-56 years of age left forearm after CPM 102 older-aged subjects (69/33) 57-76 years of age. (Naugle and Riley, 48 healthy subjects Cold pressor test (10-12ºC) Heat pain rating on the Cold water produced CPM left forearm during CPM Greater self-reported vigorous physical activity predicted greater CPM (Biurrun Manresa et 34 healthy subjects Between sessions reliability Cold pressor test (2ºC) Nociceptive flexion Significant CPM effect for all measures reflex (NFR) and NFR showed good reliability, although higher in Non-dominant hand electrical pain threshold session 1 compared with session 2 and pain intensity at the dominant sural nerve during CPM 20 healthy young subjects Within subject (exercise, rest Cold pressor test (2ºC) Pressure pain intensity at Young subjects: Significant CPM response
and neutral water bath) the right index finger Old subjects: No CPM response
Greater CPM in more physical active subjects 19 healthy old subjects No relation between CPM and fear of pain/catastrophizing or pain attitude Reference
Healthy Subjects
Control condition
Conditioning stimulus
Pain sensitivity
Main findings
‘cold pack'
parameters
Intensity
Location

(Ladouceur et al., 31 healthy subjects Within-subject different Pain ratings and RIII The painful paradigm reduced pain ratings and painful and non-painful CPM reflex by stimulation on RIII reflex during the CPM paradigm the sural nerve during The non-painful paradigm reduced pain rating the CPM paradigms when attention was focused on the conditioning stimulus. RIII was also reduced with the non-painful paradigm but to a smaller extent compared with the painful paradigm Reference
Healthy Subjects
Control condition
Conditioning stimulus
Pain sensitivity
Main findings
‘hot water'
parameters
Intensity
Location

(Willer et al., 1990) 9 healthy subjects Within-subject placebo and Hot water bath (46ºC) Nociceptive flexion The NFR response was decreased during and naloxone conditions reflex of the sural nerve after the CPM paradigm 23-36 years of age during and after the Naloxone completely abolished the inhibitory effects of the CPM paradigm (Moont et al., 2010) 34 healthy subjects Different CPM paradigms Hot water bath (46.5ºC) Hot water produced hypoalgesia in most of the with and without distraction unpleasantness ratings subjects. The combined effects of CPM and distraction were larger than for CPM alone (Nir et al., 2011) 30 healthy subjects Within-subject different Hot water bath (44.5ºC) Heat pain rating on the Significant CPM response with 45.5ºC and right forearm during Non-dominant hand No significant correlation between CPM and conditioning pain levels Hot water bath (45.5ºC) 1 min Non-dominant hand. Hot water bath (46.5ºC) 1 min Non-dominant hand. (Nir et al., 2012) 48 healthy subjects Between-subjects different Hot water bath (45.5ºC) Heat pain rating on The perceived magnitude of the conditioning paradigms manipulating dominant forearm during pain affected the CPM response. Lower subjects experience of the Non-dominant hand perceived pain decreased the CPM response (Liebano et al., 60 healthy subjects Between subject different Hot water bath (46.5ºC) Pressure pain threshold Pressure pain and heat pain thresholds increased and heat pain threshold Right hand + active TENS at the left extensor No difference between groups with CPM + muscle of the left active versus placebo TENS Hot water bath (46.5ºC) forearm during CPM 2 min Right hand + placebo TENS (Honigman et al., 29 healthy subjects Within-subject different Hot water bath (46ºC) Heat pain ratings at the Men: Significant CPM response.
dominant forearm during Women: No CPM response
Non-dominant arm 34 healthy subjects Within-subject intersession Hot water bath (46.5ºC) Heat pain rating at the The CPM paradigm significantly reduced heat test-retest reliability for the dominant forearm during pain rating during the conditioning stimulus CPM paradigm. Tested in Non-dominant hand the CPM paradigm The inter session test-retest reliability was poor different phases of the Reference
Healthy Subjects
Control condition
Conditioning stimulus
Pain sensitivity
Main findings
‘heat pain'
parameters
Intensity
Location

7 healthy subjects Different painful and non- Painful and non-painful heat Electrical stimuli Short-lasting CPM was produced by painful painful CPM paradigms inducing first and second 22-45 years of age pain on the ankle during Degree of inhibition was largest on second pain Ankle or the abdominal region compared with first pain (Defrin et al., 2010) 17 healthy subjects Within-subject control Heat pain at different body regions Heat pain rating on the CPM during conditioning stimulus condition with non-painful forearm during CPM The CPM response increased as the distance between the test and conditioning sites increased. However, non-noxious conditioning stimulus also reduced pain ratings when performed at the contralateral leg Reference
Healthy Subjects
Control condition
Conditioning stimulus
Pain sensitivity
Main findings
‘tourniquet test'
parameters
Intensity
Location

83 healthy subjects Nociceptive flexion Reduced NFR during and 5 min after CPM in Suchowiecki, 1999) reflex (NFR) at the left both men and women sural nerve during and after CPM 113 healthy subjects Nociceptive flexion Reduced NFR during and 5 min after CPM in Suchowiecki, 2001) reflex (NFR) at the left both men and women. sural nerve during and No difference between offspring of hypertensive individuals compared with offspring of normotensive individuals (Tuveson et al., 18 healthy subjects Pressure pain threshold Significant CPM responses on pressure pain and pain rating as well as threshold on both sides during CPM heat pain threshold and The CPM effect on pressure pain and heat pain pain rating on both intensity differed between first and second thighs during and after assessed thigh, with inhibitory effects on the first assessed thigh and facilitated effects on the second Heat pain threshold was not affected during CPM (Cathcart et al., 20 healthy subjects Within-subject intrasession Temporal summation to Temporal summation was reduced at both sites test-retest reliability for the pressure pain on the right during the CPM paradigm middle finger and No difference was found between men and trapezius muscle during the CPM paradigm The CPM paradigm showed high to excellent reliability on the trapezius and moderate at the finger (Bartley and Rhudy, 41 healthy subjects Different menstrual phases Electrical pain rating and Pain ratings reduced during and after CPM nociceptive flexion reflex (NFR) at sural NFR reduced during CPM paradigm nerve during and after No difference between mid-follicular or late- luteal menstrual phases Reference
Healthy Subjects
Control condition
Conditioning stimulus
Pain sensitivity
Main findings
‘mechanical pressure'
parameters
Intensity
Location

11 healthy subjects Within-subject painful and A compression device Pressure pain threshold Significant CPM response on pain threshold at non-painful CPM paradigms and tolerance on the the leg and face during the painful paradigm. face, neck, finger, arm No effect on pain tolerance and leg during and after CPM (Oono et al., 2011) 40 healthy subjects Different painful and non- Pressure pain thresholds The most painful paradigm was associated with painful CPM paradigms at the right masseter the largest CPM response muscle and left forearm (Oono et al., 2012) 40 healthy subjects Within-subject session with Pressure pain thresholds CPM in both sessions and without additional at the right masseter Acute pain induced during CPM did not alter the muscle and left forearm Reference
Healthy Subjects
Control condition
Conditioning stimulus
Pain sensitivity
Main findings
‘electrical stimulation'
parameters
Intensity
Location

62 healthy subjects Different painful and non- Electrical stimulations. Stimulations Heat pain ratings on CPM was produced in men and women after Greenspan, 2007) painful CPM paradigms were distracting, stressful or painful right leg during CPM distracting and painful CPM paradigms Some gender differences were detected for the Left median nerve distraction CPM paradigm 68 healthy subjects Between-subject low and Low and high frequency electrical Pressure pain thresholds Pressure pain threshold was increased after both high frequency CPM at the forehead after 18-51 years of age Reference
Healthy Subjects
Control condition
Conditioning stimulus
Pain sensitivity
Main findings
‘hypertonic saline'
parameters
Intensity
Location

(Graven-Nielsen et 14 healthy subjects Within-subject isotonic Hypertonic saline injection Pressure pain threshold Pressure pain threshold increased at the arm saline injection at the tibialis anterior during hypertonic saline injection Tibialis anterior muscle Reference
Healthy Subjects
Control condition
Conditioning stimulus
Pain sensitivity
Main findings
‘more than 1 CPM paradigm'
parameters
Intensity
Location

(Svensson et al., 14 healthy subjects Between-subject different Intramuscular injection of Electrical pain rating at Both painful and non-painful CPM paradigms painful and non-painful CPM hypertonic saline the left tibialis anterior reduced pain ratings during CPM muscle during CPM Arm and leg Non-painful vibration ? Arm and leg (Lautenbacher et 20 healthy subjects Within-subject different Hot water bath (46.5ºC) Heat pain ratings at the Painful water and painful heat produced CPM. cheeks during CPM Non painful conditioning stimuli produced some inhibitory effects Hot water bath (42ºC) 1 min Hand Painful and non-painful heat stimulations 5 min Forearm (Arendt-Nielsen et 20 healthy subjects Different CPM paradigms Hypertonic saline injection Pressure pain thresholds Men had higher CPM response during hypertonic around both knees saline injection Tibialis anterior muscle during and after CPM Men and women had CPM response during cold Cold pressor test (1-2ºC) The increase was largest in men 5 min Left hand Both paradigms induced simultaneously (Granot et al., 2008) 31 healthy subjects Within-subject control Cold pressor test (12, 15, 18ºC) Heat pain ratings during CPM after 12ºC and 46.5ºC condition with non-painful Greater CPM in men compared with women Non-dominant hand No effect of age was found Hot water (44, 44.6ºC) 1 min Non-dominant hand (Wang et al., 2010) 24 healthy subjects Within-subject different Mechanical headband Pressure pain thresholds Both CPM paradigms increased pressure pain at the head, neck, elbow thresholds in both men and women and finger during CPM Cold headband 10 min Head (Streff et al., 2011) 24 healthy subjects Between-subject different Hot water bath (47ºC) Temporal summation to Both CPM paradigms produced CPM on heat and pressure on the temporal summation for heat and pressure. Non-dominant hand left middle finger after The paradigms were equally effective Pinch pressure 2 min Inter-digital web on hand 20 healthy subjects Within-subject different Pressure pain threshold Pressure pain threshold increased during and 10 at the medial joint line min after both CPM paradigms on right knee during and Intersession ICC was good for cold pressor test but poor for tourniquet test Cold pressor test (12ºC) 2 min Left hand (Razavi et al., 2013) 21 healthy subjects Within-subject different Painful heat stimulations Heat pain threshold and Significant CPM effects on heat pain threshold, heat pain rating and pressure pain threshold. Left or right forearm Pressure pain threshold No effect on temporal summation Different effect of intensity and duration of Temporal summation of conditioning stimulus depending on pain test Test stimuli were delivered to the right thigh (Zheng et al., 2014) 41 healthy subjects Within-subject different Heat pain stimulation Pressure pain threshold Pain adapters: CPM response during both CPM
and pain rating at both forearm and the right Pain non-adapters: CPM response during both
Subjects were divided into calf during and after the pain adapters and pain non- Cold pressor test (1-4ºC) Pain non-adapters rated pain intensity during adapters for analysis of CPM CPM higher compared with pain adapters No difference in CPM response between men and women was found
Appendix 2: A summary of clinical studies investigating conditioned pain modulation in human adults, primarily organized according to conditioning stimuli in
the following order: ‘cold pressor test', ‘hot water', ‘heat pain', ‘tourniquet test', ‘mechanical pressure', ‘electrical stimulation' and secondly after year of publication.
Reference
Pain subjects
Controls or control
Conditioning stimulus
Pain sensitivity
Main findings
condition
‘cold pressor test'
parameters
Intensity
Location

(Leffler et al., 11 subjects with rheumatoid 11 healthy subjects Cold pressor test (3-4ºC) Heat and cold detection Rheumatoid arthritis for less than 1 year: Heat
arthritis for less than 1 year Until pain intensity reached 7/10 thresholds, pain pain threshold increased, and heat pain rating Left hand and forearm thresholds and pain decreased during CPM ratings as well as Pressure pain threshold increased during CPM pressure pain threshold Rheumatoid arthritis for more than 5 years:
10 subjects with rheumatoid 10 healthy subjects on the right thigh during Pressure pain threshold increased during CPM arthritis for more than 5 years Healthy controls: Heat pain threshold increased
and heat pain rating decreased during CPM Pressure pain threshold increased during CPM (Sandrini et al., 24 subjects with migraine 20 healthy subjects Cold pressor test (5-6ºC) Nociceptive flexion Migraine patients: NFR was facilitated during
reflex on the sural nerve and pain rating elicited Chronic tension-type headache: NFR was
facilitated during CPM 17 subjects with chronic stimulation during and Healthy controls: Significant reduction in NFR
tension-type headache (Johannesson et al., 20 subjects with 40 healthy subjects Cold pressor test (3ºC) Pressure pain thresholds Vestibulodynia patients: Significant CPM
on the non-dominant arm response during the cold pressor test and leg during and after Healthy controls: Significant CPM response
during the cold pressor test (Ram et al., 2008) 110 subjects with chronic Between subject differences. Cold pressor test (12ºC) Heat pain intensity at the Patients on opioids: CPM was present during
73 patients received opioids left thenar eminence and after, with larger effects during CPM and 37 received non-opioids during and after CPM Patients not on opioids: CPM was present
during and after, with larger effects during CPM Non-opioid subjects had larger CPM compared with opioid subjects No significant difference between men and women in CPM (King et al., 2009) 14 subjects with irritable 28 healthy subjects Cold pressor test (avg. 12.0ºC) Heat pain rating on the Irritable bowel syndrome: No CPM response
left hand during CPM Temporomandibular disorder: Hyperalgesic
response during CPM Healthy controls: Significant CPM response
Within-subject control 14 subjects with condition with non-painful temporomandibular disorder (14/0) 31.0 (10.2) (de Souza et al., 52 subjects with fibromyalgia 10 healthy controls Cold pressor test (12ºC) Pain intensity during Fibromyalgia patients: FM with depression had
different CPM trials less CPM compared with FM without depression Right hand and forearm Healthy controls: CPM response
The amplitude of CPM was significantly smaller
in FM compared with controls
(Leonard et al., 14 subjects with classical 14 healthy subjects Cold pressor test (10ºC) Heat pain rating over Classical trigeminal neuralgia: Heat pain rating
trigeminal neuralgia trigeminal area after decreased after CPM Atypical trigeminal neuralgia: No CPM
Healthy controls: Heat pain rating decreased
14 subjects with atypical trigeminal neuralgia (5/9) 65.4 (13.6) 27 subjects with irritable 21 healthy subjects Cold pressor test (12ºC) Heat pain rating at the Irritable bowel syndrome: No CPM with
left hand during CPM painful paradigm. Reduced pain ratings after non-painful paradigm 28.9 years of age Healthy controls: Significant CPM with 12ºC
Within-subject control CPM paradigm. Reduced pain ratings after non- condition with non-painful painful paradigm (Olesen et al., 2010) 25 subjects with chronic 15 healthy subjects Cold pressor test (2ºC) Pressure pain threshold Chronic pancreatitis: Reduced CPM
at the quadriceps muscle Healthy controls:
CPM was impaired in CP compared with healthy subjects. There was no correlation between CPM and age in healthy subjects or CP subjects (Normand et al., 29 subjects with fibromyalgia 40 healthy subjects Cold pressor test (12ºC) Temporal summation of Fibromyalgia patients: FM presented a
heat on the left forearm significant deficiency of CPM compared to Right arm and hand healthy subjects 26 subjects with major depressive disorder (16/10) 46.5 (9.0) (Roosink et al., 19 subjects with post-stroke 29 subjects with pain-free Cold pressor test (0.5ºC) Pressure pain and Post-stroke shoulder pain: significant increase
electrical pain threshold in pressure pain and electrical pain thresholds at both deltoids after after cold pressor test Pain-free stroke patients: significant increase in
pressure pain and electrical pain thresholds after 23 healthy subjects cold pressor test Healthy controls: significant increase in
pressure pain and electrical pain thresholds after cold pressor test (Chua et al., 2011) 17 subjects with neck pain 27 healthy controls Cold pressor test (?ºC) Electrical pain tolerance Neck pain and cervicogenic headache: CPM
and cervicogenic headache on the thigh and response both in painful and non-painful areas Neck pain: CPM response both in painful and
non-painful areas Healthy controls: CPM response
10 subjects with neck pain (4/6) 54.5 (7.9) (Olesen et al., 2012) 62 subjects with chronic 2 sessions with CPM to test Cold pressor test (2ºC) Pressure pain threshold CPM was present at both sessions, but the test- at the quadriceps muscle retest reliability was poor (Paul-Savoie et al., 50 subjects with fibromyalgia 39 healthy subjects Cold pressor test (12ºC) Heat pain rating on the Fibromyalgia patients: CPM was impaired in
left forearm after CPM. FM compared with healthy subjects. Right arm and hand CPM was negatively correlated to sleep quality. There was no correlation between CPM and age. (Sutton et al., 2012) 23 subjects with provoked 23 healthy subjects Cold pressor test (5ºC) Heat pain tolerance and Provoked vestibulodynia: CPM response on
temporal summation to both pain tolerance and temporal summation Non-dominant hand heat pain on the Healthy controls: CPM response on both pain
dominant forearm during tolerance and temporal summation (Valencia et al., 58 subjects with shoulder 56 healthy subjects Cold pressor test (8ºC) Heat pain intensity at the Shoulder pain: Significant CPM after cold
thenar eminence on the nonsurgical or non- Healthy controls: Significant CPM after cold
dominant hand after (Garrett et al., 30 subjects with 30 healthy subjects Cold pressor test (5-16.5ºC) Temporal summation to Temporomandibular disorder: reduction in
temporomandibular disorder pressure pain at the temporal summation during cold pressor test Healthy controls: reduction in temporal
Within-subject control summation during cold pressor test condition with non-painful conditioning. (Valencia et al., 134 subjects with shoulder 190 healthy subjects Cold pressor test (8ºC) Heat pain intensity at the Shoulder pain: Significant CPM response
thenar eminence on the Healthy controls: Significant CPM response
nonsurgical or non- Both groups showed comparable CPM responses. Within-subject intrasession dominant hand after CPM was relative stable between sessions, but and intersession test-retest not within sessions. CPM was not affected by reliability for the CPM change in pain intensity (Edwards et al., 37 subjects with persistent 34 subjects without pain after Cold pressor test (4ºC) Pressure pain thresholds Postoperative pain after lumpectomy: Reduced
postoperative pain after at both trapezius muscles CPM and enhanced temporal summation No pain after lumpectomy: Women without
pain had larger CPM response compared with (Martel et al., 2013) 55 subjects with chronic back 2 different sessions of CPM Cold pressor test (4ºC) Pressure pain threshold Cold pressor test produced CPM in both men and on the right trapezius women. The CPM response was significantly muscle during CPM larger in men. The reliability of the CPM response in women were good (Nahman-Averbuch 26 subjects with migraine 35 healthy subjects Repetitive cold pressor tests (10ºC) Heat pain rating at the Migraine: Significant CPM response, but the
lower left leg during and response decreased after repeated cold pressor tests
Healthy controls: Significant CPM response
(Schliessbach et al., 464 subjects with chronic Cold pressor test (1.5ºC) Pressure pain tolerance In general CPM was present in pain patients at the second toe after 23.7% of the subjects had no CPM response (Niesters et al., 10 subjects with chronic CPM was performed on 3 Cold pressor test (6-18ºC Heat pain intensity at the No significant CPM response was found peripheral neuropathic pain different days with ketamine, corresponding to a VAS=30/100) dominant forearm during After the three treatments, a significant CPM morphine or placebo. response was found with no difference between Foot and lower leg the three treatments The magnitude of CPM correlated positively with pain relief from the treatments (Bouwense et al., 48 subjects with chronic 15 healthy controls Cold pressor test (1ºC) Electrical pain threshold Chronic pancreatitis: Reduced CPM
and pain tolerance on Healthy controls: Healthy controls exhibited a
significantly greater CPM response compared with CP patients (Ng et al., 2014) 30 subjects with chronic 30 healthy subjects Cold pressor test (2ºC) Heat pain threshold at Chronic whiplash: Reduced CPM
whiplash associated disorder the midcervical spine Healthy controls: CPM was significantly larger
Non-dominant hand in healthy subjects compared with WAD (Chalaye et al., 22 subjects with fibromyalgia 25 healthy controls Cold pressor test (12ºC) Heat pain rating on left Fibromyalgia patients: Pain ratings decreased
forearm after CPM after CPM paradigm Right hand and forearm Healthy controls: Pain ratings decreased after
CPM paradigm
The decrease was significantly larger in controls
(Jarrett et al., 2014) 20 subjects with irritable 20 Healthy subjects Cold pressor test (12ºC) Heat pain rating at the Irritable bowel syndrome: Significant CPM
dominant arm during Non-dominant hand Healthy controls: Significant CPM response
(Ness et al., 2014) 14 subjects with bladder pain 14 healthy subjects Cold pressor test (0-5ºC) Heat pain threshold, Bladder pain syndrome: Heat pain tolerance
tolerance and rating at decreased during CPM paradigm (22-56 years old) the right ankle during Healthy controls: Heat pain tolerance increased
(22-56 years old) Within-subject control with during CPM paradigm non-painful water. 42 patients undergoing Cold pressor test (1ºC) Pressure pain threshold Significant CPM response surgery for funnel chest at dominant quadriceps CPM predicted morphine consumption Non-dominant hand (Pickering et al., 9 subjects with post herpetic 9 healthy subjects Cold pressor test (8ºC) Heat pain intensity on Post herpetic neuralgia: Reduced CPM in
volar forearm after CPM patients compared with controls (Smits et al., 2014) 24 subjects with cold 14 healthy subjects Cold pressor test (1.8ºC) Pressure pain threshold Cold intolerance after nerve lesion or
intolerance after nerve lesion at the affected site amputation: significant CPM response
Healthy controls: Significant CPM response,
The response was significantly larger in the healthy subjects Reference
Pain subjects
Controls or control
Conditioning stimulus
Pain sensitivity
Main findings
condition
‘hot water'
parameters
Intensity
Location

(Staud et al., 2003b) 11 subjects with fibromyalgia 22 healthy subjects Hot water test (46ºC) Temporal summation of Men had a significant CPM response on temporal heat at the right hand. Women and FM subjects had no CPM response. 11 healthy subjects (0/11) 40.2 (16.8) (Meeus et al., 2008) 31 subjects with chronic 31 healthy subjects Hot water test (46ºC) Pain ratings during cold Chronic fatigue syndrome: Significant CPM
fatigue syndrome and chronic a gradual spatial immersion Healthy controls: Significant CPM response
(Nahman-Averbuch 27 subjects with neuropathy Hot water test (46.5ºC) Heat pain threshold at Hot water produced CPM in pain patients after chemotherapy the right forearm during CPM was inversely correlated with clinical pain (Defrin et al., 2014) 60 ex-soldiers (torture Hot water test (46ºC) Heat rating at the Larger CPM in subjects without pain compared forearm during CPM with subjects with pain Pain intensity correlated with CPM Reference
Pain subjects
Controls or control
Conditioning stimulus
Pain sensitivity
Main findings
condition
‘heat pain'
parameters
Intensity
Location

(Lautenbacher and 26 subjects with fibromyalgia 26 healthy subjects Painful and non-painful heat Electrical detection and Fibromyalgia patients: No CPM response
pain threshold at the Healthy controls: Painful and non-painful heat
increased electrical pain threshold (Pielsticker et al., 29 subjects with chronic 25 healthy subjects Painful and non-painful heat Electrical detection and Chronic tension-type headache: Significant
tension-type headache pain thresholds at the CPM effect after the painful CPM paradigm forearm and temple Healthy controls: CPM was significantly larger
Within-subject different region after CPM in healthy subjects compared with CTTH painful and non-painful CPM (Teepker et al., 32 subjects with migraine 20 healthy subjects Painful and non-painful heat Electrical pain threshold Migraine patients: Significant CPM response
to the right forearm Healthy controls: Significant CPM response
Reference
Pain subjects
Controls or control
Conditioning stimulus
Pain sensitivity
Main findings
condition
‘tourniquet test'
parameters
Intensity
Location

10 subjects with fibromyalgia 10 healthy subjects Heat and cold detection Fibromyalgia patients: Heat pain rating was
thresholds and pain decreased after CPM thresholds as well as Healthy controls: Pressure pain threshold
pressure pain threshold increased during. Heat pain rating was decreased on the right quadriceps muscle during and after CPM 15 subjects with painful 15 healthy subjects Heat and cold detection Painful osteoarthritis of the hip:
Ordeberg, 2000b) osteoarthritis of the hip thresholds and pain Before surgery: No CPM response Forearm ipsilateral to painful hip thresholds as well as After surgery: Significant CPM response pressure pain threshold Healthy controls: Significant CPM at both time
Both groups were reassessed on the painful hip and 6-14 month after OA surgery contralateral hip during and after CPM (Leffler et al., 10 subjects with long term 10 healthy subjects Heat and cold detection Trapezius myalgia: Heat pain and pressure pain
trapezius myalgia thresholds and pain threshold increased during CPM thresholds as well as Healthy controls: Heat pain and pressure pain
pressure pain threshold threshold increased during CPM on the right thigh during (Tuveson et al., 15 subjects with painful 15 Healthy subjects Pain intensity for Painful peripheral neuropathy: The CPM
peripheral neuropathy paradigm reduced ongoing neuropathic pain Pressure pain threshold Significant CPM response on pressure pain and pain rating as well as Healthy controls: Significant CPM response on
heat pain threshold and pressure pain and heat pain pain rating on pain free thigh or arm during and after CPM (Tuveson et al., 10 subjects with central post 10 healthy subjects Pain intensity for Central post stroke pain: no change in ongoing
pain during CPM. CPM response to pressure pain Pressure pain threshold and pain rating as well as Healthy controls: CPM response to pressure
heat pain threshold and pain rating on pain free thigh or arm during and after CPM (Cathcart et al., 46 subjects with tension-type 25 healthy controls Pressure pain threshold Tension-type headache: Increased temporal
and temporal summation summation and decreased CPM in headache at the right middle finger patients compared with healthy controls and trapezius muscle (Skou et al., 2013) 20 subjects with knee pain 20 subjects without knee pain Pressure pain threshold Knee pain after knee revision: Decreased pain
after revision of total knee after total knee arthroplasty at the knee, tibialis threshold during CPM paradigm anterior muscle and No pain after knee revision: Significant CPM
forearm during and after response during the CPM paradigm (Meeus et al., 2013) 15 subjects with chronic 16 healthy subjects Temporal summation of Chronic whiplash:
whiplash associated disorder pressure pain on the right Healthy controls:
hand middle finger Comparable CPM responses. 30 subjects with acute 31 healthy controls Pressure pain temporal Acute whiplash: Significant CPM response
whiplash associated disorder summation at the right Chronic whiplash: No CPM response
trapezius and the right Healthy controls: Significant CPM response
quadriceps muscle The effect was largest in healthy controls 35 subjects with chronic WAD (26/9) 43.8 (9.59) Reference
Pain subjects
Controls or control
Conditioning stimulus
Pain sensitivity
Main findings
condition
‘mechanical pressure'
parameters
Intensity
Location

(Oono et al., 2014) 16 subjects with 16 healthy subjects Pressure pain (VAS = 5) Pressure pain thresholds Temporomandibular disorder: Pain thresholds
temporomandibular disorder and tolerance at TMJ, increased at the forearm masseter and forearm Healthy controls: Pain thresholds and pain
during and after CPM tolerance increased at all assessment sites No significant correlation between CPM response and pain intensity or pain duration Reference
Pain subjects
Controls or control
Conditioning stimulus
Pain sensitivity
Main findings
condition
‘electrical pain'
parameters
Intensity
Location

(Wilder-Smith et 34 subjects with functional 42 healthy subjects Heat pain intensity at the Functional dyspepsia: No CPM response
foot during the CPM Healthy controls: Significant CPM response
However, there was no between group difference
Appendix 3: A summary of experimental studies examining exercise-induced hypoalgesia in healthy human adults, primarily organized according to exercise
modality in the following order: ‘aerobic', ‘aerobic and isometric', ‘isometric', ‘resistance', ‘mixed', ‘passive movements' and secondly after year of publication.
Reference
Subjects
Exercise protocol
Control condition
Pain sensitivity
Main findings
Total number
parameters
Gender (F/M)
Intensity
Age (SD) or age range
Duration
(Black et al., 1979) 1 healthy subject Within-subject naloxone Pain thresholds and pain Increased pain thresholds after exercise versus saline condition ratings during ischemic Naloxone did not affect the EIH response (Haier et al., 1981) 15 healthy subjects Within-subject naloxone Pressure pain threshold Pressure pain was increased after exercise in both versus saline condition on the index finger the naloxone and the saline condition (Vecchiet et al., 10 healthy subjects Aerobic bicycling Within-subject rest Pain intensities after Increased pain ratings (hyperalgesia) to injections condition with either 10% after exercise compared with rest 20-30 years of age or 20% sodium chloride injections after exercise and after rest (4 conditions) (Janal et al., 1984) 12 healthy subjects Within-subject naloxone Heat withdrawal laten- Reduced pain ratings to thermal and ischemic pain versus saline condition cies and pain intensity following exercise. Naloxone reduced the Pain rating during hypoalgesic response to ischemic but not thermal ischemic pain test Pain rating and time tolerance during cold pressor test (Kemppainen et al., 7 healthy subjects Aerobic bicycling Electrical dental pain Dental pain threshold and thermal limen increased Increasing workload from 100-300 watt threshold and thermal during and following the exercise session. Dental 22-46 years of age limen at the hand, pain threshold increased from 250W (Olausson et al., 11 healthy subjects Aerobic bicycling (Leg and arm) Within-subject control Electrical dental pain Dental pain threshold increased during and Heart rate 150 beats/min following both exercise sessions (Kemppainen et al., 6 healthy subjects Aerobic bicycling Electrical dental pain Increase in threshold with increasing exercise Increasing workload from 200-300 watt cyproheptadine versus intensity. No effect of cyproheptadine on the EIH placebo condition (Kemppainen et al., 6 healthy subjects Aerobic bicycling Electrical dental pain Pain threshold was increased during and 30 min Increasing workload from 100-200 watt dexamethasone versus after exercise, but less in the dexamethasone 24-36 years of age saline condition condition compared with the saline condition (Droste et al., 1991) 10 healthy subjects Aerobic bicycling Within-subject naloxone Electrical dental pain Increase in thresholds during and immediately after Increasing workload from 100-250 watt versus saline condition and fingertip pain 20-46 years of age Until exhaustion No effect of naloxone on EIH 91 healthy subjects Aerobic bicycling Between subject non- Pain ratings during 3 min No EIH effects after exercise conditions compared stressful coloring task cold pressor test with non-dominant hand (Guieu et al., 1992) 6 healthy subjects Aerobic bicycling Nociceptive flexion The threshold of the NFR increased following the reflex threshold at the exercise session 18-27 years of age 22 healthy subjects Within subject rest Heat pain and non-pain Heat non-pain ratings decreased after exercise, but (endurance athletes) ratings applied to the heat pain ratings were not affected 6 miles (30 min) volar site of the forearm 27-56 years of age (Gurevich et al., 60 healthy subjects Aerobic step exercise Between subject non- Pressure pain rating and Pain tolerance increased and pain ratings decreased stressful completion of two pain tolerance at the following exercise 22.9 (18-44 years of age) dorsal surface of the dominant index finger (Koltyn et al., 1996) 16 healthy subjects Aerobic bicycling Within-subject rest Pressure pain threshold Pain threshold increased and pain ratings decreased and pain rating on the following exercise right forefinger (Øktedalen et al., 20 healthy trained Pain rating during Pain ratings decreased after exercise condition. No ischemic pain test difference between trained and untrained in the EIH 26-48 years of age 9 healthy untrained subjects (0/9) 38 (28-46) (Sternberg et al., 41 healthy college Subjects randomized to 3 experiments: Pain ratings during 90 s Track meet reduced cold pressor pain ratings. (Men 1:Sedentary videogame competition. cold pressor test with non-dominant hand and Athletes reduced pain ratings at baseline compared 3:Exercise condition with aerobic heat pain thresholds on 22 healthy college non- running at 85 % HR for 10 min. the fingertips and No difference between athletes and non-athletes in Track meet and exercise run caused heat (Dannecker et al., 23 healthy subjects Aerobic bicycling Pressure pain threshold No significant EIH response after exercise at the biceps brachii after 27 subjects in video DOMS was induced 48 hours prior to exercise condition and video condition (Hoffman et al., 12 healthy subjects Aerobic treadmill Within-subject quiet rest Pressure pain ratings at Pain ratings were decreased 5 min after the exercise 1:75 % VO2max for 10 min the dorsal surface on the condition with 75 % VO2max for 30 min only. No 2:75 % VO2max for 30 min non-dominant index EIH response 30 min after exercise 3:50 % VO2max for 30 min (Drury et al., 2005) 17 healthy subjects Aerobic bicycling Electrical pain threshold Pain threshold increased at VO2peak. Increasing workload from familiarization and and pain tolerance at the Pain tolerance was increased at 120 watt and 30 watt - VO2 peak reliability test right index finger VO2peak and 10 min after exercise. Largest effect at VO2peak. (Ruble et al., 2005) 14 healthy subjects Aerobic treadmill Within subject rest Hot and cold pain No EIH effects on thermal pain thresholds or pain thresholds and pain ratings 5 min and 30 min after exercise ratings on the thenar eminence of the non-dominant hand (Hoffman et al., 21 healthy athletes Between subject controls Pressure pain ratings on Reduced pain ratings in the fastest runners only the dorsal surface on the non-dominant index 9 healthy controls (1/8) 44 (11) 27 healthy subjects Aerobic treadmill exercise Pain threshold for cold Pain threshold for cold pressor test was increased 2 conditions near anaerobic threshold pressor test and pain after 30 min of exercise and 15 min after exercise rating at the end of up to 5 min cold pressor test with non-dominant hand (Pokhrel et al., 41 healthy subjects Aerobic bicycling Pain threshold and pain Pain threshold and tolerance increased significantly 70-75 % of VO2max tolerance during cold after exercise in both men and women 18-25 years of age pressor test on non-dominant hand (Ellingson et al., 21 healthy subjects Aerobic bicycling Within subject rest Heat pain ratings applied Heat pain ratings decreased during both exercise 1: 60 watt with painful cuffs on thighs to the palm of the right conditions. The size of the hypoalgesic response 2: 60 watt without cuffs was greater following painful exercise than non- painful exercise 29 healthy subjects Aerobic bicycling continuous and Between subject different Heat pain threshold and Heat pain intensity was reduced after interval interval conditions: exercise protocols pain intensity and 1: Continous 70 % HR for 24 min pressure pain threshold o No effect on pressure or heat pain thresholds 2: Interval 85 % HR for 4x4 min non-dominant hand after exercise 27 healthy subjects Aerobic bicycling Within subject rest Pressure pain threshold Pressure pain thresholds increased after high 1: 70 % HR reserve Suprathreshold pressure intensity exercise 2: 50-55 % of HR reserve Heat pain intensity was reduced after both exercise Heat pain intensity Temporal summation to Reduced temporal summation after both exercise heat pain. Applied to Reference
Subjects
Exercise protocol
Control condition
Pain sensitivity
Main findings
Total number
‘aerobic and isometric'
parameters
Gender (F/M)
Intensity
Age (SD) or age range
Duration
(Drury et al., 2004) 12 healthy subjects 1: Aerobic treadmill Within subject rest Pressure pain thresholds Pressure pain was increased after both aerobic and 65-75 % HR reserve applied to the forearm isometric exercise compared with rest The effect after aerobic exercise was larger 2:Isometric muscle contraction with compared with the isometric exercise condition hand dynamometer 100 % MVC every 2nd s for 1 min Reference
Subjects
Exercise protocol
Control condition
Pain sensitivity
Main findings
Total number
parameters
Gender (F/M)
Intensity
Age (SD) or age range
Duration
14 healthy subjects Isometric muscle contraction m. Pressure pain thresholds Pain threshold increased during, and 5 min after the quadriceps femoris at the m. quadriceps exercise condition 36.8 (Unknown) 20-54 Until task failure (Koltyn et al., 2001) 31 healthy subjects Isometric muscle contraction with hand Within-subject different Pressure pain thresholds Pain threshold increased and pain ratings decreased and pain ratings at the in women after maximal and sub-maximal 1: Maximal (2 x 5 s.) and right forefinger 2: Sustained 40-50 % MVC Pain ratings decreased in men after submaximal 24 healthy subjects Isometric muscle contractions m. Pressure pain threshold Pain thresholds increased at both sites during and quadriceps (1 kg) dominant and non- following contractions 20-27 years of age Isometric muscle contractions m. dominant m. quadriceps infraspinatus (0.5 kg). Until exhaustion (avg. 12 min) 40 healthy subjects Isometric muscle contractions with hand Within-subject opposite Pressure pain thresholds Pain thresholds increased and pain ratings hand used as control and pain intensity on the decreased bilaterally after the exercise session 18-22 years of age forefinger of both hands (Ring et al., 2008) 24 healthy subjects Isometric muscle contraction with hand Pain rating after Pain ratings decreased following 15 % and 25 % within-subject control electrical stimulation of the sural nerve. No effect on NFR Nociceptive flexion reflex threshold at the 40 healthy subjects Isometric muscle contractions with the Within subject different Pressure pain threshold Pain threshold increased and pain ratings decreased elbow flexor muscles (2 experiments). exercise protocols + and pain rating on the following the 3 maximum contractions 18-42 years of age 1: 3 maximum contractions reliability experiment right index finger Pain threshold increased and pain ratings decreased 2: 3 sustained contractions 25 % MVC (quiet rest) for PPT following the 25 % MVC until task failure until task failure 3: 3 sustained contractions 25 % MVC for 2 min 4: 3 sustained contractions 80 % MVC until task failure 23 healthy subjects Isometric muscle contraction with hand Within-subject rest control Pressure pain threshold No EIH effects compared with rest and pain rating to right 18-30 years of age 20 healthy subjects Isometric muscle contraction with elbow Two different menstrual Pressure pain threshold Pain threshold increased and pain ratings decreased and pain ratings on the following exercise in both menstrual phases right index finger Until task failure 50 healthy subjects Isometric muscle contraction with hand Within subject different Pressure pain threshold Pain threshold increased and pain ratings decreased durations as control and pain intensity to the following all 3 exercise durations. No dose forefinger of the response pattern (Koltyn et al., 2013) 88 healthy subjects Isometric muscle contraction with hand Pain ratings during Reduction in temporal summation after both (divided into two increasing heat stimuli exercise conditions 1: 40 % MVC until exhaustion delivered to the thenar 18-20 years of age dominant hand (temporal summation) (Paris et al., 2013) 38 healthy subjects Isometric muscle contraction with pinch Within subject working Heat pain and heat non- Heat non-pain ratings decreased during exercise grip by index finger and thumb on the pain ratings applied to 18-43 years of age 27 healthy young Isometric muscle contraction with hand Within subject rest Pressure pain threshold Pressure pain thresholds increased after exercise Suprathreshold pressure Heat pain intensity was reduced after exercise in Heat pain intensity Reduced temporal summation after exercise Temporal summation to heat pain Applied to both forearms (Misra et al., 2014) 42 healthy subjects Isometric muscle contraction with pinch Within subject different Heat pain ratings applied Dose-response effect with larger EIH with more grip by index finger and thumb on the exercise conditions intense contractions 18-45 years of age 26 healthy subjects Isometric muscle contraction with elbow Within-subject rest Pressure pain threshold Pressure pain threshold increased after exercise in and pain rating on the right index finger after Pain rating decreased after exercise in men 24 healthy subjects Isometric muscle contraction with elbow Within subject different Pressure pain threshold Pressure pain threshold increased after all exercise exercise protocols and and pain rating on the conditions in older men and women 1: 3 maximal contractions quiet rest control condition right index finger after Pain rating decreased after exercise in women 3: 25 % MVC until fatigue 20 healthy young Isometric muscle contraction with elbow Exercise and CPM Pressure pain intensity at Pain intensity decreased after exercise in older and protocol (control vs ice the right index finger younger men and women (Lucite edge). Assessed Arm pain during exercise was not associated with before and after exercise No relation between EIH and physical activity 19 healthy old subjects level/fear of pain/catastrophizing or pain attitude (Koltyn et al., 2014) 58 healthy subjects Isometric muscle contraction with hand Within subject naltrexone Pressure pain threshold Temporal summation to heat pain and pressure pain and placebo conditions and pain rating applied ratings decreased following exercise. Pressure pain thresholds increased with no forefinger and heat pain difference between men and women ratings during repetitive Naltrexone did not alter the EIH response. stimulations (temporal The decrease in temporal summation to heat pain summation) at the thenar was significantly correlated with the increase in Reference
Subjects
Exercise protocol
Control condition
Pain sensitivity
Main findings
Total number
parameters
Gender (F/M)
Intensity
Age (SD) or age range
Duration
13 healthy subjects Resistance exercise Within-subject rest Pressure pain thresholds Pain threshold increased and pain ratings decreased 4 different exercises with 3 sets of 10 and pain ratings at the 5 min following exercise, but not 15 min after repetitions at 75 % MVC left middle finger (Weissman-Fogel et 48 healthy subjects Resistance exercise with hand Heat pain rating at the Exercise reduced heat pain ratings in both men and non-dominant thenar eminence after exercise A significant correlation was found between pain catastrophizing and EIH (Focht and Koltyn, 21 healthy subjects Resistance exercise Within subject condition Pressure pain threshold Pain threshold increased and pain ratings decreased 4 different exercises with 3 sets of 10 with testing either in the 1 min after but not 15 min after exercise both in the repetitions at 75 % MVC morning or in the evening morning and evening Reference
Subjects
Exercise protocol
Control condition
Pain sensitivity
Main findings
Total number
parameters
Gender (F/M)
Intensity
Age (SD) or age range
Duration
17 healthy subjects Within-subject rest Pressure pain threshold Pain tolerance increased following the exercise and tolerance at the tibial Reference
Subjects
Exercise protocol
Control condition
Pain sensitivity
Main findings
Total number
parameters
Gender (F/M)
Intensity
Age (SD) or age range
Duration
(Nielsen et al., 17 healthy subjects Passive physiological movements of the Within-subject rest Pressure pain thresholds Pain threshold increased and pain ratings decreased knee joint performed by electric bicycle and pain intensity after during passive physiological movements hypertonic saline injection in tibialis anterior
Appendix 4: A summary of clinical studies examining exercise-induced hypoalgesia in human adults, primarily organized according to exercise modality in the
following order: ‘aerobic', ‘isometric' and secondly after year of publication.
Reference
Subjects
Healthy controls or
Exercise protocol
Pain sensitivity
Main findings
Total number
parameters
Gender (F/M)
control condition
Intensity
Age (SD) or range
Duration
(Droste et al., 1988) 8 subjects with symptomatic 9 subjects with asymptomatic Aerobic bicycling Electrical pain threshold Symptomatic myocardial ischemia:
myocardial ischemia myocardial ischemia Increasing workload from 50-125 at the non-dominant No significant EIH response Asymptomatic myocardial ischemia: No
Pain thresholds and pain significant EIH response ratings during ischemic (Kemppainen et al., 8 pilots with previous neck pain 8 pilots without neck pain Aerobic bicycling Pain threshold during Previous neck pain group: Pain threshold
Increasing workload from 50-200 cold pressor test and pain increased and pain rating decreased after exercise 22-35 years of age 22-35 years of age intensity during cold Healthy controls: Pain rating decreased after
pressor test with right (Vierck et al., 2001) 10 subjects with fibromyalgia 20 healthy controls Aerobic treadmill Temporal summation to Fibromyalgia patients: Temporal summation
According to protocol by Bruce et heat pain on both hands was increased after exercise Healthy controls: Temporal summation was
Until exhaustion reduced after exercise (Whiteside et al., 5 subjects with chronic fatigue 5 healthy controls Aerobic treadmill Pressure pain thresholds Chronic fatigue syndrome: Pain thresholds
decreased after exercise 30-54 years of age Healthy controls: Pain thresholds increased after
28-49 years of age (Hoffman et al., 8 subjects with chronic low back 10 healthy controls (only rest Aerobic bicycling Pressure pain rating at Chronic low back pain: Pain ratings were
the non-dominant index decreased after exercise 34 (8) Within subjects rest condition (Cook et al., 2010) 11 Gulf war veterans with 16 Gulf war veterans without Aerobic bicycling Heat pain threshold and Veterans with chronic widespread pain: Pain
chronic widespread pain pain ratings at the thenar ratings increased after exercise eminence of the non- Veterans without pain: No change in pain
thresholds or ratings following exercise Pressure pain threshold at the non-dominant forefinger (Meeus et al., 2010) 26 subjects with chronic fatigue 31 healthy sedentary subjects Aerobic bicycling Pressure pain thresholds Chronic fatigue syndrome: Pain thresholds
Increasing workload from 20-130 bilaterally at the hand, decreased after exercise the lower back, the Low back pain subjects: Pain thresholds
deltoid muscle and the increased after exercise Healthy subjects: Pain thresholds increased after
21 chronic low back pain patients (11/10) 41.55 (12.4) (Van Oosterwijck et 22 subjects with chronic fatigue 22 healthy controls Aerobic bicycling Pressure pain threshold Chronic fatigue syndrome:
1: 75 % of age-predicted heart rate at the hand, the lower -Pain thresholds decreased at the back and calf back and the calf after the 75% APHR condition -Pain thresholds decreased at the calf and hand after the self-paced condition
-Pain threshold increased at the back after the
self-paced exercise condition
Healthy controls: Pain thresholds increased after
both exercise conditions
(Newcomb et al., 21 subjects with fibromyalgia Within subjects control Aerobic bicycling Pressure pain threshold, Fibromyalgia: Pain threshold and tolerance
Different exercise protocols 1: Self-selected intensity pain ratings and increased after both exercise conditions 18-59 years of age tolerance applied to the Pain threshold increased more after the self- right forefinger selected intensity Pain ratings decreased after both exercise conditions (Van Oosterwijck et 22 subjects with whiplash 22 healthy controls Aerobic bicycling Pressure pain threshold Whiplash patients:
associated disorder at the hand, the lower Pain thresholds decreased at the back and calf back and the calf after the 75% APHR condition Pain thresholds decreased at the calf and hand
after the self-paced condition
Pain thresholds increased at the back after the
self-paced exercise condition
Healthy controls: Pain thresholds increased after
both exercise conditions
(Meeus et al., 2014) 16 subjects with rheumatoid 18 healthy controls Aerobic bicycling Pressure pain ratings and Rheumatoid arthritis: Decrease in temporal
Increasing workload 25 watt/min temporal summation at summation after exercise. from 0 watt until 75 % of APHR is the middle finger Chronic fatigue syndrome and fibromyalgia:
Within-subject paracetamol Less than 15 min Healthy controls: Decrease (non-significant) in
19 subjects with chronic fatigue and placebo conditions temporal summation after exercise syndrome and fibromyalgia (19/0) 44.6 (7.3) Reference
Subjects
Healthy controls or within-
Exercise protocol
Pain sensitivity
Main findings
Total number
subjects control condition
parameters
Gender (F/M)
Intensity
Age (SD) or range
Duration
(Kosek et al., 1996) 14 subjects with fibromyalgia 14 healthy controls Isometric muscle contraction with Pressure pain thresholds Fibromyalgia patients: Pain thresholds
at the quadriceps femoris decreased during exercise 29-59 years of age 20-54 years of age Healthy controls: Pain thresholds increased
Until exhaustion (max 5 min) (Staud et al., 2005) 12 subjects with fibromyalgia 11 healthy controls Isometric muscle contraction with Heat pain and pressure Fibromyalgia patients: Heat pain ratings
hand dynamometer pain at both forearms increased in both arms during exercise Pressure pain thresholds decreased in both arms during exercise
Healthy controls: Heat pain ratings decreased in
both arms during exercise
Pressure pain thresholds increased in both arms
during exercise
17 subjects with fibromyalgia 17 healthy controls Isometric muscle contraction with Pressure pain thresholds Fibromyalgia patients Pain threshold at the
at the exercising deltoid increased during exercise 22-56 years of age 22-53 years of age quadriceps and the Healthy controls: Pain threshold at the deltoid
Until exhaustion (max 8-10 min) opposite deltoid muscle increased during exercise 20 subjects with shoulder 21 healthy controls Isometric muscle contraction with Pressure pain thresholds Myalgia patients: Pain thresholds increased
knee extensors and shoulder at the infraspinatus and during quadriceps contractions 19-49 years of age external rotators quadriceps femoris Fibromyalgia patients: Pain thresholds did not
28-57 years of age change after any of the exercise conditions 20 subjects with fibromyalgia Until exhaustion (max 5 min) Healthy controls: Pain thresholds increased after
both exercise conditions 24-47 years of age 15 subjects with fibromyalgia Within subjects rest Isometric muscle contraction with Pressure pain threshold Fibromyalgia patients: No change in pressure
and pain ratings at the pain threshold or pain ratings after any of the 19-64 years of age right index finger exercise conditions Until exhaustion (max 5 min) Subgroup analysis showed increase in pressure 2: 25 % MVC held for 2 min pain threshold in younger patients, and those with high pain sensitivity (Ge et al., 2012) 22 subjects with fibromyalgia 22 healthy controls Isometric muscle contraction with Pressure pain thresholds Fibromyalgia patients: Pain thresholds in the
shoulder abductors in the trapezius and tibialis anterior decreased after exercise Hold arms horizontally tibialis anterior muscles Healthy controls: Pain thresholds increased in
Until exhaustion the trapezius after exercise (Kosek et al., 2013) 66 subjects with knee 43 healthy controls Isometric muscle contraction with Pressure pain thresholds Knee OA: Pain threshold increased during
osteoarthritis (OA) at the exercising quadriceps and the Hip OA: Pain threshold increased during
Until exhaustion (max 5 min) opposite deltoid muscle Healthy controls: Pain threshold increased
47 subjects with hip OA (26/21) 67.1 (4.0) (Burrows et al., 11 subjects with knee OA 11 old healthy subjects Isometric muscle contractions arm Pressure pain threshold Knee OA: Pain thresholds increased after upper
and leg with 3 sets of 10 repetitions and pain ratings applied body exercise condition to the arms and legs Old healthy subjects: Pain thresholds increased
1: 3 upper body exercises after both exercise conditions 11 young healthy subjects 2: 3 lower body exercises Young healthy subjects: Pain thresholds
increased after both exercise conditions No difference between older and younger healthy groups (Knauf and Koltyn, 9 subjects with diabetes mellitus 9 subjects with diabetes Isometric muscle contraction with Heat pain rating and Painful diabetic neuropathy: No significant
and painful diabetic neuropathy mellitus and no pain hand dynamometer temporal summation at the dominant hand and Diabetes mellitus and no pain: Decrease in pain
ratings and temporal summation after exercise

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sismologia.ist.utl.pt

StaMPS (Stanford Method for PS) Manual Nordic Volcanological Centre Institute of Earth Sciences University of Iceland Askja, 101 Reykjavik Version 2.1, June 1st, 2007 This manual provides a guide to running StaMPS, but does not attempt to explain all the process-ing. For some details on the inner workings, see Hooper et al. (2007), Hooper and Zebker (2007)and Hooper, Ph.D Thesis.

Framework for continuous palliative sedation therapy in canada

Framework for Continuous Palliative Sedation Therapy in Canada Dean MM1, Cellarius V2, Henry B3, Oneschuk D4, and Librach L5 Preamble Sedation is a commonly used procedure in many medical disciplines including palliative care. It is indicated for a variety of reasons and the type of sedation varies considerably. For example, intentional temporary sedation is sometimes used for procedures (chest-tube insertion, endoscopy, etc.) or insomnia whereas at other times sedation is unintentional (sometimes called secondary or consequential sedation) such as when sedation occurs as a side-effect of a drug being used to control a symptom. Thus the topic of sedation in palliative care practice is vast and complex. To develop this framework the authors reviewed the international literature and palliative sedation policies and protocols from within and without Canada. Recommendations from the first draft were presented at two workshops to full-time and part-time palliative care physicians and to family physicians and a subsequent draft based on feedback from the workshops was then sent to selected inter-professional reviewers across Canada. Their feedback was incorporated into the next draft and this was sent to members of the Canadian Society of Palliative Care Physicians (CSPCP) who were then surveyed for their level of agreement with the recommendations. There was a 29.3% response with over 70% agreement with all but three of the recommendations. This final document addresses planned sedation for management of intolerable and refractory symptoms. It does not address emergency sedation e.g. for an acutely agitated and delirious patient.