Pain processing during three levels of noxious stimulation produces differential patterns of central activity.

Previous functional imaging studies have demonstrated a number of discrete brain structures that increase activity with noxious stimulation. Of the commonly identified central structures, only the anterior cingulate cortex shows a consistent response during the experience of pain. The insula and thalamus demonstrate reasonable consistency while all other regions, including the lentiform nucleus, somatosensory cortex and prefrontal cortex, are active in no more than half the current studies. The reason for such discrepancy is likely to be due in part to methodological variability and in part to individual variability. One aspect of the methodology which is likely to contribute is the stimulus intensity. Studies vary considerably regarding the intensity of the noxious and non-noxious stimuli delivered. This is likely to produce varying activation of central structures coding for the intensity, affective and cognitive components of pain. Using twelve healthy volunteers and positron emission tomography (PET), the regional cerebral blood flow (rCBF) responses to four intensities of stimulation were recorded. The stimulation was delivered by a CO2 laser and was described subjectively as either warm (not painful), pain threshold just painful), mildly painful or moderately painful. The following group subtractions were made to examine the changing cerebral responses as the stimulus intensity increased: (1) just painful - warm; (2) mild pain - warm; and (3) moderate pain - warm. In addition, rCBF changes were correlated with the subjective stimulus ratings. The results for comparison '1' indicated activity in the contralateral prefrontal (area 10/46/44), bilateral inferior parietal (area 40) and ipsilateral premotor cortices (area 6), possibly reflecting initial orientation and plans for movement. The latter comparisons and correlation analysis indicated a wide range of active regions including bilateral prefrontal, inferior parietal and premotor cortices and thalamic responses, contralateral hippocampus, insula and primary somatosensory cortex and ipsilateral perigenual cingulate cortex (area 24) and medial frontal cortex (area 32). Decreased rCBF was observed in the amygdala region. These responses were interpreted with respect to their contribution to the multidimensional aspects of pain including fear avoidance, affect, sensation and motivation or motor initiation. It is suggested that future studies examine the precise roles of each particular region during the central processing of pain.

Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study.

Few placebo-controlled trials have investigated the treatment of breakthrough pain (BTP) in patients with chronic pain. We evaluated the efficacy and safety of intranasal ketamine for BTP in a randomized, double-blind, placebo-controlled, crossover trial. Twenty patients with chronic pain and at least two spontaneous BTP episodes daily self-administered up to five doses of intranasal ketamine or placebo at the onset of a spontaneous BTP episode (pain intensity > or =5 on a 0-10 scale). Two BTP episodes at least 48 h apart were treated with either ketamine or placebo. Patients reported significantly lower BTP intensity following intranasal ketamine than after placebo (P < 0.0001) with pain relief within 10 min of dosing and lasting for up to 60 min. No patient in the ketamine group required his/her usual rescue medication to treat the BTP episode, while seven out of 20 (35%) patients in placebo group did (P = 0.0135). Intranasal ketamine was well tolerated with no serious adverse events. After ketamine administration, four patients reported a transient change in taste, one patient reported rhinorrhea, one patient reported nasal passage irritation, and two patients experienced transient elevation in blood pressure. A side effect questionnaire administered 60 min and 24 h after drug or placebo administration elicited no reports of auditory or visual hallucinations. These data suggest that intranasal administration of ketamine provides rapid, safe and effective relief for BTP.

Gender differences in patterns of cerebral activation during equal experience of painful laser stimulation.

A previous functional imaging study demonstrated greater female response in the anterior insula and thalamus and left prefrontal activation in men and right prefrontal activation in women during equal heat intensity but unequal pain experience. For the current study, subjective intensities of noxious heat delivered to the back of the right hand were equalized across subjects, and regional cerebral blood flow was recorded by using positron emission tomography. The female subjects required less laser energy before reporting pain, but the difference was not significant. Correlation of regional cerebral blood flow with subjective pain experience in the whole group showed significant bilateral responses in the parietal, lateral premotor, prefrontal, secondary somatosensory, anterior cingulate and insula cortices, as well as the thalamus. There was significantly greater activation in the left, contralateral, prefrontal, primary and secondary somatosensory, parietal, and insula cortices in the male subjects compared with the female subjects and greater response in the perigenual cingulate cortex in the female subjects. Our study is the first to associate consistent pain experience with gender differences in central response. These differences may relate to differential processing of acute pain with implications for clinical disorders that show a female dominance. The subtle behavioral differences and inconsistent findings across studies, however, suggest the need for caution and further experimentation before speculating further.

The cross-modal interaction between pain-related and saccade-related cerebral activation: a preliminary study by event-related functional magnetic resonance imaging.

UNLABELLED: Pain-related cerebral activation in functional magnetic resonance imaging shows less consistent signals that decay earlier than in conventional task-related activation. This may result from pain's top-down inhibition mediated by cognitive or hemodynamic interaction that could affect activation by other modalities. Using event-related functional magnetic resonance imaging, we examined whether pain affects cerebral activation by a saccade task through such cross-modal interaction. Six right-handed volunteers underwent whole-brain echo-planar imaging on a 3.0 T magnetic resonance imaging scanner while they received thermal pain stimulus at 50 degrees C on the right forearm (P; n = 6), performed a visually guided saccade task (V; n = 6), and went through a simultaneous pain-plus-saccade paradigm (PV; n = 5). Averaged functional activation maps were synthesized and signal time courses were analyzed at activation clusters. P activated the bilateral secondary somatosensory cortex (S2). V activated the posterior, supplementary, frontal eye fields, and visual areas. PV enhanced the S2 activation and activated additional pain-related areas, including the bilateral premotor area, right insula, anterior, and posterior cingulate cortices. In contrast, V-related activation was attenuated in PV. We propose that pain caused cross-modal suppression on the oculomotor activity and that an oculomotor task enhanced pain-related activation by triggering attention toward pain. IMPLICATIONS: Pain-related cerebral activation is enhanced by attention toward pain. It may involve top-down suppression over the unrelated neural networks of saccade.

Early decay of pain-related cerebral activation in functional magnetic resonance imaging: comparison with visual and motor tasks.

BACKGROUND: Although pain-related activation was localized in multiple brain areas by functional imaging, the temporal profile of its signal has been poorly understood. The authors characterized the temporal evolution of such activation in comparison to that by conventional visual and motor tasks using functional magnetic resonance imaging. METHODS: Five right-handed volunteers underwent whole brain echo-planar imaging on a 3 T magnetic resonance imaging scanner while they received pain stimulus on the right and left forearm and performed visually guided saccade and finger tapping tasks. Pain stimulus on the right and left forearm consisted of four cycles of 15-s stimulus at 47.2-49.0 degrees C, interleaved with 30-s control at 32 degrees C, delivered by a Peltier-type thermode, and visually guided saccade and finger tapping of three cycles of 30-s active and 30-s rest conditions. Voxel-wise t statistical maps were standardized and averaged across subjects. Blood oxygenation level-dependent signal time courses were analyzed at local maxima of representative activation clusters (t > 3.5). RESULTS: Pain stimulus on the right forearm activated the secondary somatosensory (S2), superior temporal, anterior cingulate, insular, prefrontal cortices, premotor area, and lenticular nucleus. Pain stimulus on the left forearm activated similar but fewer areas at less signal intensity. The S2 activation was dominant on the contralateral hemisphere. Pain-related activation was statistically weaker and showed less consistent signal time courses than visually guided saccade- and finger tapping-related activation. Pain-related signals decayed earlier before the end of stimulus, in contrast to well-sustained signal plateaus induced by visually guided saccade and finger tapping. CONCLUSIONS: The authors speculate that pain-related blood oxygenation level-dependent signals were attenuated by the pain-induced global cerebral blood flow decrease or activation of the descending pain inhibitory systems.

Mice with glycine receptor subunit mutations are both sensitive and resistant to volatile anesthetics.

UNLABELLED: We used two mouse lines with glycine receptor mutations to determine whether glycine receptors might play an important role in anesthetic responses in vivo. Spastic (spA) mutants were slightly more sensitive (P = 0.02) to enflurane in the loss-of-righting reflex assay (50% effective concentration [EC(50)] = 1.17 +/- 0.06 atm for controls versus 0.97 +/- 0.06 atm for spA) but were also substantially more resistant (P = 0.01) to enflurane in the tail clamp assay (EC(50) = 1.96 +/- 0.10 atm for controls versus 2.58 +/- 0.25 atm for spA). spA mice were also more sensitive to halothane (P < 0.001) in the loss-of-righting reflex assay (EC(50) = 0.81 +/- 0.03 atm for controls versus 0.57 +/- 0.04 atm for spA), but the responses of mutant and control mice to tail clamp in the presence of halothane were similar. Spasmodic control and mutant mice did not differ in their responses to the two drugs. Sleep time was substantially longer in both mutant mouse lines after injection of three hypnotics (midazolam, pentobarbital, and ethanol). Our results suggest a complex involvement of glycinergic pathways in mediating anesthetic responses. Greater sensitivity to the hypnotic effect of enflurane, halothane, midazolam, pentobarbital, and ethanol in mutant mice with diminished glycinergic capacity suggests that glycinergic activity is inversely related to hypnosis, whereas resistance to enflurane in the tail clamp assay suggests that glycinergic activity potentiates the minimum alveolar anesthetic concentration response. Halothane seems to share some, but not all, of enflurane's mechanisms, indicating that not all volatile anesthetics modulate glycinergic pathways equally. IMPLICATIONS: We tested two mouse lines with glycine receptor mutations to determine whether glycine receptors might play an important role in anesthetic responses in vivo. Both sensitivity and resistance to common anesthetics were observed in mutant mice, depending on the behavioral end-point evaluated.