Selective antagonism of opioid-induced ventilatory depression by an ampakine molecule in humans without loss of opioid analgesia

Despite sensible guidelines for the use of opioid analgesics, respiratory depression remains a significant risk with a possibility of fatal outcomes. Clinicians need to find a balance of analgesia with manageable respiratory effects. The ampakine CX717 (Cortex Pharmaceuticals, Irvine, CA, USA), an allosteric enhancer of glutamate-stimulated AMPA receptor activation, has been shown to counteract opioid-induced respiratory depression in rats while preserving opioid-induced analgesia. Adopting a translational approach, we orally administered 1500 mg of CX717 to 16 male healthy volunteers in a placebo controlled double-blind study. Starting 100 min after CX717 or placebo intake, alfentanil was administered by computerized intravenous infusion targeting a plateau of effective alfentanil plasma concentrations of 100 ng/ml. One hour after start of opioid infusion, its effects were antagonized by intravenous injection of 1.6 mg of the classical opioid antidote naloxone. Respiration was quantified prior to drug administration (baseline), during alfentanil infusion and after naloxone administration by (i) counting the spontaneous respiratory frequency at rest and (ii) by employing hypercapnic challenge with CO2 rebreathing that assessed the expiratory volume at a carbon dioxide concentration in the breathable air of 55% (VE55). Pain was quantified at the same time points, immediately after assessment of respiratory parameters, by (i) measuring the tolerance to electrical stimuli (5 Hz sine increased by 0.2 mA/s from 0 to 20 mA and applied via two gold electrodes placed on the medial and lateral side of the mid-phalanx of the right middle finger) and (ii) by measuring the tolerance to heat (increased by 0.3°C/s from 32 to 52.5°C applied to a 3 x 3 cm2 skin area of the left volar forearm, after sensitization with 0.15 g capsaicin cream 0.1%). CX717 was tolerated by all subjects without side effects that would have required medical intervention. We observed that CX717 was approximately as effective as naloxone in reversing the opioid induced reduction of the respiratory frequency. Despite the presence of high plasma alfentanil concentrations, the respiratory frequency decreased only by 8.9 ± 22.4% when CX717 was pre-administered, which was comparable to the 7.0 ± 19.3% decrease observed after administration of naloxone. In contrast, after placebo pre-administration the respiratory rate decreased by 30.0 ± 21.3% (p=0.0054 for CX717 versus placebo). In agreement with this, periods of a very low respiratory frequency of <= 4 min-1 under alfentanil alone were shortened by ampakine pre-dosing by 52.9% (p=0.0182 for CX717 versus placebo). Furthermore, VE55 was decreased during alfentanil infusion by 55.9 ± 16.7% under placebo preadministration but only by 46.0 ± 18.1% under CX717 pre-administration (p=0.017 for CX717 versus placebo). Most importantly, in contrast to naloxone, CX717 had no effect on opioid induced analgesia. Alfentanil increased the pain tolerance to electrical stimuli by 68.7 ± 59.5% with placebo pre-administration. With CX717 pre-administration, the increase of the electrical pain tolerance was similar (54.6 ± 56.7%, p=0.1 for CX717 versus placebo). Similarly, alfentanil increased the heat pain tolerance threshold by 24.6 ± 10.0% with placebo pre-administration. Ampakine co-administration had also no effect on the increase of the heat pain tolerance of the capsaicin-sensitized skin (23.1 ± 8.3%, p=0.46 for CX717 versus placebo). The results of this study allow us to draw the conclusion, that opioid induced ventilatory depression can be selectively antagonized in humans by co-administering an ampakine. This is the first successful translation of a selective antagonism of opioidinduced respiratory depression from animal research into application in humans. Ampakines, namely CX717, thus are the first selective antidote for opioid-induced respiratory depression without loss of analgesia, available for the use in humans.Die Atemdepression ist die gefährlichste Nebenwirkung von Opioidanalgetika. Ihre selektive Antagonisierung, ohne die analgetischen Wirkungen zu beeinflussen, wäre ein bedeutender therapeutischer Fortschritt. Molekularbiologische und tierexperimentelle Befunden zeigten, dass möglicherweise das Ampakin CX717 (Cortex Pharmaceuticals, Irvine, CA, USA) dafür geeignet ist. Es verstärkte über eine allosterische Bindungsstelle die Wirkung von Glutamat am AMPA-Rezeptor und konnte in einem Tiermodell an Ratten die opioid-induzierte Atemdepression bei gleichbleibender Analgesie verhindern. In einem translationalen Ansatz führten wir eine doppelblind angelegte, placebokontrollierte Studie in 16 gesunden männlichen Probanden durch, denen 1500 mg CX717 oral verabreicht wurden, und 100 min später computergesteuert Alfentanil über 2 h infundiert wurde (Alfentanil-Plasmazielkonzentration im „steadystate“ von 100 ng/ml). Eine Stunde nach Start der Opioid-Infusion wurden die Wirkungen des Alfentanils durch die intravenöse Gabe von 1.6 mg Naloxon antagonisiert. Die Wirkungen des Opioids auf Atmung und Schmerz wurden jeweils mittels zweier experimenteller Parameter quantifiziert. Die Atemdepression wurde mittels Aufzeichnung der spontanen Atemfrequenz in Ruhe sowie mittels CO2-Rückatemversuch gemessen, bei welcher das exspiratorische Volumen bei einer CO2-Konzentration von 55% in der Einatemluft (VE55) als Hauptzielparameter diente. Die Schmerzwahrnehmung wurde als Schmerztoleranz auf elektrische Stimuli (sinusförmige Reize einer Stromstärke von 0-20 mA; Applikation über zwei Goldelektroden am mittleren Fingerendgelenks des rechten Mittelfingers) sowie als Toleranz auf Hitze-induzierten Schmerz gemessen (Temperaturanstieg: 0.3°C/s von 32.5 -52.5, Applikation über eine 3 x 3 cm² große Hautfläche an der volaren Seite des linken Unterarms, nach Sensibilisierung der Haut mit 0.15 g Capsaicin Creme 0.1%). Während der Alfentanil-Infusion (Plasmakonzentrationen ca. XXX) verminderte sich die Atemfrequenz unter Gabe von CX717 nur um 8.9 ± 22.4%, vergleichbar mit 7.0 ± 19.3% Rückgang nach Gabe von Naloxon. Dagegen kam es unter Placebo zu einer Senkung der Atemfrequenz um 30 ± 21.3% (p=0.0054 für CX717 versus Placebo). Zusätzlich wurden Perioden mit sehr niedriger Atemfrequenz von <= 4 min-1 unter Alfentanil nach pre-Medikation mit CX717 um 52.9% verkürzt (p=0.0182 für CX717 versus Placebo). Darüber hinaus war die VE55 während der Alfentanil Infusion nach Placebo-Gabe um 55.9 ± 16.7% verringert, während es nach Gabe von CX717 nur zu einer Verminderung von 46.0 ± 18.1% kam (p=0.017 für CX717 versus Placebo). Im Gegensatz zu der signifikanten Antagonisierung der atemdepressiven Wirkungen von Alfentanil hatte CX717 keine statistisch signifikanten Auswirkungen auf die alfentanilinduzierte Analgesie, während Naloxon unselektiv auch die Analgesie antagonisierte. Alfentanil allein erhöhte die Schmerztoleranz auf elektrische Stimuli um 68.7 ± 59.5%. Unter Gabe von CX717 war die Steigerung der elektrischen Schmerztoleranz ähnlich (54.6 ± 56.7%, p=0.1 für CX717 versus Placebo). Entsprechend erhöhte die alleinige Gabe von Alfentanil die Hitze-Toleranz-Schwelle um 24.6 ± 10.0%, während eine pre-Medikation mit CX717 auch hier keinen Einfluss auf den Anstieg der Hitzetoleranz hatte (23.1 ± 8.3%, p=0.46 für CX717 versus Placebo). Aus diesen Ergebnissen kann man einen selektiven Antagonismus der atemdepressiven Wirkungen des Opioids Alfentanil durch das Ampakin CX717 ableiten. Die vorliegende Arbeit stellt also eine erfolgreiche Translation tierexperimenteller Forschungsergebnisse in den Menschen dar. CX717 stellt somit das erste selektive Antidot für die Opioid-induzierte Atemdepression beim Menschen dar, das nicht zu einem Verlust der Analgesie führt

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

Background: A delta 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 delta 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 delta 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 delta 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 delta 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 delta 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

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

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

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

Estimates of the CO₂, H₂S and vanillin stimuli with respect to pain, smell or pleasantness, rated by means of a visual analog scale displayed at 3.4–6.6 s after stimulus presentation and ranging from “no pain” to “pain experienced at maximum” or “no odour” to “intensive odour” or “unpleasant” to “very pleasant”.

<p>CO₂ was always painful and never smelled. H₂S or vanillin stimuli were never painful but smelled.</p

Brain activations observed following the intranasal administration of 500 ms pulses of gaseous CO₂ at 75% v/V, which was clearly above pain threshold.

<p><b>Left column:</b> Pain-stimulus associated activations. <b>Middle and right column:</b> Pain-stimulus associated brain activations where the contrast pain > smell was significant (conjunction of second-level t-contrasts 1 −1 0 and 1 0 −1 denoting CO₂, H₂S and vanillin stimuli associated responses respectively). The left Rolandic operculum and insular cortex contralateral to the stimulation displayed these pain predominant activations although activations were observed bilaterally. Statistically significantly activated voxels (p<0.05 FWE-corrected; t>5.14) are presented overlaid (red) on 3D surface renderings of a standard MNI brain (Panel A) and as coloured overlay on the horizontal and sagittal plane of a structural standard T1-weighted MRI template (left). In the right parts of the figure, the colour depth of the displayed voxels reflects the respective t value of the voxel. Furthermore, stimulus related brain activations corresponding to the different stimuli are reported as mean percent signal change in a 5 mm spherical search volume around a selected FWE-corrected peak coordinate (MNI 42 −10 22; bottom). Single subject activations are depicted as dots and the 95% confidence interval as white bars. Results reflect a 12-subject group analysis.</p

Clusters of brain regions, which were activated more following pain than following non-nociceptive stimuli (Conjunction of CO₂>H₂S and CO₂>Vanillin).

<p>The table contains the anatomic location of the voxels with highest voxel level t in the respective region of a 12-subject group analysis. Voxels are given at a threshold of p<0.05 family wise error (FWE) corrected. Coordinates are reported in the MNI space [mm].</p>*<p>contralateral to the stimulus application side.</p