PhD dissertation. Ole Kudsk Jensen

Transcription

1 DIFFUSE CENTRAL SENSITIZATION OF THE NOCICEPTIVE SYSTEM IN PATIENTS WITH LOW BACK PAIN AND SICKNESS ABSENCE Influence of baseline diffuse hyperalgesia, pain thresholds on thumbnails, structural and functional spinal factors, and psychosocial factors PhD dissertation Ole Kudsk Jensen Faculty of Health Sciences Aarhus University and Spine Center Department of Internal Medicine Region Hospital Silkeborg Denmark 2009

2 PREFACE This thesis is based on studies performed during my employment as leader of the multidisciplinary unit Center for Bevægeapparatlidelser, Spine Centre, Dept. of Internal Medicine, Region Hospital Silkeborg. The multidisciplinary unit was established August 1 st, 2004 as a joint-venture project between six municipalities, including Silkeborg, the former County of Aarhus, now Central Region Denmark, and Centre of Public Health, University of Aarhus. Aknowledgements I would like to offer my sincerest thanks to Claus Vinther Nielsen, Chief Physician, PhD, Ulrich Fredberg, Chief Physician, PhD, and Kristian Stengaard-Pedersen, Professor, DMSc. Without their encouragement and support, this work would never have been initiated or come to an end. Furthermore, Niels Trolle Andersen, Associate Professor at the University of Aarhus, has contributed with fruitful discussions and invaluable statistical help. I am deeply grateful to all staff members of the multidisciplinary unit Center for Bevægeapparatlidelser. They have offered much help, inspiration and moral support. Especially, I would like to thank physiotherapist David Christiansen, with whom I have spent many hours discussing low back pain research. In addition, I appreciate the support from co-workers at the Centre of Public Health, especially the help and support from Jakob Hjort, data-manager, MPH, Chris Jensen, Senior Researcher, PhD, and Elinborg Thorsteinsson, MPH. Furthermore, I am grateful for the interest and support from co-workers at the Spine Center and Department of Internal Medicine, Region Hospital Silkeborg, especially Søren Holst Jensen, MD, Kjeld Andersen, MD, and Birte Juul, MD, PhD. They have taken care of many patients to let me concentrate on few. In addition, I would like to thank Søren Fruensgaard, MD, and his colleagues at the Department of Surgery, Region Hospital Silkeborg, for support and criticism. The project has been supported economically by Central Region Denmark. I am grateful for the steady support from Region Hospital Silkeborg. Finally, I would like to thank my wife Birgit Skoffer and my three sons Esben, Jakob and Simon for interest, support and not least: patience.

3 Study supervisors Professor, Chief Physician Kristian Stengaard-Pedersen, MD, DMsc Department of Rheumatology Aarhus University Hospital Aarhus Denmark Chief Physician Claus Vinther Nielsen, MD, PhD Department of Clinical Social Medicine, Centre of Public Health, Central Denmark Region and University of Aarhus Aarhus Denmark Evaluation Board Professor Cody Bünger, MD, DMsc Department of Orthopedics Spinal Unit Aarhus University Hospital Aarhus Denmark Professor Tom Bendix, MD, DMsc Clinical Locomotion Science Campusvej 55 Odense Denmark Chief physician Jens Ivar Brox, MD, PhD Department of Orthopedic Surgery National Hospital Oslo Norway

4 THIS THESIS IS BASED ON THE FOLLOWING PAPERS 1. LOW BACK PAIN MAY BE CAUSED BY DISTURBED PAIN REGULATION A cross-sectional study in low back pain patients using tender point examination Ole Kudsk Jensen, MD, Claus Vinther Nielsen, MD, PhD, Kristian Stengaard-Pedersen, MD, DMSc 04/09/2009 accepted for publication in European Journal of Pain 2. MEASURING PRESSURE-PAIN THRESHOLD ON THE THUMBNAILS IN SICK-LISTED LOW BACK PAIN PATIENTS: HARDLY USEFUL Ole Kudsk Jensen, MD, Claus Vinther Nielsen, MD, PhD, Kristian Stengaard-Pedersen, MD, DMSc Under preparation 3. ONE-YEAR PROGNOSIS IN LOW BACK PAIN PATIENTS SICK-LISTED FOR 3-16 WEEKS Prediction models identifying patients still off work Ole Kudsk Jensen, MD, Kristian Stengaard-Pedersen, MD, DMSc, Claus Vinther Nielsen, MD, PhD Submitted for publication in the Spine Journal 4. ONE-YEAR PROGNOSIS IN LOW BACK PAIN PATIENTS SICK-LISTED FOR 3-16 WEEKS Prognostic factors influencing pain and disability in patients with and without nerve root affection Ole Kudsk Jensen, MD, Claus Vinther Nielsen, MD, PhD, Kristian Stengaard-Pedersen, MD, DMSc Submitted for publication in the Spine Journal

5 CONTENTS page 1. BACKGROUND Introduction Pain mechanisms in low back pain (LBP) Pain sources 5 Clinical and experimental studies X-ray studies MRI studies LBP and widespread pain Pain physiology Widespread pain mechanisms 7 Fibromyalgia Predispositions Conclusions Risk factors and prognostic factors for LBP Risk factors for LBP Risk factors for sickness absence due to LBP 10 The predictive value of findings on X-ray or MRI Prognostic factors in patients with non-specific LBP 10 Psychological distress and depression Prognostic factors in patients with nerve root pain Conclusions AIMS METHODS Patients LBP classification Baseline variables Outcome variables Power calculations Statistics SUMMERY OF RESULTS PRESENTED IN MANUSCRIPTS Manuscript Design Data analysis Results Manuscript Design Methods Data analysis Results Manuscript Design Follow-up Data analysis Results 20 1

6 4.4. Manuscript Design Follow-up Data analysis Results KEYPOINTS OF DISCUSSIONS Tender points (manuscript 1) Pressure-pain thresholds (manuscript 2) Prediction models for return-to-work (manuscript 3) Prediction models for disability and pain (manuscript 4) Limitations CONCLUSIONS AND PERSPECTIVES DANSK RESUMÉ ENGLISH SUMMARY REFERENCES MANUSCRIPTS 2

7 KEY CONCEPTS Nociceptive system: The section of the nervous system involved in transmission, up-regulation and downregulation of pain. It comprises peripheral nociceptors and processes, nociceptive peripheral nerves and transmission of pain in nerves, medulla and the brain, as well as facilitating and inhibiting processes in the dorsal horn of medulla and at supraspinal levels. Central sensitization: Pain due to increased neuronal activity caused by up-regulation or insufficient downregulation of pain in the dorsal horn of medulla. Supraspinal levels are also involved. Fibromyalgia: A diffuse pain condition defined by widespread pain of at least three months duration and the presence of more than ten tender points. Disc degeneration: A condition where the spinal disc loses structural integrity from wear and tear, aging, or trauma. Consequences may be: disc space narrowing, osteophyte formation, disc bulging, or herniation. Lumbar disc herniation: A condition where the centre (nucleus pulposus), or part of the centre of the intervertebral disc, is protruding into the outer fibrous layer (annulus fibrosus) of a protruding disc, a socalled contained herniation. The nucleus pulposus also may protrude through the annulus of the disc, a socalled complete herniation. A fragment may loose contact to the disc, a so-called sequestered herniation. It may or may not come in contact with a nerve root or compress one or more nerve roots. Spinal stenosis: A condition that occurs when the spinal canal containing the spinal cord, or the small spinal canal that contains the nerve root, becomes restricted: Usually, the stenosis is caused by disc degeneration and/or facet joint degeneration. Nerve root pain: A sharp, well-localized pain down one leg that at least approximates to a dermatomal pattern. It radiates below the knee and often into the foot or toes. Risk factor: A risk factor is something that is likely to increase the chances that a particular event will occur, e.g. disease, pain or sick-listing. It is not required that the association is causal. Prognosis: A prediction of the probable course or outcome of disease. Prognostic factor: Any factor - e.g. age, family or life style - that is weighed in determining prognosis of disease. Systematic review: A systematic review synthesizes the results of multiple primary investigations by using strategies that limit bias and random error. These strategies include a comprehensive search of all potentially relevant articles and the use of explicit, reproducible criteria in the selection of articles for review. Primary research designs and study characteristics are appraised, data are synthesized, and results are interpreted. ABBREVIATIONS BMI: CI: LBP: MRI: OR: PPT: RR: TP: Body Mass Index confidence interval low back pain Magnetic Resonance Imaging Odds Ratio pressure pain threshold Risk Ratio or relative risk tender point 3

8 1. BACKGROUND 1.1. Introduction Low back pain (LBP) is a common disorder with a life-time prevalence of 60-80% and a one-year prevalence at 40-50% (1-3). Epidemiological studies have failed to show an increase in incidence or prevalence during the previous half century (4). However, in the same period sick-listing and early retirement due to LBP have increased dramatically in all western countries, though tending to level off in the 1990s (3-5). In England the number of days compensated by LBP sickness/invalidity benefits rose more than ten times between the 1960s and 1990s (4). Work loss attributed to LBP is estimated to affect 12-18% of the working population per year, of which 15% is related to sick-listing for more than one month (4), and 2-3% of the population are sick-listed for more than two weeks per year, women more frequently than men (6). LBP is now one of the most frequent causes of long-term sick-listing. In Denmark long-term sickness absence due to LBP still increased in the period (7). About 85% of LBP is estimated to be non-specific: X-ray or magnetic resonance imaging (MRI) of the lumbar spine fail to demonstrate the cause of pain (8). Recently, this estimate has been supported by a prospective study including patients with no actual or previous LBP-disability, in whom baseline MRI of the lumbar spine were performed (9). Comparing new MRI to baseline MRI during the next five years only disclosed new or worsened structural findings in 16% of those having a new episode of severe pain of at least one week duration. However, in patients with radiating pain and signs of neural compromise, MRI may demonstrate the cause of pain in about 90% of cases, usually a disc herniation (10). Disc herniations often resolve spontaneously, but operation is relevant in patients not improving with conservative care (8). The duration of leg pain is shortened, and this may improve cost-benefit because of shorter sick-listing (11;12) However, it is still unclear if it affects long-term prognosis positively (13-15). In operated as well as non-operated patients continuing pain problems occur frequently causing withdrawal from the labour market in almost 20% of the patients(16;17). Owing to older age, interference with the job situation occurs less often in patients with spinal stenosis, but operation for this condition is better than conservative care (18;19). Serious, specific back disease is rare, but should be diagnosed without delay by being aware of the so-called 'red flags', i.e. symptoms or signs indicating further investigation (8). A very rare, feared complication to back disease is permanently impaired bladder/bowel function or paresis of leg/ foot (8). However, sicklisting and disability due to LBP are usually caused by non-specific, permanent or recurrent pain (4). Non-specific LBP is a complex phenomenon influenced by individual physical and psychological aspects as well as social, occupational and cultural factors (4). LBP lasting for longer than 6 weeks is difficult or impossible to cure, as effective treatment is not available(20), but exercise a and behavioural therapy b are the best documented management strategies (21-23). The consequences of pain, for example loss of job, may be reduced. In LBP patients with sickness absence multidisciplinary interventions are more effective than single interventions in helping patients return to work (21). This type of intervention preferably comprise combinations of physical activity/exercise and cognitive-behavioural and occupational interventions (4;24). a Exercise therapy is defined as any programme in which the participants are required to carry out repeated voluntary, dynamic movements or static, muscular contractions, where such exercises is intended as a treatment for low back pain. The exercise has to be supervised or prescribed. b In general, three behavioural treatment approaches can be distinguished: operant, cognitive and respondent. Operant can be explained as positive reinforcement of healthy behaviour, as for example graded activity. Cognitive treatment aims to identify and modify patients cognitions regarding their pain and disability. Respondent treatment aims to modify the physiological response system directly, e.g., by reduction of muscular tension as for instance applied relaxation or biofeedback 4

9 However, brief intervention may be an attractive alternative and is effective in reducing sick leave and disability as compared to usual care (25). The aim of this study was to measure sensitization of the nociceptive system in LBP patients with and without nerve root affection, to analyse for associations with spinal and non-spinal factors, and to investigate the prognostic influence of sensitization in models taking into account other prognostic factors, including psychosocial factors Pain mechanisms in LBP Pain sources Clinical and experimental studies: Nociceptors are located in all tissues in and around the spine, except in the central part of the discs. In the discs they are located in the outermost 1-3 mm of annulus. In severely degenerated discs, nociceptive nerve endings have also been identified in the nucleus (26). It is believed, that disc pain may be caused by leaking nucleus material through annulus ruptures to the outer part of annulus (27). In patients with non-specific LBP there is no agreement on which vertebral structures are the cause of back pain (5). Discography may cause pain, however, the pain response is more influenced by psychological factors and non-lumbar pain than the presence of annulus ruptures (28). Discography has no proven value in the selection of patients for fusion operation (29;30). Pain may come from the facet joints (31) or sacroiliac joints (32), but false-positive results of diagnostic blocks are frequently occurring. False-positive results may be overcome by repeated, blinded blocks (triple blocks), and the pain source treated by injection therapy or radiofrequency procedures. Controversy exists regarding indication and effect of this type of procedures (33;34). A Cochrane review found little evidence for the effectiveness of radiofrequency procedures, and only a limited number of patients have been included in controlled trials (34). According to an updated Cochrane review, there is insufficient evidence to support the use of injection therapy in subacute and chronic LBP. However, it cannot be ruled out that specific subgroups of patients may respond to a specific type of injection therapy (35). Nevertheless, searching for a localized source of pain may be unfruitful in patients with more diffuse pain. Muscle nociceptors may play a role (5;36), but this question has not been sufficiently elucidated, since muscle nociceptors are difficult to study (37;38). An animal study showed (39) that spinal processing of pain from the multifidus muscle is widely distributed, and the centre of pain processing is located in the periaquaductal grey matter of the brainstem. In sciatica caused by disc herniation, the pain is caused partly by compression of the nerve root and partly by chemical substances originating from nucleus pulposus (40-43). This may explain some of the discrepancies between size of morphologic changes and symptoms or neurological findings. X-ray studies: Consistently, cross-sectional studies have shown that disc degeneration is a weak risk factor for LBP. According to a meta-analysis including 5,025 persons in eleven studies (44), disc degeneration was seen more often in persons with LBP than without OR 1.83 ( ). Other abnormalities, such as transitional vertebra, spondylosis, spondylolisthesis, spina bifida and Scheuermann s disease were not significantly associated with pain, although these results might have been weakened by fewer persons included in that part of the study (45). As for disc degeneration, these results have been confirmed by a later cross-sectional study (46) showing an association between disc space narrowing and back pain the preceding year: OR 1.7 ( ). No statistically significant associations between back pain and the presence of osteophytes or endplate sclerosis were found. Calculation of attributable risk indicated that disc degeneration may be the cause of pain in 19-27% of the LBP patients with disc degeneration (Table 1). MRI studies: According to a twin study, disc degeneration in the lumbar spine was predominantly inherited and dependent on age. Less than 7% of these structural changes could be explained by physical loading at work or by physical activity in leisure time (47). The statistical models in the study explained 43-75% of the variation. However, disc degeneration explained little of the LBP reported by the patients (48): The association 5

10 between LBP the preceding year and disc space narrowing was OR 1.8 ( ), and a similar association was found for annular tears. According to linear regression models, only 7% of the LBP was explained by disc degeneration and 6% by annular tears. Correspondingly, a Danish population study (49) including 412 persons found disc height reductions associated with LBP the preceding year: OR 2.5 ( ). In that study the one-year-prevalence of LBP was 69%, which is somewhat higher than found in other studies. The consequence was an overestimation of the association when expressed as OR. Most strongly associated with LBP were Modic changes OR 4.2 ( ). Calculation of attributable risk indicated that Modic changes may be the cause of pain in 28% of the LBP patients with Modic changes, which was a little higher than for disc degeneration (Table 1). Anterolisthesis was associated with pain the preceding year as well as hypointensive disc signals, annular tears, high intensive zones and foraminal stenosis. Attributable risk: A measure of the proportion of the total risk which can be attributed to the risk factor under consideration, i.e. the proportion of patients, in whom the abnormality in question may be ascribed as cause. Attributable risk = (RR-1) RR = ((prevalence in exposed)-(prevalence in non-exposed)) / (prevalence in exposed) RR: Risk Ratio Association between disc degeneration and pain: Odds Ratio (OR) = 1.83 ( ) corresponds to RR = 1.31 ( ) calculated from original table (44) AT = (1.31-1) 1.31 = % confidence interval: (1.24-1) 1.24 = 0.19, (1.38-1) 1.38 = 0.27 Conclusion: In 19-27% of patients with LBP and disc degeneration, disc degeneration may be the cause, or part of the explanation for pain. Alternative calculation: prevalence of patients with pain when disc degeneration was present: 59.7% prevalence of patients with pain when disc degeneration was not present: 45.7% AT = ( ) = 0.23 Modic changes: Pain during the preceding year was reported by 88% with Modic changes and by 63% without Modic changes (49). Alternative calculation: prevalence of patients with pain when Modic changes were present: 88% prevalence of patients with pain when Modic changes were not present: 63% AT = ( ) 0.88 = 0.28 Conclusion: In 28% of patients with LBP and Modic changes, Modic changes may be the cause. Confidence intervals could not be calculated. Table 1 The proportion of LBP patients, in whom disc degeneration and Modic changes may be the cause of pain, calculated by attributable risks using data from cross-sectional studies LBP and widespread pain 53 patients with non-specific LBP were assessed for diffuse pain and tenderness (50). At entrance, none had diffuse pain nor diffuse tenderness, but at reassessment 18 years later, fibromyalgia was present in 25% of the patients, all but one females. In a population study (51), psychological distress was measured before LBP started. Subsequently, the patients were recruited, when they consulted their general practitioner because of LBP. The following 6

11 variables were significantly associated with persistent pain and disability the following 12 months: older age, female sex, previous LBP, psychological distress, poor self-rated health, low level of physical activity, smoking, dissatisfaction with employment, duration of symptoms, pain radiation to leg, widespread pain and restriction of spinal mobility. The strongest predictor was widespread pain OR 6.4 (2.7-15). A study (52) compared two groups of patients with healthy controls: patients with chronic, non-specific LBP and fibromyalgia. The pressure-pain and tolerance thresholds on the thumb were decreased as much in LBP patients as in the fibromyalgia patients. Furthermore, the pain processing, as visualized by functional MRI (fmri) of the brain, comprised significantly more areas of the brain in the pain patients as compared to the healthy controls. A population survey (53) investigated musculoskeletal pain and found nearly as many cases of localized LBP as LBP combined with widespread pain. Patients with LBP plus widespread pain were more often women, reported more pain and poorer general health, and had more often long-lasting pain and emotional problems. In a workplace survey(54) with 2 years follow-up and 59% adherence, LBP and widespread pain were identified as the two most significant causes of both short-time and long-time sickness absence Pain physiology (55) Pain is registered by nociceptors in the tissues, these being more or less specific. The pain stimulus is transmitted through myelinated Aδ-fibres and unmyelinated C-fibres to the dorsal horn of medulla. Aδ-fibres conduct fast and are responsible for the acute, sharp pain, whereas C-fibres conduct slowly and are responsible for the dull or burning, chronic pain. The pain is modulated in the dorsal horn of medulla; it may be enhanced or inhibited by local factors, incoming impulses from remote mechanoreceptors and descending, inhibiting impulses from the midbrain and the brainstem. The pain is transmitted to the thalamus, and from there further to the insula, the somatosensory cortex, the prefrontal cortex, the anterior cingulate gyrus and the amygdale. This complex network is responsible for pain procession. Opoid receptors are predominantly localised in the basal parts of the brain, and, when stimulated, transmit impulses to the midbrain and brainstem to nerve cells in the periaquaductal gray matter and the raphe nucleus. When these nerve cells are stimulated, the inhibiting descending system is activated, and impulses travel down the medulla causing inhibition of the pain processing in the dorsal horn. Noradrenaline and serotonin are involved as neurotransmitters. The inhibiting system may be activated in major trauma, for instance in traffic accidents or war, causing transient painlessness in victims, as seen occasionally. Furthermore, this mechanism has been shown to be responsible for the well-being associated with running (56), so-called Marathon s High, and the pain decrease associated with acupuncture (57). The peripheral nociceptors may be sensitized by inflammation or trauma inducing more neuronal activity. Regional sensitization of the cells in the dorsal horn of medulla occurs in cases of nerve damage, as for instance in patients with sciatica caused by disc herniation. The nerve damage causes a change of touch sensation and temperature in the dermatom. Receptors in the dorsal horn, especially the N-methyl-D-aspartic acid (NMDA) are up-regulated causing lowering of the pain-pressure threshold in the region innervated by the damaged nerve (mechanical hyperalgesia). Furthermore, it may cause allodynia, i.e. light touch is felt like pain. The receptor field may increase, so larger areas are involved. A diffuse sensitization of the nociceptive system may occur without nerve damage, as for example in fibromyalgia: Widespread pain mechanisms Fibromyalgia: Tender Point (TP) examination is one of several methods to measure sensitization of the nociceptive system. It is a standardized and validated method originally developed for research purpose to define the diffuse pain condition fibromyalgia (58;59). Population studies have shown that many TPs are associated with the female sex, psychological distress, depression, poor sleep and fatigue. Women and men have median 6 and 3 tender points, respectively (60;61). Widespread pain of more than three months duration is reported by % of the population(62). Fibromyalgia is a subgroup of the people with widespread pain and affects 2-4% of the population, predominantly women (62). The condition requires more than ten tender points (58). 7

12 However, fibromyalgia is more and more considered as one end of a continuum instead of a well-defined disease entity (63). In fibromyalgia the increased sensitivity for pressure has been confirmed in the laboratory. Repeated mechanical pressure causes more pain in fibromyalgia patients than in controls (temporal summation) and the pain continues for longer time (aftersensation) (64). Central nervous system mechanisms involve both the medulla and the brain. There is evidence for an activation of the NMDA-receptors: injection of ketamine, a NMDA-receptor inhibitor, reduces pain and significantly increases the pain threshold (65;66). Furthermore, areas of referred pain following injection of hypertonic saline are larger in fibromyalgia patients than in controls (67); this is a sign of central sensitization. The concentration of the two pain transmitters, substance P and glutamate, are increased in the spinal fluid in fibromyalgia patients, and the activity of the pain inhibiting system is reduced (68;69). Similar pressures on the thumb in fibromyalgia patients and controls result in different pain processing as visualized by fmri of the brain (70). Clinical trials in fibromyalgia patients have proven some relief by treatment with anti-depressive drugs acting on both noradrenaline and serotonin uptake, but not by treatment with drugs affecting only one of the mechanisms (71;72). So far, peripheral mechanisms have not been demonstrated of significant importance in fibromyalgia. Predispositions: A study included 31,328 twins (73) to investigate genetic and environmental factors in four common illnesses (chronic widespread pain, chronic fatigue, irritable bowel syndrome, and recurrent headache) and two psychiatric disorders (major depression and generalized anxiety disorder). The model only included female twins. It was concluded that most of the cause of widespread pain could be attributed to a common pain factor shared with the other functional syndromes, a minor influence came from depression and generalized anxiety disorder. About half of the cause was genetic and half environmental. True genetic studies are as yet not available. Several studies have documented a higher frequency of previous psychological and physical trauma in fibromyalgia patients than in controls (74). A higher occurrence of childhood abuse and stressful life events have been identified(75-77) and posttraumatic stress disorder is more prevalent in fibromyalgia patients (78) Conclusions In patients with sciatica due to disc herniation or spinal stenosis, the pain is well-explained by nerve root affection, whether mechanically or chemically induced. Non-specific LBP may partly be explained by disc degeneration and Modic changes, the latter being strongly associated with disc degeneration(79). However, the attributable risks are low, so these structural changes may only partly explain the pain in a minority of patients. In some patients the facet joints and sacroiliac joints may play a role, and this pain source might be improved by injection therapy or denervation procedures. However, the evidence for effectiveness of such treatment is still limited. Possibly, there is a link between non-specific LBP and widespread pain/ fibromyalgia. The presence of widespread pain in conjunction with LBP seems to influence LBP-prognosis. It is not clear, if widespread pain in LBP patients are caused by spine related factors or other factors not related to spinal structures. 8

13 working without low back pain Risk factors for low back pain Risk factors for sicklisting and low back pain working with low back pain Risk factors for sicklisting sicklisting due to low back pain Prognostic factors for low back pain Prognostic factors for return to work, pain and function no pain, working intermittent or chronic pain, working sick-listing due to low back pain partial or full return to work, pain and function? no return to work, disability pension? pain and function? Figure 1 Flow-chart showing possible events in relation to work and LBP 1.3. Risk factors and prognostic factors A model for LBP and sick-listing is shown in Figure 1. In this context, working without pain is considered the natural reference point, although it is possible to have no work and no LBP as well. Risk factors for LBP with and without sick-listing will be considered, however, the focus will be on prognostic factors for those sick-listed because of LBP Risk factors for LBP Risk factors for LBP have been reviewed by Waddell(4) and Nachemson et al (80). Risk factors may be individual or environmental in terms of physical and psychosocial aspects of work. However, the strongest risk factor for LBP is always previous LBP. Individual aspects comprise genetic or familial influence, gender and age dependent risk factors (for instance, first time non-specific LBP is seldom after the mid-50s), smoking, lower social class and emotional distress. Aspects of work comprise heavy physical work and psychosocial aspects such as job satisfaction. Sitting at work is not considered a risk factor for LBP, but may aggravate LBP. Whole body vibration may be a risk factor, but is hardly relevant anymore because of better 9

14 seats. Body build, including obesity, tallness or differences in leg length, are not risk factors, and neither is alcohol (over)use. All effect sizes are small or variable, except previous back pain. Two examples of prospectively identified risk factors are giving below: In a population study Biering-Sørensen et al (1) included 928 people and registered 135 exposure variables at baseline. At one year follow-up new LBP was reported by 17% of the patients with no previous LBP at baseline. The risk factors for first time LBP were frequent epigastric pain, previous hospital admission, daily smoking, low endurance of back muscles, longer distance to work and higher age. Recurrent LBP was found in 62% with different risk factors in men and women: in men increasing LBP, sciatica and living alone, in women recent LBP, waking during night because of LBP, worsened pain while standing, rumbling of the stomach and smoking. Hoogendoorn et al (81) registered occupational risk factors and followed 861 workers with no LBP at baseline for three years. Increased risk of LBP was found in workers working with the trunk flexed minimum 60º for more than 5% of the time and for workers working with the trunk rotated minimum 30º for more than 10% of the time. Furthermore increased risk was identified in workers lifting minimum 25 kg more than 15 times a day. The predictive value of findings on X-ray or MRI in asymptomatic people: Previously, several prospective X-ray studies in asymptomatic people have failed to predict future LBP or sickness absence due to LBP (4). Since then, prospective MRI studies have confirmed this conclusion: Forty-six asymptomatic individuals with a high rate of disc herniations were followed for 5 years (82). Disc herniations and neural compromise did not worsen at follow-up whereas disc degeneration worsened in about 40% of the participants. Neither pain-related medical consultations nor work incapacity were predicted by structural changes on MRI. Work incapacity was best predicted by physical job characteristics, job disaffection, and working in shifts. MRI was performed at baseline and three years later in 123 initially asymptomatic people (83). Only few changes occurred during the following three years. There were no associations between new LBP and baseline endplate changes (Modic), disc degeneration, annular tears or facet joint degeneration. There was a tendency to positive association between new LBP and spinal stenosis or nerve root contact at baseline, but no statistically significant association. All five persons with new disc extrusion had pain. Depression at baseline doubled the risk for new LBP. In another study (84) MRI was performed at baseline and follow-up 5 years later in 100 patients with mild or no LBP at baseline. These patients had known psychosocial risk factors and a high frequency of non-lumbar pain. Disability events and health-care visits for LBP were predicted by non-lumbar pain, heavy physical work and especially by psychosocial variables (fear avoidance, DRAM: distress and risk assessment method). A tendency to positive association between new LBP and moderate or severe Modic changes were seen, but no associations were identified with other structural findings Risk factors for sickness absence due to LBP Two large studies, one population based (85) and one work-place study from a shipyard (86), identified quite similar risk factors for LBP with sickness absence, except for previous LBP not being a risk factor in one of the studies (86). The strongest risk factors were previous sick leave in general and especially sick-listing due to LBP, the latter increasing the risk almost seven times. Furthermore, previous care seeking and use of analgesics for LBP were significant risk factors. Finally, lower educational level or unskilled occupation as well as previous sciatica or disc herniation independently increased the risk. Low endurance of the backextensor muscles was identified as risk factor in one of the studies (85). No clear associations were demonstrated regarding BMI, smoking, nervousness or exercise in leisure time Prognostic factors in patients with non-specific LBP A systematic review (87) identified 19 studies fulfilling predetermined quality criteria. Included were only prospective cohort studies and randomised controlled trials analyzed as cohort studies, representing 35,698 persons, of whom 25,095 were from an insurance setting. Patients had to be included within 6 months from injury and at least one follow-up was required. Outcome was registered as: time to return to work, 10

15 recurrence/improvement, working/not working, health care cost, persistent disability/pain. The prognostic factors identified were as follows: Time to return to work: Negative predictors were older age, female sex, psychological distress, functional disability, radiating pain and pain worse on standing and lying. No pain, no sprains, good flexion and the absence of neurologic signs were positive predictors. Previous hospitalization and previous episodes of back pain were negative predictors. The influence of compensation claim was inconclusive. The availability of modified jobs and light mobilisation were positive predictors. Less than 30 days waiting time until treatment and more than 2 years at the same job were also positive predictors. Job problems and problems with colleagues were negative predictors. Recurrence/improvement: Negative predictors were positive Straight Leg Raise less than 50, pain in the lower extremity/below the knee and poor lumbar extension. Young workers had less risk and male workers more risk. Furthermore nurses and drivers had increased risk. Working/not working: Negative prognostic factors were higher age, female sex, more children living at home, lack of internal locus of control, high functional disability. Positive predictors were few previous X-rays and greater mobility. Low control over work and the presence of compensation claim were negative predictors. Health care costs: Increased health care use was associated with depression, more days in pain, high pain, disability pay, and if arthritis was present in addition to injury. Persistent disability/pain: Negative predictors were previous episodes of LBP, radiating leg pain and widespread pain. Negative predictors were also female sex, depression and fear avoidance. High functional disability and job dissatisfaction were predictive of persistent disability. A second systematic review (88) included only studies in persons with sick leave for more than one day and less than 6 weeks. 14 studies were identified comprising 104,676 persons, of whom 90,000 were from an insurance setting. Outcome was defined as duration of sick leave. Only two of the background papers were shared with the former review. The review concluded as follows: There was strong evidence for previous LBP not being able to predict the duration of sick leave, but also strong evidence that high disability (low level of function) at inception was a risk factor. There was no clear picture regarding pain intensity at baseline, some studies reporting significant influence and some not. There was conflicting evidence for physical examination as predictive for the duration of sick-leave. High level of leg pain or radiating pain increased risk. There was no clear picture regarding age, but most high quality studies reported older age as a risk factor. Men returned faster to work than women. Educational level, marital status, income and number of dependents had no influence on sick leave. There was moderate evidence for higher BMI as a risk factor, but no evidence for smoking. There was no evidence that physical fitness or being active in sporting reduced risk. There was moderate evidence for poor general health as a negative risk factor for duration of sick leave. Social dysfunction and isolation were risk factors for the duration of sick leave, but there was insufficient evidence for anxiety, depression and life events. Lack of locus of control was not a significant predictor. There was strong evidence for heavy physical work as a predictive factor, but insufficient evidence for shift work, or work with much sitting, walking or awkward postures. There was strong evidence for vibration having no influence and insufficient evidence for high work quantity and tempo as risk factors. There was insufficient evidence for the employment duration, but moderate evidence for co-worker or supervisor support as beneficial. There was no evidence for lack of job satisfaction as a risk factor. There was insufficient evidence for influence of job demands, job strain, job control or work flexibility. There was strong evidence for no influence of the type of occupation on duration of the sick leave. A third systematic review (89) included 17 studies (>5 of 11 quality criteria) representing 2,046 persons. To be included were required LBP > 4 weeks or recurrent pain the preceding year and at least one intervention. Sick-listing was not a mandatory inclusion criterion, but was measured as outcome. Follow-up had to be at least one year. None of the references was shared with the former review and only two papers with the latter: 11

16 No core set of predictors could be identified. No risk factors for sickness absence were identified. Optimistic expectations were the strongest predictors for fewer days on sick leave and no sickness absence at follow-up. A systematic review (90) studied the ability of instruments/models to predict function-related outcome associated with chronic LBP. Sixteen studies were included. The instruments/models had only moderate ability to predict or explain function-related outcome and explained maximally 51% of the variability. There was great variability in the predictors included and not all known risk factors were included in the models. Risk factors for low back pain (LBP) Risk factors for sickness absence due to LBP Prognostic factors for patients with nonspecific LBP Possible prognostic factors previous LBP genetic/familial gender (more often sciatica in men) age (predominantly 30-50) psychological distress/depression possibly lower social class work postures (bending, trunk rotated) heavy lifting at work low endurance of back-extensor muscles smoking previous hospitalisation in general previous hospitalisation for LBP previous care seeking for LBP previous sciatica or disc herniation lower education/ unskilled occupation older age high level of functional disability sciatica (leg pain) poor general health increased psychological and psychosocial stress f.ex. depression, somatisation negative cognitive characteristics f.ex. fear avoidance poor relations with colleagues heavy physical work demands presence of compensation high level of pain multiple pain sites/ widespread pain long duration of episode negative expectations about persistent pain and return to work lack of available, modified job function restriction of spinal motion Table 2 Risk factors and prognostic factors. The prognostic factors indicated by bold were consistently reported according to the review of reviews (91). Discrepancies across reviews were found in review of reviews (91) studying 17 systematic reviews: differences in selection criteria influenced studies included, and various approaches to data interpretation influenced review conclusions about evidence for specific prognostic factors. Only in seven selected reviews (87;88;92-95) investigating similar research questions, it was possible to compare the results. Few risk 12

17 factors were consistently reported to be associated with poor outcome (shown with bold in Table 2). To be reported consistently as risk factor, similar reporting in at least three reviews was required. Two large studies, not included in the reviews listed above, have been published recently: A primary care study (96) included 973 consecutive patients and achieved 97% follow-up at one year. Only patients seeking primary care because of LBP lasting between 24 hours and 2 weeks were included. Patients with radicular pain or pain the preceding month before the episode were not included. Of those working full time before onset, 38% and 7% were sick-listed at baseline and 3 months, respectively. Seven baseline variables were independently associated with delayed recovery: older age, higher intensity of pain, depression, perceived risk for persistent pain, ongoing compensation, many days of reduced activity due to actual pain and longer duration of episode. In a study comprising 1,885 workers (97), the following baseline risk factors for full time sick-listing at one year were identified: pain below the knee, high disability in daily activities (Roland Morris Questionnaire), a chiropractor not first health care provider, high number of pain sites, very hectic job, no offer of light duty and previous injury involving a month or more off work. When the strongest risk factor, disability, was removed from the model, the following variables were significantly associated with outcome: catastrophizing, recovery expectations, fear avoidance and mental health. Psychological distress and depression in patients with LBP, cause or effect: Aiming at elucidating the role of psychological factors in the transition of acute to chronic LBP, a systematic review (98) was performed. Included were LBP cohort studies with measurement of at least one psychological variable at baseline. In one of the retrieved studies (51) psychological distress was measured before the onset of pain. It was concluded that there was strong evidence for the role of psychological distress/depression in the transition of acute to chronic LBP and moderate evidence for the role of somatisation. There was scarcely evidence for fear or anxiety in predicting outcome. A large population study (99) achieved 80% response rate to a self-report survey sent to more than individuals. Chronic back pain was present in 9% and depression in 5.9% of the participants. Depression was present in 18.9% of the patients with chronic back pain. Adjusted for confounders, depression affected six times more patients with chronic back pain as compared to patients without. A population based random sample of 790 adults with no or mild pain at baseline was surveyed with followup at 12 months (100). Using validated screening instruments, participants were screened for depressive symptoms at baseline and screened for back and neck pain the following year. Adjusted for other risk factors including exercise frequency, moderate depressive symptoms at baseline were associated with twice the frequency of troublesome neck/back pain at 12 months; severe depressive symptoms at baseline were associated with 4-double increase in troublesome neck/back pain Prognostic factors in patients with nerve root pain Several surgical cohort studies (4;101) have studied risk factors for adverse outcome in patients with verified nerve root affection. Adequate selection of patients for surgery and optimal techniques are important aspects, however, psychosocial risk factors are important for outcome as well. It is not known if psychosocial risk factors in these patients are more or less important, as compared to patients with non-specific LBP. A systematic review (102) identified 22 papers investigating cardiovascular risk factors in patients with lumbar radicular pain. In almost all studies investigating overweight as risk factor, an association with clinically defined sciatica was found. Only in one study, a dose-response relationship was found. Some studies showed increased risk of radicular pain in smokers with long smoking history. Physical activity was more ambiguously associated with radicular pain Conclusions (Table 2) Except for previous LBP being a strong risk factor for LBP, only weak risk factors have been identified. Disc-degeneration-related structural findings on lumbar spinal X-ray or MRI seemed to have no or little predictive value. 13

18 The following risk factors for sickness absence due to LBP were identified: previous sick-listing in general; previous sick-listing and care seeking for LBP; previous sciatica; unskilled occupation; low educational level. The prognostic factors for outcome in patients with LBP were different: older age; high level of functional disability; sciatica; poor general health; increased psychological or psychosocial stress; negative cognitive characteristics; poor relations with colleagues; heavy physical work; the presence of compensation. Other possible risk factors were: high pain intensity; widespread pain; long duration of episode; negative expectations; lack of available modified job function. Depression was found to be associated with long-lasting LBP. LBP may precede depression and depression may precede LBP. To some extent, risk factors were similar in patients with radicular pain, but a few risk factors were different, especially overweight. 2. AIMS The purpose of the present investigation was To measure sensitization of the nociceptive system in patients sick-listed because of LBP by tender point examination (manuscript 1) pressure pain threshold measurement on the thumbnails (manuscript 2) and to compare tender points and pressure pain thresholds to find out, if the two measures of sensitization in LBP patients were comparable (manuscript 2) To analyse if many tender points and low pressure-pain thresholds on the thumbnails were associated with structural changes in the spine, such as disc degeneration and disc herniation with nerve root affection, or were more associated with other variables such as sex, age, pain intensity, pain duration, psychological distress, depression and various social variables (manuscript 1 and 2) To establish a prediction model for return to work (manuscript 3) To analyse, if the number of tender points and the level of pressure-pain thresholds at baseline, adjusted for other prognostic factors and confounders, influenced the one-year prognosis regarding return to work, pain and disability (manuscript 3 and 4) 3. METHODS Patients In the period November July patients were referred from their general practitioner to the Research Unit of the Spine Center, Region Hospital Silkeborg, Denmark (Figure 2). Of these 351 patients were included in a clinical trial studying the effect of brief clinical intervention vs. multidisciplinary intervention, one group receiving clinical evaluation and guidance by a specialist of rheumatology and rehabilitation as well as a physiotherapist, the other group in addition coaching from a social worker, a vocational therapist or specialist of social medicine in a multidisciplinary setting. Details of the study will be published elsewhere. To be included the patients fulfilled: partly or fully sick-listed from work 4-12 weeks due to LBP with or without symptoms and signs of nerve root affection, LBP should be the prime reason for sick-listing and at least as bothering as eventual pain elsewhere, age years, referred from a well-defined area of about inhabitants in and around Silkeborg, and the patient should be able to speak and understand Danish. Exclusion criteria: registered as unemployed, living outside the referral area, continuing or progressive signs or symptoms of nerve root affection implicating plans for surgery, low back surgery within the last year, previous lumbar fusion operation, suspected cauda equina syndrome, progressive paresis or other serious back disease, (e.g. tumor), pregnancy, known dependency on drugs or alcohol or primary psychiatric disease. A total of 25 patients were excluded for the following reasons: metastatic malignancy of the spine (2), osteoporotic fractures (4), spondylolisthesis (6), osteomalacia (2), peripheral arteriosclerosis (2), sacroiliitis (1), severe scoliosis (1), hydronephrosis (1), trochanteric bursitis (1), withdrawing after inclusion (4), 61 years old (1), leaving 326 patients for the present study. Self reported sick-listing was median 41 days, (mean 46 days, 3-6 weeks), 24 patients sick-listed for less or more than 4-12 weeks. 14

19 LBP classification MRI of the lumbar spine was performed in 75% of the patients and was always performed, when possible nerve root pain was present, or if specific or serious back disease was suspected. The last year of inclusion, MRI was performed in all patients. The MRI examinations included T 1 and T 2 -weighted sequences of the lumbar spine, but comprised only STIR sequences of the sacroiliac joints, if inflammatory back disease was suspected clinically. Most MRI examinations were performed at the Region Hospital Silkeborg using a 0.7 T machine. The images were described by a specialist of radiology, and all examinations were evaluated by one of the authors as well (OKJ). When in doubt, the images were discussed with the back surgeons at weekly conferences. No standard grading system was applied. Other investigations were performed when clinically relevant. Possible nerve root pain was defined as sharp or shooting pain or tingling or numbness below the gluteal fold. Verified nerve root affection was defined as structural changes on MRI corresponding to minimum one of the following signs: positive Lasegue 60º, missing or inhibited reflex, altered sensation in a dermatome or paresis. In cases of spinal stenosis, spinal claudicatio in combination with MRI findings were sufficient. Patients were classified as having non-specific LBP (A) or verified nerve root affection (B). Patients with non-specific LBP were further subdivided into two groups. The first part of the classification was based on clinical judgment: If there was no complaint of nerve root pain and no signs of nerve root affection, including negative Laseque, the patient was classified as having non-specific LBP. When in doubt, MRI was always performed. The subdivision of the non-specific LBP group was based on questionnaire answers. If the patient had ticked the pain to radiate to the lower leg or foot, he or she was classified as having nonspecific radiating pain. A. 1) Non-specific LBP without leg pain (LBP only): 96 patients (29%), including 12 patients with disc herniations without radiating pain or neurologic signs. MRI was performed in 55.1% of this group. 2) Non-specific radiating pain with or without neurologic signs, but no structural findings on MRI explaining the symptoms: 118 patients (36%), 13 of these with neurologic signs, but no relevant findings on MRI. MRI was performed in 68.3% of the patients without neurologic signs, and in 12 of 13 (92.3%) of those with neurologic signs. Another 15 patients had disc herniations with pain radiating below the knee, but no neurologic signs. B. Verified nerve root affection with relevant structural lesion on MRI: 111 patients (34%) with disc herniation (n=97) and spinal stenosis (n=14). The symptomatic disc herniations were located at LV-SI in 62 patients, LIV-V in 33 patients and LII-IV in 2 patients. Spinal stenosis was located laterally in 9 patients and centrally in 5 patients. MRI was performed in 98.2% of these patients Baseline variables At inclusion, all patients completed a comprehensive questionnaire displaying a drawing of the low back hatched from the thoracolumbar junction down to the gluteal fold. The questionnaire included items from different sources: The LBP Rating Scale has been validated previously (103); it comprises a sum score based on questions of worst, average and actual pain during the preceding 2 weeks and includes questions on intensity of both back and leg pain. Two additional questions asked about pain radiating to the lower leg or foot. Disability in daily life activities was measured by Roland Morris Questionnaire, in Danish validation only including 23 questions (104). The validated Common Mental Disorders Questionnaire (CMDQ) (105) included questions of psychological distress divided into four dimensions: bodily distress, worrying and health anxiety, mental distress and depressive symptoms. The questionnaire responses were compared to the results of a semi-structured psychiatric interview in a stratified second phase sample of 701 patients. There was good agreement between the classification based on the questionnaires and the psychiatric interviews. Bodily distress comprised 11 questions about headache, dizziness, pains in the heart and breast, nausea or upset stomach, soreness of muscles, trouble of getting the breath, hot or cold spells, numbness or tingling in parts of the body, a lump in the throat, feeling weak in parts of the body and heavy feelings in the arms and legs. One question of LBP was omitted. Worrying and health anxiety comprised 7 questions as for example about worries, that there is something seriously wrong with the body, many different pains and aches, thoughts, that the doctor might be 15

20 wrong if telling not to worry, worries about the health etc. Mental distress questions comprised 8 questions as for example about nervousness or shakiness inside, spells of terror or panic, feeling fearful and feeling that everything is an effort etc. Depressive symptoms included 6 questions of feeling blue, feeling of worthlessness, thoughts of ending ones life, feelings of been trapped or caught, feeling lonely and blaming oneself for things. In all four dimensions scores were higher, when psychological distress was higher. Questions about diffuse pain the preceding two weeks included: being much bothered by pain or discomfort in the neck, shoulders, arms, hands, back, buttocks, legs, knees and feet. Fear avoidance about physical activity was measured by three questions concerning pain increased by physical activity, increasing pain indicating stop of the activity, and lack of ability to do normal activity and work with the present pain. These questions have been validated in Sweden (106). Work-related questions comprised questions about blaming the work for LBP (work the only cause vs. partly or not the cause), a question about expectations about return to work within 6 months (10 box scale, 8-10 vs. <8) and questions about eventual ongoing compensation (compensation claim, yes or no). Items of social aspects included questions of school and vocational education, marital status and children, presence of home ownership, job function, personal and family income, sports and exercise activity in leisure time and smoking. These questions were imported from a questionnaire previously used in a population study by the Centre of Public Health, Central Denmark Region. By one of the authors (OKJ), a medical record was made in all patients, and a standard clinical low back examination, including measure of body weight and height, was performed. Forward-flexion was measured by the Modified Schober: the lumbosacral junction was marked, and a mark was placed 10 cm more proximally and 5 cm more distally. The increment under forward bending was measured. Side-flexion was measured by setting a mark on the lateral side of the femur, where the fingertips ended. A new point was set after maximal side-bending and the difference measured. The side-flexion was computed as the mean of the right and left side. Waddell s signs were registered (4). At the end of the examination a tender point examination was performed: A gradually increasing pressure was applied by the thumb at 18 spots on the body, the pressure intended to increase by 1 kg per sec. up to 4 kg. The spots were located symmetrically on the neck, shoulders, forearms, second ribs, buttocks and legs (58). First, the pressure was demonstrated to the patient distally on the forearm. The patient was instructed to identify, if the pressure caused mild discomfort or was painful. Only painful points were counted as positive. Periodically, an algometer (Somedic AB, Stockholm, Sweden) was used to calibrate the pressure applied by the thumbs. Disc height reductions of the five lower lumbar levels on plain lateral X-ray were measured by one of the authors (OKJ): height reductions were classified as no height reduction: 0, 0-25% slight: 1, 25-75% moderate: 2 and 75% reduction severe: 3 (107). If there was air in a moderately degenerated disc, it was classified as severe. A similar classification has been found valid for the 4 upper lumbar segments(108). A disc degeneration score (DDS) was computed as the sum of the scores. The X-rays were from different sources, various departments of radiology as well as chiropractors. In 60 randomly selected patients, the personal identification on the X-rays was blinded, and the classification was repeated by the same author (OKJ). The agreement was good or acceptable in the upper 4 segments (agreement 83-95%, Kappa ), but not in the lumbosacral segment (agreement 73%, Kappa 0.34). Therefore, DDS only comprised the sum of the 4 upper lumbar segments (agreement for the sum 68%, Kappa 0.54), and the dichotomized score did not involve the lumbosacral level. No actual X-rays (less than two years old) of the lumbar spine were available in 78 patients, but Magnetic Resonance Imaging (MRI) of the lumbar spine was available in these patients Outcome variables Manuscript 1: Tender points, dichotomised into upper quartile vs. three lower quartiles for the whole group, and for men and women separately. The intensity of back pain as discrete variable. Manuscript 2: Pressure-pain thresholds of the thumbnails dichotomised into lower quartile vs. three upper quartiles for the whole group, and for men and women separately. Return to work vs. not returning to work at one year. Manuscript 3: Not returning to work vs. return to work at one year. Manuscript 4: Disability and intensity of back+leg pain at one year analysed as discrete variable. 16