Wolfgang Larbig

Effects of Regional Anesthesia on Phantom Limb Pain Are Mirrored in Changes in Cortical Reorganization

The causes underlying phantom limb pain are still unknown. Recent studies on the consequences of nervous system damage in animals and humans reported substantial reorganization of primary somatosensory cortex subsequent to amputation, and one study showed that cortical reorganization is positively correlated with phantom limb pain. This paper examined the hypothesis of a functional relationship between cortical reorganization and phantom limb pain. Neuroelectric source imaging was used to determine changes in cortical reorganization in somatosensory cortex after anesthesia of an amputation stump produced by brachial plexus blockade in six phantom limb pain patients and four pain-free amputees. Three of six phantom limb subjects experienced a virtual elimination of current phantom pain attributable to anesthesia (mean change: 3.8 on an 11-point scale; Z = −1.83;p < 0.05) that was mirrored by a very rapid elimination of cortical reorganization in somatosensory cortex (change = 19.8 mm; t(2) = 5.60;p < 0.05). Cortical reorganization remained unchanged (mean change = 1.6 mm) in three phantom limb pain amputees whose pain was not reduced by brachial plexus blockade and in the phantom pain-free amputation controls. These findings suggest that cortical reorganization and phantom limb pain might have a causal relationship. Methods designed to alter cortical reorganization should be examined for their efficacy in the treatment of phantom limb pain.

The effect of opioids on phantom limb pain and cortical reorganization.

&NA; The efficacy of oral retarded morphine sulphate (MST®) was tested against placebo in a double‐blind crossover design in 12 patients with phantom limb pain after unilateral leg or arm amputation. Two counterbalanced treatment phases of 4 weeks each were initiated with an intravenous test infusion of MST® or Placebo. The titration phase was 2 weeks. The dose of MST® was titrated to at least 70 mg/day and at highest 300 mg/day. Pain intensity was assessed hourly on visual analog scales during a 4‐week treatment‐free phase, both treatment phases and at two follow‐ups (6 and 12 months). Reorganization of somatosensory cortex, electric perception and pain thresholds as well as selective attention were measured pre‐ and post‐treatment. A significant pain reduction was found during MST® but not during placebo. A clinically relevant response to MST® (pain reduction of more than 50%) was evident in 42%, a partial response (pain reduction of 25–50%) in 8% of the patients. Neuromagnetic source imaging of three patients showed initial evidence for reduced cortical reorganization under MST® concurrent with the reduction in pain intensity. Perception and pain thresholds were not significantly altered whereas attention was significantly lower under MST®. Thus, opioids show efficacy in the treatment of phantom limb pain and may potentially influence also cortical reorganization. These data need to be replicated in larger patient samples.

Somatosensory event-related potentials to painful and non-painful stimuli: effects of attention.

&NA; In order to determine the effects of attention and distraction on painful and non‐painful stimuli, the amplitude changes of 3 components (N150, P200, P300) of the Somatosensory event‐related potential (SERF) elicited by painful and non‐painful electrical stimuli were investigated. Painful and non‐painful stimuli were determined using a visual analog scale. SERPs were recorded from 16 healthy volunteers at 5 midline and 4 left and 4 right hemispheric sites. The differences between the amplitudes of attended and ignored stimuli were quantified with a baseline‐to‐peak measure. ANOVA results revealed no significant attention or stimulus intensity effects for N150 but highly significant differences in P200 and P300 amplitudes between attended and ignored stimuli. In addition, P200 and P300 amplitudes were larger for strong stimuli than for weak stimuli, with no significant differences between non‐painful and painful stimuli. These findings are consistent with the existence of a relative, rather than an absolute, relationship between SERP component amplitudes and subjective pain reports. Furthermore, the data give evidence that attentional manipulations represent a powerful method to decrease the perception of pain and that, when used with subjective and behavioral measures, the SERP represents a valuable asset in the multidimensional approach to pain measurement and assessment.

The cortical somatotopic map and phantom phenomena in subjects with congenital limb atrophy and traumatic amputees with phantom limb pain

The extent of the cortical somatotopic map and its relationship to phantom phenomena was tested in five subjects with congenital absence of an upper limb, four traumatic amputees with phantom limb pain and five healthy controls. Cortical maps of the first and fifth digit of the intact hand, the lower lip and the first toe (bilaterally) were obtained using neuroelectric source imaging. The subjects with congenital upper limb atrophy showed symmetric positions of the left and right side of the lower lip and the first toe, whereas the traumatic amputees with pain showed a significant shift (about 2.4 cm) of the cortical representation of the lower lip towards the hand region contralateral to the amputation side but no shift for the toe representation. In healthy controls, no significant hemispheric differences between the cortical representation of the digits, lower lip or first toe were found. Phantom phenomena were absent in the congenital but extensive in the traumatic amputees. These data confirm the assumption that congenital absence of a limb does not lead to cortical reorganization or phantom limbs whereas traumatic amputations that are accompanied by phantom limb pain show shifts of the cortical areas adjacent to the amputation zone towards the representation of the deafferented body part.

The relationship of phantom limb pain to other phantom limb phenomena in upper extremity amputees

Abstract In thirty‐two unilateral upper extremity amputees with and without phantom limb pain, various phantom limb phenomena were investigated. In general, the incidence of non‐painful phantom limb sensations was higher in patients with phantom limb pain than in pain‐free amputees. Kinesthetic and kinetic phantom limb sensations were reported more frequently than exteroceptive cutaneous sensations. There was a significant positive correlation between phantom limb pain and stump pain. Patients more frequently assigned sensory than affective pain qualities to their phantom limb pain, whereas no differences between pain qualities were observed for stump pain. No support was found for a relationship between the presence of telescoping (i.e., shrinkage of the phantom limb) and phantom limb pain. These findings point to central as well as to peripheral factors contributing to phantom limb pain.

NMDA-receptor antagonist and morphine decrease CRPS-pain and cerebral pain representation

&NA; A combination therapy of morphine with an NMDA‐receptor antagonist might be more effective than morphine without a NMDA‐receptor antagonist for the relief of neuropathic pain in patients with complex regional pain syndrome (CRPS). In order to test the efficacy of this combination therapy we performed a double‐blind randomized placebo‐controlled study on patients suffering from CRPS of the upper extremity. We used functional magnetic resonance imaging during movement of the affected and unaffected upper hand before and after a treatment regimen of 49 days that contrasted morphine and an NMDA‐receptor antagonist with morphine and placebo. We postulated superior pain relief for the combination therapy and concomitant changes in brain areas associated with nociceptive processing. Only the combination therapy reduced pain at rest and during movement, and disability. After treatment, activation in the contralateral primary somatosensory (cS1) and anterior cingulate cortex was significantly reduced when the affected hand was moved. Pain relief during therapy was related to decreased activation in cS1 and secondary somatosensory cortex (S2). Our data suggest that the combination of morphine with an NMDA‐receptor antagonist significantly affects the cerebral processing of nociceptive information in CRPS. The correlation of pain relief and decrease in cortical activity in cS1 and S2 is in accordance with the expected impact of the NMDA‐receptor antagonist on cerebral pain processing with emphasis on sensory‐discriminative aspects of pain.

Evidence for a change in neural processing in phantom limb pain patients

&NA; The present study was designed to investigate differences in neural processing of pain‐related semantic information in amputees with and without chronic phantom limb pain and healthy controls. One‐hundred‐and‐twenty words (40 neutral, 40 body‐related, 40 pain‐related) were presented in pseudorandom order to probe group differences in the perception of pain‐related information. Visual evoked potentials (VEP) to the words were recorded from 11 scalp locations, EMG was measured at the stump and the contralateral side and bilaterally from the M. corrugator. In addition, heart rate and skin conductance responses were obtained. Both early and late VEP components were altered. Pain‐free amputees showed a reduced N100 amplitude compared to phantom limb pain patients and healthy controls whereas the phantom limb pain patients displayed a significantly enhanced late positivity (500–800 msec after word onset). VEP components were unaffected by word type. The peripheral EMG responses were significantly different among the groups: phantom limb pain patients showed larger EMG reactions on the stump than on the contralateral side, whereas pain‐free amputees showed the opposite effect. The data suggest an enhanced central and peripheral processing of visual stimuli in phantom limb pain patients.

Biofeedback of somatosensory event-related potentials: can individual pain sensations be modified by biofeedback-induced self-control of event-related potentials?

This study investigates the effects of biofeedback based upon event-related brain potentials evoked by nociceptive electrical stimuli. In a visual and monetary feedback paradigm, 10 subjects received positive feedback within one training session when systematically showing two different behavior patterns: one pattern correlated with a decrease (down-training) and one with an increase (up-training) of the peak-to-peak size of the N150-P260 complex, respectively. Training conditions were changed randomly from trial to trial over 300 trials. All subjects achieved control on both behavior patterns resulting in a simultaneous modification of the size of this complex according to the training conditions. Furthermore, the individual pain report measured with a visual analogue scale was altered in accordance with the biofeedback-induced behavioral modifications. A decrease in subjective pain report was achieved after down-training while an increase was observed after the up-training.

Kortikale Reorganisation und Schmerz

ZusammenfassungDie neurowissenschaftliche Forschung der letzten Jahre erbrachte den Nachweis, dass im adulten menschlichen Gehirn erhebliche neuroplastische Veränderungen auftreten können. Am Beispiel des Phantomschmerzes wird die funktionelle kortikale Reorganisation im somatosensorischen und motorischen System beschrieben. Nach Deafferenzierung tritt bei Amputierten mit Phantomschmerzen eine mittels nichtinvasiver bildgebender Verfahren nachweisbare Verschiebung benachbarter Repräsentanzen des sensomotorischen Homunkulus in die deafferenzierte Kortexregion auf. Diese Umorganisation funktioneller Hirnkarten lässt sich nicht bei schmerzfreien Amputierten und Personen mit kongenitalem Verlust von Gliedmaßen nachweisen. Es wird ein Modell der Entstehung von Phantomschmerz dargestellt, bei dem vorhergehende chronische Schmerzzustände eine wichtige Rolle spielen. Die Modulation von Plastizität und Phantomschmerz durch anästhesiologische Interventionen wird dargestellt und Ergebnisse der präemptiven Analgesie bei Phantomschmerz werden diskutiert. Opioidtherapie und verhaltensrelevante Stimulation können das kortikale somatosensorische Schmerzgedächtnis ebenfalls beeinflussen.AbstractThe neuroscientific research of the past years has shown that extensive plastic change occurs in the adult human brain. The functional reorganization of the somatosensory and motor maps related to phantom limb pain is described. Subsequent to deafferentation amputees with phantom limb pain show a shift of neighbouring representation zones into the deafferented zone of the somatosensory and motor cortex that can be detected with noninvasive neuroimaging methods. This reorganization of the sensory and motor maps is not found in painfree amputees and persons with congenital loss of a limb. We discuss a model of the development of phantom limb pain that incorporates both peripheral and central factors and assigns an important role to chronic pain before the amputation. The modulation of plasticity and phantom limb pain by anesthesiological interventions is described and the results of preemptive analgesia for the prevention of phantom limb pain are discussed. Opioid treatment and behaviorally relevant stimulation are effective means to eliminate phantom limb pain and cortical somatosensory pain memories.

Cigarette smoking, blood lipids, and baroreceptor-modulated nociception

Activation of arterial blood pressure has been shown to influence higher central nervous activity. In animals, induction of sleep-like states and increases of seizure and pain thresholds in response to baroreceptor stimulation have been reported. In certain human groups, mechanical stimulation of the carotid baroreceptors also increases pain thresholds. The present paper examines the hypothesis that smokers show baroreceptor dependent antinociception as compared to non-smokers. It is speculated that one effect which rewards smoking is the nicotine induced phasic blood pressure increase which leads to baroreceptor stimulation and dampens pain perception. One hundred and twenty subjects were investigated using a recently developed mechanical baroreceptor stimulation technique and an electrical pain stimulus. The group of heavy smokers showed the predicted effect: their pain thresholds were enhanced during conditions of increased baroreceptor activity as compared to the control condition. The group of medium, light and non-smokers, however, did not show this effect. Neither blood lipid levels nor diastolic or systolic blood pressure paralleled the group differences on baroreceptor dependent antinociception. In heavy smokers, the nicotine induced phasic blood pressure increase might have baroreceptor dependent pain dampening effects, which might be among the reinforcing qualities of smoking.