Central encoding of the strength of intranasal chemosensory trigeminal stimuli in a human experimental pain setting.

An important measure in pain research is the intensity of nociceptive stimuli and their cortical representation. However, there is evidence of different cerebral representations of nociceptive stimuli, including the fact that cortical areas recruited during processing of intranasal nociceptive chemical stimuli included those outside the traditional trigeminal areas. Therefore, the aim of this study was to investigate the major cerebral representations of stimulus intensity associated with intranasal chemical trigeminal stimulation. Trigeminal stimulation was achieved with carbon dioxide presented to the nasal mucosa. Using a single-blinded, randomized crossover design, 24 subjects received nociceptive stimuli with two different stimulation paradigms, depending on the just noticeable differences in the stimulus strengths applied. Stimulus-related brain activations were recorded using functional magnetic resonance imaging with event-related design. Brain activations increased significantly with increasing stimulus intensity, with the largest cluster at the right Rolandic operculum and a global maximum in a smaller cluster at the left lower frontal orbital lobe. Region of interest analyses additionally supported an activation pattern correlated with the stimulus intensity at the piriform cortex as an area of special interest with the trigeminal input. The results support the piriform cortex, in addition to the secondary somatosensory cortex, as a major area of interest for stimulus strength-related brain activation in pain models using trigeminal stimuli. This makes both areas a primary objective to be observed in human experimental pain settings where trigeminal input is used to study effects of analgesics.

Delta-9-tetrahydrocannabinol reduces the performance in sensory delayed discrimination tasks. A pharmacological-fMRI study in healthy volunteers.

BACKGROUND: Cannabis proofed to be effective in pain relief, but one major side effect is its influence on memory in humans. Therefore, the role of memory on central processing of nociceptive information was investigated in healthy volunteers. METHODS: In a placebo-controlled cross-over study including 22 healthy subjects, the effect of 20 mg oral Δ9-tetrahydrocannabinol (THC) on memory involving nociceptive sensations was studied, using a delayed stimulus discrimination task (DSDT). To control for nociceptive specificity, a similar DSDT-based study was performed in a subgroup of thirteen subjects, using visual stimuli. RESULTS: For each nociceptive stimulus pair, the second stimulus was associated with stronger and more extended brain activations than the first stimulus. These differences disappeared after THC administration. The THC effects were mainly located in two clusters comprising the insula and inferior frontal cortex in the right hemisphere, and the caudate nucleus and putamen bilaterally. These cerebral effects were accompanied in the DSDT by a significant reduction of correct ratings from 41.61% to 37.05% after THC administration (rm-ANOVA interaction "drug" by "measurement": F (1,21) = 4.685, p = 0.042). Rating performance was also reduced for the visual DSDT (69.87% to 54.35%; rm-ANOVA interaction of "drug" by "measurement": F (1,12) = 13.478, p = 0.003) and reflected in a reduction of stimulus-related brain deactivations in the bilateral angular gyrus. CONCLUSIONS: Results suggest that part of the effect of THC on pain may be related to memory effects. THC reduced the performance in DSDT of nociceptive and visual stimuli, which was accompanied by significant effects on brain activations. However, a pain specificity of these effects cannot be deduced from the data presented.

Effects of oral Δ9-tetrahydrocannabinol on the cerebral processing of olfactory input in healthy non-addicted subjects.

BACKGROUND: Considering the increasing acknowledgment of the human sense of smell as a significant component of the quality of life, olfactory drug effects gain potential clinical importance. A recent observation in a human experimental context indicated that Δ9-tetrahydrocannabinol (THC) impaired the subject's performance in olfactory tests. To further analyze the role of THC in human olfaction, the present report addresses its effects on the central processing of olfactory stimuli. METHODS: Employing a placebo-controlled randomized crossover design, an oral dose of 20 mg THC was administered in 15 healthy volunteers. The central processing of olfactory input, consisting of short pulses of gaseous vanillin or hydrogen sulfide, and for comparison, of non-odorous but painful carbon dioxide, were investigated before and after administration of THC or placebo in a pharmacological functional magnet resonance imaging study. RESULTS: Following THC administration, the vanillin stimuli lost their pleasantness and became hedonically inert. This observation had its functional correlate in reduced stimulus-associated brain activations located in the left amygdala, the hippocampus and superior temporal pole (peak MNI coordinates x = - 27, y = - 1, z = - 26 mm p = 0.039). Differences in amygdala activations were significantly correlated with the corresponding differences in vanillin pleasantness (p = 0.025). By contrast, no effects were observed on the perception of processing of H2S stimuli. CONCLUSIONS: The results support that THC induced a modulation of the central processing of olfactory input. The THC-induced reduction in the pleasantness of a pleasurable odor was accompanied by reduced activations in the limbic system. Results agree with previous observation of negative effects of cannabinoids on the human sense of smell and strengthen the evidence that THC-based medications will be among drugs with olfactory side effects.

Brain Mapping-Based Model of Δ(9)-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix.

Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) has progressed with justified caution, which also owes to the incomplete mechanistic understanding of its analgesic effects, in particular its interference with the processing of sensory or affective components of pain. The present placebo-controlled crossover study therefore focused on the effects of 20 mg oral THC on the connectivity between brain areas of the pain matrix following experimental stimulation of trigeminal nocisensors in 15 non-addicted healthy volunteers. A general linear model (GLM) analysis identified reduced activations in the hippocampus and the anterior insula following THC administration. However, assessment of psychophysiological interaction (PPI) revealed that the effects of THC first consisted in a weakening of the interaction between the thalamus and the secondary somatosensory cortex (S2). From there, dynamic causal modeling (DCM) was employed to infer that THC attenuated the connections to the hippocampus and to the anterior insula, suggesting that the reduced activations in these regions are secondary to a reduction of the connectivity from somatosensory regions by THC. These findings may have consequences for the way THC effects are currently interpreted: as cannabinoids are increasingly considered in pain treatment, present results provide relevant information about how THC interferes with the affective component of pain. Specifically, the present experiment suggests that THC does not selectively affect limbic regions, but rather interferes with sensory processing which in turn reduces sensory-limbic connectivity, leading to deactivation of affective regions.

Similar maximum systemic but not local cyclooxygenase-2 inhibition by 50 mg lumiracoxib and 90 mg etoricoxib: a randomized controlled trial in healthy subjects.

PURPOSE: Once daily doses of 100-400 mg lumiracoxib have been proposed to inhibit local prostaglandin synthesis longer than systemic prostaglandin synthesis due to local accumulation in inflamed, acidic tissue. Lower, less toxic doses, however, might still achieve the clinical goal and merit further contemplation. METHODS: In a randomized, double-blind, placebo-controlled, three-way cross-over study, 18 healthy men received, with an interval of 24 h, two oral doses of 50 mg lumiracoxib or for comparison, 90 mg etoricoxib, for which local tissue accumulation has not been claimed as therapeutic component. Systemic and local drug concentrations, assessed by means of subcutaneous in-vivo microdialysis, were related to COX-2 inhibiting effects, quantified as inhibition of prostaglandin ex-vivo production in whole blood as well as local tissue prostaglandin (PG) concentrations. RESULTS: Twenty-four hours after the first dose, only etoricoxib was detectable in plasma and inhibited PGE2 production. In contrast, after the second dose, systemic PGE2 concentrations were significantly reduced by both coxibs, indicating similar maximum systemic effects of the selected doses. The local COX-2 inhibition by etoricoxib was most pronounced for PGD2. To the contrary, no indication was given of local inhibition of PG production by lumiracoxib at the dose tested. CONCLUSIONS: Doses of 50 mg lumiracoxib and 90 mg etoricoxib produced similar maximum inhibition of systemic COX-2 function whereas 50 mg lumiracoxib was ineffective in producing local COX-2 inhibition. At a 50 mg dosage, lumiracoxib does not provide peripheral effects that outlast its systemic actions in therapies of rheumatic diseases such as osteoarthritis.

The human operculo-insular cortex is pain-preferentially but not pain-exclusively activated by trigeminal and olfactory stimuli.

Increasing evidence about the central nervous representation of pain in the brain suggests that the operculo-insular cortex is a crucial part of the pain matrix. The pain-specificity of a brain region may be tested by administering nociceptive stimuli while controlling for unspecific activations by administering non-nociceptive stimuli. We applied this paradigm to nasal chemosensation, delivering trigeminal or olfactory stimuli, to verify the pain-specificity of the operculo-insular cortex. In detail, brain activations due to intranasal stimulation induced by non-nociceptive olfactory stimuli of hydrogen sulfide (5 ppm) or vanillin (0.8 ppm) were used to mask brain activations due to somatosensory, clearly nociceptive trigeminal stimulations with gaseous carbon dioxide (75% v/v). Functional magnetic resonance (fMRI) images were recorded from 12 healthy volunteers in a 3T head scanner during stimulus administration using an event-related design. We found that significantly more activations following nociceptive than non-nociceptive stimuli were localized bilaterally in two restricted clusters in the brain containing the primary and secondary somatosensory areas and the insular cortices consistent with the operculo-insular cortex. However, these activations completely disappeared when eliminating activations associated with the administration of olfactory stimuli, which were small but measurable. While the present experiments verify that the operculo-insular cortex plays a role in the processing of nociceptive input, they also show that it is not a pain-exclusive brain region and allow, in the experimental context, for the interpretation that the operculo-insular cortex splay a major role in the detection of and responding to salient events, whether or not these events are nociceptive or painful.

Extended cortical activations during evaluating successive pain stimuli.

Comparing pain is done in daily life and involves short-term memorizing and attention focusing. This event-related functional magnetic resonance imaging study investigated the short-term brain activations associated with the comparison of pain stimuli using a delayed discrimination paradigm. Fourteen healthy young volunteers compared two successive pain stimuli administered at a 10 s interval to the same location at the nasal mucosa. Fourteen age- and sex-matched subjects received similar pain stimuli without performing the comparison task. With the comparison task, the activations associated with the second pain stimulus were significantly greater than with the first stimulus in the anterior insular cortex and the primary somatosensory area. This was observed on the background of a generally increased stimulus-associated brain activation in the presence of the comparison task that included regions of the pain matrix (insular cortex, primary and secondary somatosensory area, midcingulate cortex, supplemental motor area) and regions associated with attention, decision making, working memory and body recognition (frontal and temporal gyri, inferior parietal lobule, precuneus, lingual cortices). This data provides a cerebral correlate for the role of pain as a biological alerting system that gains the subject's attention and then dominates most other perceptions and activities involving pain-specific and non-pain-specific brain regions.

Quick discrimination of A(delta) and C fiber mediated pain based on three verbal descriptors.

BACKGROUND: A(δ) and C fibers are the major pain-conducting nerve fibers, activate only partly the same brain areas, and are differently involved in pain syndromes. Whether a stimulus excites predominantly A(δ) or C fibers is a commonly asked question in basic pain research but a quick test was lacking so far. METHODOLOGY/PRINCIPAL FINDINGS: Of 77 verbal descriptors of pain sensations, "pricking", "dull" and "pressing" distinguished best (95% cases correctly) between A(δ) fiber mediated (punctate pressure produced by means of von Frey hairs) and C fiber mediated (blunt pressure) pain, applied to healthy volunteers in experiment 1. The sensation was assigned to A(δ) fibers when "pricking" but neither "dull" nor "pressing" were chosen, and to C fibers when the sum of the selections of "dull" or "pressing" was greater than that of the selection of "pricking". In experiment 2, with an independent cohort, the three-descriptor questionnaire achieved sensitivity and specificity above 0.95 for distinguishing fiber preferential non-mechanical induced pain (laser heat, exciting A(δ) fibers, and 5-Hz electric stimulation, exciting C fibers). CONCLUSION: A three-item verbal rating test using the words "pricking", "dull", and "pressing" may provide sufficient information to characterize a pain sensation evoked by a physical stimulus as transmitted via A(δ) or via C fibers. It meets the criteria of a screening test by being easy to administer, taking little time, being comfortable in handling, and inexpensive while providing high specificity for relevant information.

Bioequivalence criteria for transdermal fentanyl generics: do these need a relook?

With the increasing appearance of transdermal fentanyl generics since 2004 when patent protection of the reference Duragesic expired, opportunities to switch between different generics have arisen. Transdermal fentanyl is subject to bioequivalence regulation because only approximately 92% of the dose is absorbed as a result of the need to maintain a diffusion gradient from plaster to skin. Considering the high potency of fentanyl and the potential dangerous adverse effects of full mu opioid receptor agonists, we assessed evidence suggesting a revision of the confidence limits of bioequivalence of 80-125%. A few cases have been reported where a prescribed ascension in transdermal fentanyl dosing triggered respiratory depression. Values of concentration that produce a 50% effective response for decreasing the ventilatory volume lie within the plasma concentration range of 1.4-2.5 ng/mL during transdermal fentanyl analgesia. However, an exchange of the reference with a generic with higher bioavailability would trigger respiratory depression only in extreme situations and is clinically supported by only a single case report. Experimental or clinical evidence is required to provide the necessary database for final judgement of bioequivalent limits of fentanyl generics. At present, the evidence is not sufficient to advise other bioequivalence criteria than those previously applied to transdermal fentanyl.