Herta Flor1 and Frank Andrasik2

The Migraine And Headache Program

Migraines Causes and Treatments

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department of Clinical and Cognitive Neuroscience, University of Heidelberg, Central Institute of Mental Health, Mannheim, Germany and 2Institute for Human and Machine Cognition, University of West Florida, Pensacola, FL, USA

15.1 Introduction

Despite the many advances in the pathophysiology and treatment of pain, chronic pain still remains elusive to treat. Once the pain problem has exceeded the acute and subacute stage, peripheral factors seem to loose their importance and central changes become much more important (Sandkuhler, 2000; Ji et al., 2003). One major factor that seems to contribute to chronicity are memory traces that occur as a consequence of ongoing and/or very intense pain and that are enhanced by learning processes designed to imprint and consolidate these pain-related memory traces. In this chapter we will review the evidence on plastic changes along the neuraxis and their relationship to pain in humans and then delineate treatment approaches that are designed less towards analgesia but more towards reversing maladaptive plasticity with the hypothesis that this would consequently also reduce chronic pain and extinguish pain memories.

15.2 Pain and plasticity

Chronic musculoskeletal pain

In the last two decades our understanding of the modifiability of the primary sensory and motor areas of the brain has greatly changed (see Chapters 6-8 of Volume 1). Animal models have shown that long-lasting and/or intense states of pain (e.g., when an inflammation is present) lead to the sensitization of spinal cord neurons (e.g., Sandkuhler, 2000) as well as an altered representation of the painful area in the brainstem (Tinazzi et al., 2000), thalamus (Vos et al., 2000) and cortex (Benoist et al., 1999). In chronic pain patients both perceptual and cerebral hyper-reactivity to tactile or noxious stimuli have been observed. For example, Kleinbohl et al. (1999) showed that patients with back pain as well as patients with tension headache sensitize more than healthy controls, that is, they show steeper increases in perceived pain intensity with repetitive painful stimulation. In addition, perception and pain thresholds as well as pain tolerance levels were found to be significantly lower in patients with chronic back pain compared to persons with episodic headaches and healthy controls, and these thresholds varied as a function of chronicity (the more chronic pain, the lower the threshold) (Flor et al., 2004). This chronicity distinction is particularly important when considering tension-type headache. Chronic forms of tension-type headache consistently reveal evidence of central sensitization to thermal, electrical and pressure stimulation (Langemark et al., 1989; Schoenen et al., 1991; Bendtsen et al., 1996), whereas patient groupings whose diagnoses are episodic or episodic mixed with chronic do not (Bovim, 1992; Jensen et al., 1993; Jensen, 1996). In fibromyalgia syndrome, hypervigilance and exaggerated perception of both painful and non-painful tactile stimuli has been reported (Staud et al., 2001), however, this sensitivity has not been observed with respect to auditory stimuli (Lorenz, 1998).

Elevated responses to painful and non-painful tactile stimulation as assessed by magnetoen-cephalography were reported in chronic back pain patients (Flor et al., 1997). Stimulation at the affected back but not at the finger led to a significantly higher magnetic field in the time window <100 ms whereas both types of stimulation caused higher fields in the later time windows (>200 ms) in the patients compared to the controls. When the source of this early activity was localized, it was shown to originate from primary somatosensory cortex (SI). Whereas the localization of the fingers was not significantly different between patients and controls, the localization of the back was more inferior and medial in the patients indicating a shift and expansion toward the cortical representation of the leg. These data suggest that chronic pain leads to an expansion of the cortical representation zone related to nociceptive input much like the expansions of cortical representations that have been documented to occur with other types of behaviorally relevant stimulation (Braun et al., 2000). Nociceptive input is of high relevance for the organism and it might be useful to enhance the representation of this type of stimulation to prepare the organism for the adequate response. The amount of expansion of the back region was positively correlated with chronicity suggesting that this pain-related cortical reorganization develops over time. Using functional magnetic resonance imaging (fMRI), Gracely et al. (2002) reported a similar hyperreactivity to painful stimulation in a number of brain regions including SI cortex in fibromyalgia patients. In a continuous pain rating in the scanner it was shown that patients with fibromyalgia displayed an increasing level of pain across several stimulation trials and failed to return to baseline. This was true for both the affected (trapezius muscle) and the non-effected body part (finger muscle). In patients with chronic upper back pain it was shown that the stimulation of the trapezius but not the flexor digitorum muscle showed sensitization, suggesting site-specificity. The accompanying fMRI measurements revealed enhanced activation in somatosensory cortex but reduced activation in anterior cingulate cortex compared to the healthy controls (see Fig. 15.1). The cerebral activation was also site-specific in the back pain patients but generalized in the fibromyal-gia patients.

This type of central alteration may correspond to what Katz and Melzack (1990) have termed a somatosensory pain memory in patients with phantom limb pain. Although they referred mainly to explicit memories, that is, the patients' recollection that the phantom pain was similar to previously experienced pains, somatosensory memories can also be implicit as already stated by them. Implicit pain memories are based on changes in the brain that are not open to conscious awareness but lead to behavioral and perceptual changes - such as hyperalgesia and allodynia - the patient is not aware of. It is therefore impossible for the patient to counteract these pain memories. This type of memory trace may lead to pain perception in the absence of peripheral stimulation since an expansion of a representational zone is related to higher acuity in the perception of tactile input (Merzenich et al., 1984).

Implicit pain memories can be established and altered by learning processes such as habituation and sensitization, operant and classical conditioning or priming. There is now ample evidence that learning not only affects pain behaviors and the subjective experience of pain but also the physiologic processing of painful stimulation. For example, a spouse who habitually reinforces pain can also influence the pain-related cortical response. When chronic back pain patients were stimulated with electric impulses at either the finger of the back in either the presence or absence of the spouse, spouse presence influenced the electroencephalographic potentials that were recorded from the patients' skull. Whereas the spouses who habitually ignored the pain or punished their partners for expressing pain had no effect, spouses who habitually reinforced pain behaviors caused a 2.5-fold increase in the patients' brain response to pain applied to the back. At the finger no difference for the presence or the absence of the spouse was observed nor was there a difference for the healthy controls (see Fig. 15.2). The main difference between these conditions was observed in an area that corresponds to the location of the anterior cingulate cortex that has been shown to be involved in the processing of the emotional aspects of pain (Rainville et al., 1997).

Figure 15.1. The top left panel (a) shows the pain ratings (visual analogue scale (VAS) 0-100) of the fibromyalgia patients to the stimulation of the back (black) or the finger (grey). The patients were stimulated in blocks of 20s with 20-s rest intervals. The top right (b) panel shows the same ratings for the healthy controls. The straight lines show the slope of the ratings. A negative slope indicates a reduction in pain rating and thus habituation and a positive slope indicates sensitization and increased pain ratings. The numbers to the right give the slope. The bottom panel (c) shows the difference in activation between the fibromyalgia patients (FMS) and the healthy controls related to the secondary somatosensory cortex. Note that the FMS patients show more activation both during the back and finger stimulation.

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