Generalized deep-tissue hyperalgesia in patients with chronic low-back pain.

Some chronic painful conditions including e.g. fibromyalgia, whiplash associated disorders, endometriosis, and irritable bowel syndrome are associated with generalized musculoskeletal hyperalgesia. The aim of the present study was to determine whether generalized deep-tissue hyperalgesia could be demonstrated in a group of patients with chronic low-back pain with intervertebral disc herniation. Twelve patients with MRI confirmed lumbar intervertebral disc herniation and 12 age and sex matched controls were included. Subjects were exposed to quantitative nociceptive stimuli to the infraspinatus and anterior tibialis muscles. Mechanical pressure (thresholds and supra-threshold) and injection of hypertonic saline (pain intensity, duration, distribution) were used. Pain intensity to experimental stimuli was assessed on a visual analogue scale (VAS). Patients demonstrated significantly higher pain intensity (VAS), duration, and larger areas of pain referral following saline injection in both infraspinatus and tibialis anterior. The patients rated significantly higher pain intensity to supra-threshold mechanical pressure stimulation in both muscles. In patients, the pressure pain-threshold was lower in the anterior tibialis muscle compared to controls. In conclusion, generalized deep-tissue hyperalgesia was demonstrated in chronic low-back pain patients with radiating pain and MRI confirmed intervertebral disc herniation, suggesting that this central sensitization should also be addressed in the pain management regimes.     

Effect of hypnotic pain modulation on brain activity in patients with temporomandibular disorder pain

Hypnosis modulates pain perception but the associated brain mechanisms in chronic pain conditions are poorly understood. Brain activity evoked by painful repetitive pin-prick stimulation of the left mental nerve region was investigated with use of fMRI in 19 patients with painful temporomandibular disorders (TMD) during hypnotic hypoalgesia and hyperalgesia and a control condition. Pain intensity and unpleasantness of the painful stimulation was scored on a 0-10 Numerical Rating Scale (NRS). NRS pain and unpleasantness scores during hypnotic hypoalgesia were significantly lower than in the control condition and significantly higher in the hypnotic hyperalgesia condition. In the control condition, painful stimulation caused significant activation of right posterior insula, primary somatosensory cortex (SI), BA21, and BA6, and left BA40 and BA4. Painful stimulation during hypnotic hyperalgesia was associated with increased activity in right posterior insula and BA6 and left BA40 whereas hypnotic hypoalgesia only was associated with activity in right posterior insula. Unexpectedly, direct contrasts between control and hypnotic hyperalgesia conditions revealed significant decreases in S1 during hyperalgesia. Direct contrasts between control and hypnotic hypoalgesia conditions demonstrated significant decreases in right posterior insula and BA21, as well as left BA40 during hypoalgesia. These findings are the first to describe hypnotic modulation of brain activity associated with nociceptive processing in chronic TMD pain patients and demonstrate that hypnotic hypoalgesia is associated with a pronounced suppression of cortical activity and a disconnection between patient-based scores and cortical activity in S1 during hypnotic hyperalgesia.     

Analysis of stimulus-evoked pain in patients with myofascial temporomandibular pain disorders

The pathophysiological mechanisms of myofascial temporomandibular disorders (TMD) are still under investigation. The hypothesis that TMD pain is caused by a generalized sensitization of higher order neurons in the nociceptive pathways combined with a decreased efficacy of endogenous inhibitory systems has recently gained support in the literature. This study was designed to further investigate the somatosensory sensibility within and outside the craniofacial region. Twenty-two patients fulfilled the research diagnostic criteria for TMD for myofascial pain (Dworkin and LeResche, J Craniomandib Disord Facial Oral Pain 6 (1992) 301) and 21 age- and sex-matched subjects served as a control group. The somatosensory sensibility to a deep tonic input was tested by standardized infusions of hypertonic saline into the masseter and anterior tibialis muscle. Furthermore, pressure pain thresholds (PPTs) and heat pain thresholds (HPTs) were assessed with phasic stimuli at the same sites before and following the infusions. Myofascial TMD patients reported infusion of hypertonic saline to be more painful on 10 cm visual analogue scales (peak pain 8.8 +/- 0.4 cm) than control subjects (6.8 +/- 0.5 cm, t-test: P = 0.003) in the masseter but not in the anterior tibialis (7.4 +/- 0.5 vs. 6.6 +/- 0.5 cm, P=0.181). The perceived area of experimental masseter pain measured on drawings was marginally larger in TMD patients (2.6+/-0.5 arbitrary units (a.u.)) than in control subjects (1.4 +/- 0.2 a.u., Mann-Whitney: P = 0.048) but no differences were observed for the anterior tibialis (P = 0.771). The PPTs were lower in the myofascial TMD patients compared to the control group, both in the masseter (analysis of variance (ANOVA): P = 0.002) and in the anterior tibialis (P = 0.005), whereas there were no significant differences in HPT (ANOVAs: P = 0.357, P = 0.101). There were no significant correlations between measures of somatosensory sensibility and measures of clinical pain intensity, pain duration, graded chronic pain scores or somatization or depression scores (Pearson: R < 0.304, P > 0.172). The present study in a well-defined group of myofascial TMD patients found that the responsiveness to both tonic and phasic deep stimuli, but not to phasic superficial inputs at the pain threshold level, in the craniofacial region was higher compared with a control group. These findings suggest that myofascial TMD pain is associated with a facilitation of stimulus-evoked pain primarily, but not exclusively related to the painful region.     

Heterogeneous sensory processing in persistent postherniotomy pain

Previous studies on sensory function in persistent postherniotomy pain (PPP) have only identified pressure pain threshold to be significantly different from pain-free patients despite several patients reporting cutaneous pain and wind-up phenomena. However the limited number of patients studied hinders evaluation of potential subgroups for further investigation and/or treatment allocation. Thus we used a standardized QST protocol to evaluate sensory functions in PPP and pain-free control patients, to allow individual sensory characterization of pain patients from calculated Z-values. Seventy PPP patients with pain related impairment of everyday activities were compared with normative data from 40 pain-free postherniotomy patients operated >1 year previously. Z-values showed a large variation in sensory disturbances ranging from pronounced detection hypoesthesia (Z = 6, cold) to pain hyperalgesia (Z = −8, pressure). Hyperalgesia for various modalities were found in 80% of patients, with pressure hyperalgesia in ∼65%, and cutaneous (mechanical or thermal) hyperalgesia in ∼35% of patients. The paradoxical combination of tactile hypoesthesia and hyperalgesia was seen in ∼25% of patients. Increased pain from repetitive tactile and/or brush stimulation was found in 51%, suggesting a role of altered central nociceptive function in this subpopulation. A high incidence (26%) of pressure hyperalgesia was found in the contralateral groin, with a significant correlation (rho = 0.58, p = 0.002) to the hyperalgesic level on the painful side, again suggesting central nervous mechanisms in PPP. In conclusion, this study shows that a standardized trauma results in heterogeneous combinations of hypo- and hyperalgesia. Z-score evaluation of sensory function identifies subpopulations in PPP, which may be used in selecting surgical and/or pharmacological treatment strategies.     

The Specificity and Mechanisms of Hemilateral Sensory Disturbances in Complex Regional Pain Syndrome

Hyperalgesia often extends from the affected limb to the ipsilateral forehead in patients with complex regional pain syndrome (CRPS). To investigate whether this is more common in CRPS than other chronic pain conditions, pressure-pain thresholds and sharpness to a firm bristle were assessed on each side of the forehead, at the pain site, and at an equivalent site on the contralateral side in 32 patients with chronic pain other than CRPS (neuropathic or nociceptive limb pain, radicular pain with referral to a lower limb or postherpetic neuralgia), and in 34 patients with CRPS. Ipsilateral forehead hyperalgesia to pressure pain was detected in 59% of CRPS patients compared with only 13% of patients with other forms of chronic pain. Immersion of the CRPS-affected limb in painfully cold water increased forehead sensitivity to pressure, especially ipsilaterally, whereas painful stimulation of the healthy limb reduced forehead sensitivity to pressure pain (albeit less efficiently than in healthy controls). In addition, auditory discomfort and increases in pain in the CRPS-affected limb were greater after acoustic startle to the ear on the affected than unaffected side. These findings indicate that generalized and hemilateral pain control mechanisms are disrupted in CRPS, and that multisensory integrative processes may be compromised.

Perspective

The findings suggest that hemilateral hyperalgesia is specific to CRPS, which could be diagnostically important. Disruptions in pain-control mechanisms were associated with the development of hyperalgesia at sites remote from the CRPS limb. Addressing these mechanisms could potentially deter widespread hyperalgesia in CRPS.     

Mechanisms of pain referral in patients with whiplash associated disorder

The aim was to investigate the mechanisms of pain referral in patients with whiplash associated disorder. Pain was induced in 12 controls and 12 patients with whiplash associated disorder by intramuscular electrical stimulation in the infraspinatus muscle and the ipsilateral upper arm, i.e., the area where all subjects perceived referred pain during conditioning stimulation in the infraspinatus muscle. Conditioning stimulation amounted to a pain intensity rated as 2/10 and 4/10. During conditioning stimulation in the infraspinatus muscle, sensitivity to test stimuli was assessed in the referred pain area (i.e., upper arm) and vice versa. Test stimuli consisted of intramuscular electrical stimulation corresponding to innocuous perception threshold, electrical pain threshold, and pain intensities rated as 2/10, 4/10 and 6/10, respectively. Compared to controls, patients with whiplash associated disorder had increased pain sensitivity (p≤0.01) and indicated larger areas of referred pain ((p≤0.003) during stimulation at the infraspinatus muscle; p≤0.03 during stimulation at the upper arm), including proximal referral of pain which was never reported by controls (p≤0.05). During conditioning stimulation in the infraspinatus muscle (4/10) all subjects reported referred pain in the upper arm (corresponding to the test site) and innocuous perception thresholds (p<0.05)(patients) and electrical pain thresholds (p<0.001) (controls) decreased. Conditioning stimulation in the upper arm did not affect sensitivity to test stimuli in the infraspinatus muscle. In conclusion, patients with whiplash associated disorder had increased sensitivity to painful stimulation, reported larger areas of referred pain during the same subjectively painful conditioning stimulation (i.e., lower absolute stimulus intensities), including proximal pain referral which was never seen in controls, indicating aberrant processing of nociceptive input. The perceptual integration of nociceptive stimuli during simultaneous stimulation did not differ between groups suggesting that divergence of nociceptive input from the focal pain area leading to excitation of neurones with projected fields in the referred pain area most likely explains referred pain in both groups alike.     

The relation between catastrophizing and facial responsiveness to pain

Pain catastrophizing has recently been suggested to have a social function based on a positive association observed with facial responsiveness to noxious stimulation. However, this assumption is based on studies applying nociceptive stimuli of fixed intensity, such that high catastrophizers not only displayed increased pain behavior but also rated the stimulation as being more painful. The aim of this study was to investigate the relation between catastrophizing and facial responsiveness while controlling for individual differences in pain sensitivity. The facial expression of pain was investigated in 44 young and pain-free individuals in response to painful and non-painful phasic heat stimuli. Painful temperatures were tailored to the individual sensitivity to produce moderate pain. Facial responses were videotaped and objectively examined using the Facial Action Coding System. We also assessed skin conductance activity as an autonomic indicator of pain-related responses. Catastrophizing was assessed using the Pain Catastrophizing Scale (PCS). In accordance with previous findings, subjects scoring higher on pain catastrophizing required lower thermal intensities to induce a moderately painful sensation (r=-0.40, p=0.007). However, catastrophizing did not correlate with facial responsiveness to perceptually controlled painful stimulation (r=-0.02, p=0.88). Moreover, correlation analyses revealed no significant associations between catastrophizing and skin conductance responses. The present findings provide further support for the impact of pain catastophizing on pain sensitivity. However, our finding of no relation between catastrophizing and facial responsiveness when participants are experiencing comparable psychophysical pain intensities, challenges previous assumptions that high catastrophizers display amplified pain behavior; at least in young and pain-free individuals.     

Chemotherapy-evoked neuropathic pain: Abnormal spontaneous discharge in A-fiber and C-fiber primary afferent neurons and its suppression by acetyl-L-carnitine

The combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non-opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/-4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra-additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics.     

Psychophysics of phasic and tonic heat pain stimuli by quantitative sensory testing in healthy subjects.

The increased use of quantitative sensory testing in the study of pain raises the need to characterize various aspects of psychophysical response to noxious stimulation in healthy subjects. The present study aims to address several issues regarding the use of heat pain stimuli: (a) Are pain scores for short‐term repeated phasic stimuli consistent? (b) Does an exposure to tonic heat pain stimulus cause sensitization and change the scores for subsequent phasic stimuli? and (c) Are pain scores for phasic and tonic heat pain correlated? To address these questions, a series of four phasic heat pain stimuli of 47 °C were given to the forearms of 70 healthy volunteers, over the course of an hour. Pain scores by Visual Analog Scale (VAS) were obtained for each stimulus. In 50 subjects, a tonic heat pain of 70 s duration at 47.5 °C was given between the first and second phasic stimuli. Pain scores were obtained at four points along this tonic stimulus. Repeated measures ANOVA and a sensitive post hoc analysis indicated that, while the pain perception was reduced on the second, nearly immediate trial, subsequent VAS scores of pain perception were not different from the first (#1: 35.2±19.2; #2: 31.4±20.2, #3: 33.0±21.6; and #4: 33.2±20.1, respectively), with strong correlation among the phasic tests. The average tonic pain score was 53.7±23.1. Administration of tonic pain stimuli did not result in different VAS scores of subsequent phasic pain stimuli, compared to those subjects who did not receive tonic pain stimuli. Tonic and phasic pain were positively correlated (e.g., for the first phasic stimuli). However, no relation was found between the level of perceived pain, either for phasic or for tonic stimuli, and presence or absence of temporal summation during the tonic pain. In conclusion: (i) phasic pain scores assessments at 30′ and 60′ after baseline is consistent; (ii) tonic heat pain, despite relatively high VAS scores, does not cause a change in the scoring of subsequent phasic stimuli; and (iii) phasic and tonic pain scores correlate with each other. Thus, the normal pattern of pain perception is stable and not altered by single tonic pain stimulation.     

Modulation of sensitized C‐fibers by adrenergic stimulation in human neuropathic pain

The chronic constriction injury model is widely used in studying mechanisms of neuropathic pain. In this model neuropathic pain can be influenced by sympathetic interventions. It is assumed that similar mechanisms as in animals are responsible for pain arising from nerve entrapment syndromes in humans. The aim of the present study was to investigate if in patients with nerve entrapment nociceptive afferents can be modulated by adrenergic stimulation. Methods: Twenty patients with pain due to a unilateral entrapment of the median nerve and 10 controls were included in the study. Spontaneous pain, mechanical and thermal evoked pain were assessed within the innervation territory of the lesioned nerve and the corresponding contralateral segment in patients and on the right hand side in healthy volunteers. The examinations were performed at baseline, during whole body cooling (sympathetic activation) and whole body warming (sympathetic inhibition), and after norepinephrine iontophoresis. Results: All patients reported spontaneous pain. Mechanical allodynia, punctate hyperalgesia and cold allodynia was not found. According to side‐to‐side differences in heat pain thresholds, patients were separated in patients with (n=10) and without (n=10) heat hyperalgesia. Adrenergic stimulation did not induce or enhance spontaneous or mechanical evoked pain in any patient or control subject. However in patients with pre‐existing heat hyperalgesia sympathetic stimulation aggravated heat hyperalgesia significantly. Further in these patients the decrease in heat pain thresholds observed after norepinephrine iontophoresis was significantly higher compared to patients without pre‐existing heat hyperalgesia. Conclusion: Sympathetic–afferent interaction does not play a major role in pain generation due to nerve entrapment. Nevertheless in a subgroup of patients nociceptive afferents show sensitivity to physiological and pharmacological sympathetic stimulation. This finding is important because it emphasises that despite there is no clinical detectable effect on pain sympathetic afferent interaction can be found.     

Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: A randomized, double-blind, placebo-controlled study

Fibromyalgia (FM) syndrome is characterized by pain and widespread hyperalgesia to mechanical, thermal, and electrical stimuli. Despite convincing evidence for central sensitization of nociceptive pain pathways, the role of peripheral tissue impulse input in the initiation and maintenance of FM is unclear. Therefore this randomized, double-blind, placebo-controlled trial of 22 female normal controls (NCs) and 28 female FM subjects tested the effects of trapezius muscle (TrapM) tender point injections with 1% lidocaine on local pain thresholds as well as on remote heat hyperalgesia at the forearm. Prior to muscle injections shoulder pain was standardized by tonic mechanical muscle stimulation, resulting in local pain ratings of 4.0 ± 0.5 VAS units. Tonic muscle stimulation was interrupted for the TrapM injections but was continued afterwards at the same level. NC as well as FM subjects experienced significant increases of TrapM pressure pain thresholds from lidocaine injections but not from placebo injections (p < 0.001). Additionally, heat hyperalgesia of FM participants was significantly reduced at areas remote from the injection site (forearm) by lidocaine but not by placebo (p = 0.02). Neither lidocaine nor saline injections significantly affected clinical FM pain ratings, a result most likely due to the very low dose of lidocaine (50 mg) used in this trial. Conclusion: Lidocaine injections increased local pain thresholds and decreased remote secondary heat hyperalgesia in FM patients, emphasizing the important role of peripheral impulse input in maintaining central sensitization in this chronic pain syndrome; similar to other persistent pain conditions such as irritable bowel syndrome and complex regional pain syndrome.     

Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus

BACKGROUND AND AIMS: Experimental pain models based on single stimuli have to some degree limited visceral pain studies in humans. Hence, the aim of this study was to investigate the effect of multi-modal visceral pain stimuli of the oesophagus in healthy subjects before and after induction of visceral hyperalgesia. We used a multi-modal psychophysical assessment regime and a neurophysiological method (nociceptive reflex) for the characterisation of the experimentally induced hyperalgesia. METHODS: A probe for multi-modal (cold, warm, electrical, and mechanical) visceral stimulation was positioned in the lower part of the oesophagus in eleven healthy subjects. Mechanical stimuli were applied as distensions with a bag, which also had electrodes mounted for electrical stimulation. Thermal stimulation with temperatures from 0 to 60 degrees C was applied with re-circulating water in the bag. To assess the interaction between visceral and somatic pathways, the nociceptive withdrawal reflex to electrical stimuli at the ankle was measured with and without simultaneous mechanical oesophageal distension to painful levels. Finally, the oesophageal sensitisation was induced by perfusion with hydrochloric acid. Multimodal responses (pain threshold, stimulus response function, size of nociceptive reflex, and referred pain areas) were assessed before and after the induced hyperalgesia. RESULTS: The multi-modal psychophysical responses and reflex sizes were assessed twice before sensitisation, and the parameters were reproducible. Sensitisation of the oesophagus resulted in hyperalgesia to electrical and mechanical stimuli (29 and 35% decrease in pain threshold) and allodynia to cold and warmth stimuli (11% increase in sensory rating). After sensitisation, the referred pain area to mechanical stimuli increased more than 300% with a change in the localisation of the referred pain to all stimuli, and the amplitude of nociceptive reflex increased 100%, all indicating the presence of central hyperexcitability. CONCLUSIONS: Visceral hyperalgesia/allodynia can be induced experimentally and assessed quantitatively by the newly introduced multi-modal psychophysical assessment approach. The significant changes of the experimentally evoked referred pain patterns and of the nociceptive reflex evoked from a distant somatic structure indicate that even short-lasting visceral hyperalgesia can generate generalised sensitisation.     

Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain

Patients with sensory disturbances of painful and non-painful character show distinct changes in touch and/or pain sensitivity. The patterns of sensory changes were compared to those of human surrogate models of neuropathic pain to assess the underlying mechanisms. We investigated 30 consecutive in-patients with dysaesthesia of various origins (peripheral, spinal, and brainstem lesions) and 15 healthy subjects. Tactile thresholds were determined with calibrated von Frey hairs (1.1mm). Thresholds and stimulus-response functions for pricking pain were determined with a series of calibrated punctate mechanical stimulators (0.2mm). Allodynia was tested by light stroking with a brush, Q-tip, and cotton wisp. Perceptual wind-up was tested by trains of punctate stimuli at 0.2 or 1Hz. Intradermal injection of capsaicin (n=7) and A-fiber conduction blockade (n=8) served as human surrogate models for neurogenic hyperalgesia and partial nociceptive deafferentation, respectively. Patients without pain (18/30) showed a continuous distribution of threshold shifts in the dysaesthetic skin area with a low to moderate increase in pain threshold (by 1.52+/-0.45 log2 units). Patients with painful dysaesthesia presented as two separate groups (six patients each): one showing lowered pain thresholds (by -1.94+/-0.46 log2 units, hyperalgesia) and the other elevated pain thresholds (by 3.02+/-0.48 log2 units, hypoalgesia). The human surrogate model of neurogenic hyperalgesia revealed nearly identical leftward shifts in stimulus-response function for pricking pain as patients with spontaneous pain and hyperalgesia (by a factor of about 5 each). The sensory changes in the human surrogate model of deafferentation were similar to patients with hypoalgesia and spontaneous pain (rightward shift of the stimulus-response function with a decrease in slope). Perceptual wind-up did not differ between symptomatic and control areas. There was no exclusive association of any parameter obtained by quantitative sensory testing with a particular disease (of either peripheral or central origin). Our findings suggest that neuropathic pain is based on two distinct mechanisms: (I) central sensitization (neurogenic hyperalgesia; in patients with minor sensory impairment) and (II) partial nociceptive deafferentation (painful hypoalgesia; in patients with major sensory deficit). This distinction as previously postulated for postherpetic neuralgia, is obviously valid also for other conditions. Our findings emphasize the significance of a mechanism-based classification of neuropathic pain.     

Supraspinal cholecystokinin may drive tonic descending facilitation mechanisms to maintain neuropathic pain in the rat

Complete or partial spinal section at T(8) has been shown to block tactile allodynia but not thermal hyperalgesia following L(5)/L(6) spinal nerve ligation (SNL), suggesting the supraspinal integration of allodynia in neuropathic pain. In the present study, the possibility of mediation of nerve injury-associated pain through tonic activity of descending nociceptive facilitation arising from the rostroventromedial medulla (RVM) was investigated. Specifically, the actions of brainstem cholecystokinin and the possible importance of sustained afferent input from injured nerve fibers were determined using pharmacological and physiological approaches in rats with SNL. Lidocaine given bilaterally into the RVM blocked tactile allodynia and thermal hyperalgesia in SNL rats and was inactive in sham-operated rats. Bilateral injection of L365,260 (CCK(B) receptor antagonist) into the RVM also reversed both tactile allodynia and thermal hyperalgesia. Microinjection of CCK-8 (s) into the RVM of naive rats produced a robust tactile allodynic effect and a more modest hyperalgesia. CCK immunoreactivity was not significantly different between SNL and sham-operated rats. The anti-nociceptive effect of morphine given into the ventrolateral periaqueductal gray region (PAG) was substantially reduced by SNL. The injection of L365,260 into the RVM or of bupivacaine at the site of nerve injury restored the potency and efficacy of PAG morphine in SNL rats. These results suggest that changes in supraspinal processing are likely to contribute to the observed poor efficacy of opioids in clinical states of neuropathic pain. These data also indicate that the activation of descending nociceptive facilitatory pathways is important in the maintenance of neuropathic pain, appears to be dependent on CCK release, and may be driven from sustained afferent input from injured nerves to brainstem sites. Collectively, these data support the hypothesis that abnormal tonic activity of descending facilitation mechanisms may underlie chronic pain from peripheral nerve injury.     

Cerebral mechanisms of experimental hyperalgesia in fibromyalgia

The present study examined the hyperresponsiveness of the central nervous system in patients with fibromyalgia syndrome (FMS) related to mechanical hyperalgesia. The goals were to differentiate between increased pain ratings and hyperalgesia related either to peripheral or to central sensitization and to correlate with cerebral activation pattern. Seventeen patients and 17 healthy controls were examined, placing an experimental incision in the right volar forearm and causing tonic pain. Experimental pain, primary and secondary hyperalgesia were assessed during the time course of the experimental pain, and the changes in hyperalgesia were correlated to brain activation (functional magnetic resonance imaging). Patients with FMS experienced the experimental pain during the time course as more painful than healthy controls (F_score = 3.93, p_score = 0.008). While they did not present a different course of primary hyperalgesia (F_score = 1.01, p_score = 0.40), they did show greater secondary hyperalgesia (F_score = 5.45, p_score = 0.004). In patients with FMS, the cerebral pattern corresponding to secondary hyperalgesia was altered. The activity in the dorsolateral prefrontal cortex was inversely correlated with secondary hyperalgesia in healthy controls (R = ?0.34 p = 0.005); in patients, this correlation was disrupted (R = 0.19 p = 0.12). These findings point to an alteration of pain transmission at the central level in FMS (e.g., loss of inhibition) and might be related to changes in cerebral‐midbrain‐spinal mechanisms of pain inhibition.     

Cerebral blood-flow changes evoked by two levels of painful heat stimulation: A positron emission tomography study in humans

Positron emission tomography (PET) and accumulation of H₂ ¹⁵O as a marker of neuronal activity were used to create maps of cerebral blood-flow changes evoked by painful heat stimulation in 10 subjects. Two levels of painful tonic and phasic heat stimuli were applied with use of a newly developed contact heat thermode on the volar surface of the dominant (right) arm. The subjects participated in two separate PET sessions. Maps reflecting low and high levels of painful tonic heat were obtained in the first session, and low and high levels of painful phasic heat in the second session. The subjects scored their peak pain intensity and unpleasantness on 10-cm visual analogue scales. For each subject, PET images were aligned to nuclear magnetic resonance (NMR) images and remapped into the standardized co-ordinate system of Talairach. After normalization of the PET volumes, subtraction images were formed voxel-by-voxel and converted to a t-statistic volume. The perceived pain intensity and unpleasantness were identical with painful tonic and phasic heat stimulation. Directed searches revealed significant blood-flow increases in the contralateral primary sensorimotor cortex (MI/SI), SII, insular cortex and cingulate cortex when the low tonic heat map was subtracted from the high. A similar, but not identical, pain-processing network was observed for the maps representing the subtraction of low and high phasic heat. In this subtraction, the blood-flow increases in MSI/SI did not reach statistical significance, and significant blood flow decreases were found in the contralateral middle temporal gyrus. Finally, the location of the activation site in the cingulate cortex was different from that observed during tonic heat pain. This study has provided more evidence for the existence of a common pain-processing network engaged during the perception of different levels of toxic and phasic heat pain.     

BOLD effects in different areas of the cerebral cortex during painful mechanical stimulation

The contribution of four cortical areas (S1, S2, insular cortex and gyrus cinguli) to pain processing was assessed by functional magnetic resonance imaging (fMRI). Phasic (mechanical impact) and tonic stimuli (squeezing) were applied to the back of a finger, both at two different strengths. Stimuli were adjusted to inflict weak and strong pain sensations. It had been shown before that stronger noxious mechanical stimuli induce a weaker input from myelinated mechanoreceptors, but a more vigorous input from nociceptive primary afferents, and vice versa. Sizes of activation clusters and percent increase of the blood oxygenation level dependent (BOLD) signal during activation were compared in the areas of interest. Phasic stimulus patterns were more closely reflected in the time course of the MR signal in S1, S2 and the cingulate than tonic patterns, since the tonic stimuli tended to induce slow MR signal increase also during the resting periods which is in parallel to the persisting character of the tonic pain sensations. In S1 only the contralateral side was activated in most cases, and the more painful stimuli did not induce greater BOLD responses compared to the less painful stimuli in this area. Paradoxically, more painful stimuli produced smaller activation clusters in S1, both in tonic and phasic stimulus trials. In contralateral S2 more painful phasic stimuli induced significantly stronger BOLD responses than the weaker stimuli. The responses to tonic stimuli did not differentiate painfulness and were significantly smaller than the phasic. Activation clusters in this area were also smaller for tonic stimuli. In the gyrus cinguli more painful phasic stimuli induced stronger BOLD responses, but no difference was seen between tonic stimulation of different strength. Though the insular cortex was often bilaterally activated, no significant differences between stimulus quality or intensity were found. Our results provide evidence for a contribution of the S2 projection area and of the cingulate cortex to the processing of the intensity dimension of phasic mechanical pain. Such evidence was not found for the S1 area, which probably receives dominant input from non-nociceptive mechanoreceptors.     

Reversal of visceral and cutaneous hyperalgesia by local rectal anesthesia in irritable bowel syndrome (IBS) patients

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal illnesses and is characterized by altered visceral perception. The aim of the study was to determine if local anesthetic blockade of peripheral visceral nociceptive input reduces both visceral and cutaneous secondary hyperalgesia in IBS patients. Ten women with IBS (mean age 30+/-10 years) and ten control subjects (all women) (mean age 29+/-7 years) rated pain intensity and unpleasantness to distension of the rectum (35 mmHg) and thermal stimulation (47 degrees C) of the foot before and after rectal administration of either lidocaine jelly or saline jelly in a double blind crossover design. Intrarectal lidocaine (300 mg) reduced reported rectal and cutaneous pain in all of the IBS patients. The effects were statistically much greater than those of placebo and most of the effects were present within 5-15 min after the onset of the treatment. In the control subjects, rectal lidocaine did not decrease pain report from visceral and cutaneous stimuli. The results of this study support the hypothesis that local anesthetic blockade of peripheral impulse input from the rectum/colon reduces both visceral and cutaneous secondary hyperalgesia in IBS patients. The results provide further evidence that visceral hyperalgesia and secondary cutaneous hyperalgesia in IBS reflects central sensitization mechanisms that are dynamically maintained by tonic impulse input from the rectum/colon. Rectal administration of lidocaine jelly may also be a safe and effective means of reducing pain symptoms in IBS patients.     

Modality-specific facilitation and adaptation to painful tonic stimulation in humans.

The study assessed the influence of stimulus modality on adaptation or facilitation of pain during tonic cold and tourniquet pressure stimulation. Experimental set-up for the cold stimulation consisted of a thermo-tank with water, cooled to 3 degrees C, circulation pump, electronic thermometer and an electronic 10 cm visual analogue scale (VAS). Experimental set-up for the tonic pressure stimulation consisted of a pneumatic tourniquet cuff, a computer-controlled air compressor, and an electronic VAS. The first experiment assessed temporal profiles of pain intensity and skin temperature during immersion of the non-dominant hand and lower arm into cold water for 3 min or until the pain tolerance limit was reached. The second experiment assessed temporal profile of cuff pain intensity during constant compressions for 10 min beginning at pain intensities of 2, 4, and 6 cm on the VAS ("VAS 2", "VAS 4" and "VAS 6" sessions). Subjects enduring cold stimulation for less than 3 min were defined as non-adapting to cold and vice versa. The intensity of cold pain in non-adapting subjects increased significantly faster than in adapting subjects and reached significantly higher magnitude. The course of pain intensity during constant compression, estimated by a linear regression line, was increasing or decreasing, representing facilitation or adaptation of pain, respectively. The typical profile of adaptation consisted of an "overshoot" in pain intensity, followed by a decrease in pain intensity. There was significant correlation in VAS slopes between sessions separated by 2-5 days, suggesting consistent pattern in pain responses to tonic pressure stimulation. Adaptation or facilitation rates and the overshoot magnitude were dependent on the initial pain intensity (2, 4, or 6 cm on the VAS). The facilitation rate was highest and the adaptation rate was lowest during the "VAS 2" session, while the facilitation rate was lowest and the adaptation rate was highest during the "VAS 6" session. The overshoot magnitude was lowest during "VAS 6" session. Adapting and non-adapting/facilitating responses to cold and to pressure during "VAS 6" session were not correlated, suggesting that pain course and therefore stimulus tolerance during tonic stimulation are modality-specific. The results of the study suggest that tolerance of tonic painful pressure and cold stimulations is specific to stimulus modality and may represent separate nociceptive mechanisms.