Key Articles Kirkaldy-Willis WH, Wedge JH, Yong-Hing K, Reilly J (1978) Pathology and pathogene- sis of lumbar spondylosis and stenosis. Spine 3(4):319 – 28 In this study, autopsy specimens of lumbar spines were used to define the degenerative cascade of the spine. Progressive degenerative changes in the posterior joints lead to destruction and instability. Similar changes in the disc result in herniation, internal dis- ruption, and resorption. Combined changes in posterior joint and disc can produce entrapment of a spinal nerve in the lateral recess and/or central stenosis. Changes at one level often lead, over a period of years, to multilevel spondylosis and/or stenosis. Miller JA, Schmatz C, Schultz AB (1988) Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens. Spine 13(2):173 –8 This meta-analysis is based on data from 16 published reports. Macroscopic disc degen- eration grades were correlated with age, sex, and level in 600 lumbar discs from 273 cadavers (0–96 years of age). Male discs were significantly more degenerated than female discs in the second, and fifth to seventh life decades. L4/L5 and L3/L4 level discs showed more degeneration than other levels. Higher mechanical stress, perhaps combined with longer nutritional pathways, may be responsible for the earlier degeneration of male discs. Boos N, Weissbach S, Rohrbach H, Weiler C, Spratt KF, Nerlich AG (2002) 2002 Vo lvo Award in Basic Science: Classification of age-related changes in lumbar intervertebral discs. Spine 27(23):2631 – 44 This paper provides a systematic semiquantitative assessment of age-related morpho- logic changes in the intervertebral disc and cartilaginous endplate which is based on 20250 histologic variables. The study revealed significant temporospatial variations with regard to presence and abundance of histologic disc alterations across levels, regions, macroscopic degeneration grades and age groups. The detailed analysis resulted in a practicable and reliable histologic classification system for lumbar discs which can serve as a morphologic reference framework. The article provides clear histo- logic evidence for the detrimental effect of a diminished blood supply to the interverte- bral disc that appears to initiate disc tissue breakdown beginning in the first half of the second life decade. HornerHA,PhilM,UrbanJPG(2001) 2001 Volvo Award Winner in Basic Science: Effect of nutrient supply on the viability of cells from the nucleus pulposus of the interverte- bral disc. Spine 26(23):2543 – 49 Nucleus pulposus cells were cultivated in a system where nutrient supply was dependent on diffusion, therefore simulating the situation in the intervertebral disc. It was found that the cell density was dependent on nutrient supply and was inversely related to disc thickness. Oxygen supply was not necessary for cell viability but was needed for proteog- lycan production. Lack of glucose or low pH led to cell death suggesting nutrient restric- tions contribute to disc degeneration. Roberts S, Urban JPG, Evans H, Eisenstein SM (1996) Transport properties of the human cartilage endplate in relation to its composition and calcification. Spine 21(4):415 –20 Transport properties of solutes of different sizes and shapes were correlated with the composition of the cartilage matrix. The more hydrated the matrix, the easier solutes were found to move. Increasing contents of proteoglycan, collagen or calcification resulted in greater restriction of solute movement. This finding confirmed that calcifica- tion of the cartilage endplate might have consequences for the nutrient supply to the disc and therefore for the onset of disc degeneration. Weiler C, Nerlich AG, Zipperer J, Bachmeier BE, Boos N (2002) 2002 SSE Award in Basic Science: Expression of major matrix metalloproteinases is associated with interverte- bral disc degradation and resorption. Eur Spine J 11(4):308 – 20 The role of matrix metalloproteinases (MMPs) in matrix degradation leading to disc degeneration was investigated in 30 cross-sections of lumbar intervertebral discs from cadavers (0–86 years of age). Expression of major MMPs was found to correlate with age and the occurrence of signs of degeneration, i.e. clefts and tears. These data indicated that major MMPs play an important role in matrix degradation that might lead to disc degen- eration and possibly to the induction of low back pain. Age-Related Changes of the Spine Chapter 4 115 BattieMC,VidemanT,GibbonsLE,FisherLD,ManninenH,GillK(1995) 1995 Volvo Award in Clinical Sciences. Determinants of lumbar disc degeneration. A study relating lifetime exposures and magnetic resonance findings in identical twins. Spine 20(24):2601 – 12 Effects of lifetime exposure of 115 twin pairs to commonly suspected risk factors on disc degeneration were assessed by magnetic resonance imaging and their influence was com- pared to age and familial aggregation, reflecting genetic and shared environmental influ- ences. The results of this study suggested that disc degeneration may be primarily explained by genetic influences, with environmental factors, widely suspected of acceler- ating disc degeneration, only having very modest effects. Adams MA, Freeman BJC, Morrison HP, Nelson IW, Dolan P (2000) Mechanical initia- tion of intervertebral disc degeneration. Spine 25(13):1625 –36 It was investigated whether minor damage to a vertebral body can lead to progressive dis- ruption of the adjacent intervertebral disc. 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Künzel, Norbert Boos Core Messages ✔ Chronic (persistent) pain has a high prevalence in the general population and is predominately felt as musculoskeletal pain ✔ A temporal classification of pain (i.e. acute, sub- acute, chronic) is arbitrary and does not reflect the underlying mechanisms of pain ✔ Pain is better differentiated into nociceptive, inflammatory, and neuropathic pain ✔ Neuropathic pain has lost its protective role and is maladaptive ✔ The physiologic processes involved in pain can be differentiated into transduction, conduction, transmission, modulation, projection and per- ception ✔ Nociceptive signals are modulated by various excitatory and inhibitory mechanisms on their pathways to the brain ✔ Genetic predisposition and biopsychosocial fac- tors have a significant influence on pain per- ception ✔ Pain pathways can undergo distinct alterations as a result of peripheral tissue damage and neural injuries (neuroplasticity) ✔ The neuroplasticity of the pain pathways can be described in terms of peripheral sensitiza- tion, transcriptional changes in the dorsal root ganglion, central sensitization and disinhibition ✔ Persistent pain is not prolonged acute pain but follows distinct alterations in the pain pathways ✔ Neuropathic pain is different from nociceptive pain and results from primary damage or dis- ease of the peripheral or central nervous system ✔ Not all persistent pain is neuropathic. The clini- cal differentiation of persistent inflammatory and neuropathic pain, however, remains a chal- lenge ✔ Treatment of acute pain should be aggressive, multimodal and preemptive to avoid pain per- sistence ✔ Adjuvant drugs (e.g. antidepressants, anticon- vulsants, anxiolytics) enhance the central effect of analgesics and should be included for an adequate treatment of moderate to severe pain ✔ The scientific evidence for a long-term effec- tiveness of surgical treatment of persistent spi- nal pain is lacking Historical Background Precartesian Theories Pain remained enigmatic in ancient times Early civilizations provided a wide variety of explanations for pain and attrib- uted it to factors such as religious influences of gods, the intrusion of magical flu- ids, the frustration of desires and deficiency or excess in the circulation of Qi [70]. The relief of pain therefore was the task of shamans or priests, who used herbs, rites, and ceremonies to alleviate pain. The early Greeks gave more specific explanations for pain [70]. According to Plato (427–347 A.D.), the heart and the liver were the centers of appreciation of all the sensations, and pain arose not only from peripheral sensation but as an emotional response in the soul, which was located in the heart [70]. Hippocrates assumed a wrong mixture of fluids to be the cause of pain. However, Galen of Pergamon (130–200 A.D.)madethefirst observations on the nervous system and the spine but still believed the so-called “fluid doctrine” of Hippocrates (see Chapter 1 ). Basic Science Section 123 Cartesian Theory Descartes first suggested a pathway which transmits noxious stimulus directly to the brain The French philosopher Ren´e Descartes (1596–1650) presented a dualistic view of the human body and soul,i.e.heassumedaseparationofthemindandthe body. The body was seen as a machine working according to the laws of nature and the “rational soul” was the “conductor of the orchestra” [70]. With the sug- gestedseparationofthesoulfromthehumanbody,anendlesscontroversyarose about the mind-body relation which has been plaguing and intriguing philoso- phers and neuroscientists ever since [7]. Descartes also proposed a simple path- way of the transmission of a noxious stimulus to the brain [22]. However,Descar- tes’ theory was only published after his death in the Trait ´edel’Homme[7]. Des- cartes gave a purely mechanical view of the involuntary withdrawal of a foot that comes into contact with a noxious stimulus: “the small rapidly moving particle of fire moves the skin of the affected spot causing a thin thread to be pulled. This opens a small valve in the brain and through it animal spirits are sent down to the muscles which withdraw the foot” [22]. After that it was believed for a long time that there was a one-to-one relationship between the amount of damage and the perceived pain. The theory of Descartes implies that a specific pain pathway car- riesthemessagefromapainreceptorintheskintoapaincenterinthebrain. However, it has become apparently clear that pain cannot be alleviated by simply cutting this pathway. On the contrary, a dissection of this pathway can even exac- erbate the pain [22]. Gate Control Theory Neural “gates” transmit or block nociceptive transmission to the CNS Major progress in our understanding of pain and its mechanisms followed the introduction of a new theory by Melzack and Wall in 1965 [77]. The authors sug- gested a gate control system which modulates sensory input from the skin before it evokes pain perception and response. Accordingly, the substantia gelatinosa in the dorsal horn functions as a gate control system that modulates the afferent patterns before they influence the central transmission cells. The afferent pattern in the dorsal column system acts as a central control trigger which activates selective brain processes that influence the modulation properties of the gate control system. The transmission cells activate neural mechanisms which com- promise the action system responsible for response and perception [77]. This theory underwent multiple modifications and extensions throughout the follow- ingyears.Althoughithasbeenshownthatspecificelementsofthegatecontrol theory are invalid or too simplistic, the fundamental model remains. Gates in the dorsal horn consisting of interneurons balance the level of sensory fiber activity and are influenced by descending brain signals. This concept explains how pain can be felt with and without tissue damage and how psychological factors can influence pain [84]. Modern Pain Theories Since the introduction of Melzack and Wall’s theory, most of the research has focused on two general processes that can control the pain gate [19], i.e.: the inhibitory mechanism the exhibitory mechanism Pain has a morphological and molecular correlate Inhibitory neuronal circuits control nociceptive transmission in the spinal cord and act as gatekeepers suppressing undesirable inputs [19], while increased exci- tation can occur as a result of neural plasticity [130]. In the last decade, intriguing progress has been made in dissecting out the molecular and cellular mechanisms 124 Section Basic Science . cross-sections of lumbar intervertebral discs from cadavers (0–86 years of age). Expression of major MMPs was found to correlate with age and the occurrence of signs of degeneration, i.e. clefts and tears Comparison of structure, mechanical properties, and functions of lumbar spinal ligaments. Spine 15: 787–795 53. Iannuzzi-Sucich M, Prestwood KM, Kenny AM (2002) Prevalence of sarcopenia and predic- tors. central effect of analgesics and should be included for an adequate treatment of moderate to severe pain ✔ The scientific evidence for a long-term effec- tiveness of surgical treatment of persistent