EEG-based sensory testing reveals altered nociceptive processing in elite endurance athletes.

Increased exercise loads, as observed in elite athletes, seem to modulate the subjective pain perception in healthy subjects. The combination of electroencephalography (EEG) and standardized noxious stimulation can contribute to an objective assessment of the somatosensory stimulus processing. We assessed the subjective pain ratings and the electroencephalogram (EEG)-based response after standardized noxious mechanical and thermal stimuli as well as during conditioned pain modulation (CPM) in 26 elite endurance athletes and compared them to 26 recreationally active controls. Elite endurance athletes had consistently stronger somatosensory responses in the EEG to both mechanical and thermal noxious stimuli than the control group. We observed no significant group differences in the subjective pain ratings, which may have been influenced by our statistics and choice of stimuli. The CPM testing revealed that our conditioning stimulus modulated the subjective pain perception only in the control group, whereas the EEG indicated a modulatory effect of the conditioning stimulus on the spectral response only in the athletes group. We conclude that a higher activation in the cortical regions that process nociceptive information may either be an indicator for central sensitization or an altered stimulus salience in the elite endurance athletes' group. Our findings from our CPM testing were limited by our methodology. Further longitudinal studies are needed to examine if exercise-induced changes in the somatosensory system might have a critical impact on the long-term health of athletes.

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.

[Generating knowledge from complex data sets in human experimental pain research]. / Wissensgenerierung aus komplexen Datensätzen in der humanexperimentellen Schmerzforschung.

Pain has a complex pathophysiology that is expressed in multifaceted and heterogeneous clinical phenotypes. This makes research on pain and its treatment a potentially data-rich field as large amounts of complex data are generated. Typical sources of such data are investigations with functional magnetic resonance imaging, complex quantitative sensory testing, next-generation DNA sequencing and functional genomic research approaches, such as those aimed at analgesic drug discovery or repositioning of drugs known from other indications as new analgesics. Extracting information from these big data requires complex data scientific-based methods belonging more to computer science than to statistics. A particular interest is currently focused on machine learning, the methods of which are used for the detection of interesting and biologically meaningful structures in high-dimensional data. Subsequently, classifiers can be created that predict clinical phenotypes from, e.g. clinical or genetic features acquired from subjects. In addition, knowledge discovery in big data accessible in electronic knowledge bases, can be used to generate hypotheses and to exploit the accumulated knowledge about pain for the discovery of new analgesic drugs. This enables so-called data-information-knowledge-wisdom (DIKW) approaches to be followed in pain research. This article highlights current examples from pain research to provide an overview about contemporary data scientific methods used in this field of research.

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.

Effects of 20 mg oral Δ(9) -tetrahydrocannabinol on the olfactory function of healthy volunteers.

AIMS: Olfactory loss impairs the patient's quality of life. In individualized therapies, olfactory drug effects gain clinical importance. Molecular evidence suggests that among drugs with potential olfactory effects is Δ(9) -tetrahydrocannabinol (THC), which is approved for several indications, including neuropathic pain or analgesia in cancer patients. The present study aimed at assessing the olfactory effects of THC to be expected during analgesic treatment. METHODS: The effects of 20 mg oral THC on olfaction were assessed in a placebo-controlled, randomized cross-over study in healthy volunteers. Using an established olfactory test (Sniffin' Sticks), olfactory thresholds, odour discrimination and odour identification were assessed in 15 subjects at baseline and 2 h after THC administration. RESULTS: Δ(9) -Tetrahydrocannabinol impaired the performance of subjects (n = 15) in the olfactory test. Specifically, olfactory thresholds were increased and odour discrimination performance was reduced. This resulted in a significant drop in composite threshold, discrimination, identification (TDI) olfactory score by 5.5 points (from 37.7 ± 4.2 to 32.2 ± 5.6, 95% confidence interval for differences THC vs. placebo, -7.8 to -2.0, P = 0.003), which is known to be a subjectively perceptible impairment of olfactory function. CONCLUSIONS: Considering the resurgence of THC in medical use for several pathological conditions, the present results indicate that THC-based analgesics may be accompanied by subjectively noticeable reductions in olfactory acuity. In particular, for patients relying on their sense of smell, this might be relevant information for personalized therapy strategies.

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.

Correction: Dreismickenbecker et al. Electroencephalography-Based Effects of Acute Alcohol Intake on the Pain Matrix. Brain Sci. 2023, 13, 1659.

This paper [...].

Nociceptive Processing of Elite Athletes Varies between Sport-Specific Loads: An EEG-Based Study Approach.

INTRODUCTION: For the downstream nociceptive processing of elite athletes, recent studies indicate that athletes probably tolerate more pain as compared with a normally active population. Phenotyping the nociceptive processing of athletes in different types of endurance sports can provide insight into training-specific effects, which may help in understanding the long-term effects of specific exercise. METHODS: Twenty-six elite endurance athletes from the disciplines of rowing, triathlon, and running and 26 age- and sex-matched, recreationally active control subjects who participated in the subjective pain perception and processing of standardized noxious stimuli were investigated by EEG. This included standardized heat pain thresholds (HPT) and contact heat-evoked potentials from heat stimulation, measured with EEG as well as pinprick-evoked potentials from mechanical stimulation. RESULTS: After noxious stimulation, athletes showed a higher activation of the event-related spectral perturbation (ERSP) patterns in the N2P2 EEG response at the Cz Electrode compared with the controls. After noxious contact heat stimulation, triathletes had a higher ERSP activation compared with the controls, whereas the rowers had a higher ERSP activation after noxious mechanical stimulation. Also, HPT in triathletes were increased despite their increased central activation after thermal stimulation. We found a correlation between increased HPT and training hours and years, although athletes did not differ within these variables. CONCLUSIONS: Although we were able to identify differences between athletes of different endurance sports, the reasons and implications of these differences remain unclear. The study of sport-specific somatosensory profiles may help to understand the mechanisms of exercise-related long-term effects on pain processing and perception. Furthermore, sport-specific somatosensory effects may support the personalization of exercise interventions and identify risk factors for chronic pain in elite athletes.

Exogenous delta9-tetrahydrocannabinol influences circulating endogenous cannabinoids in humans.

Delta9-tetrahydrocannabinol (THC) competes with the endogenous cannabinoids arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG) at cannabinoid receptors. This may cause adaptive changes in the endocannabinoid signaling cascade with possible consequences for the biological functions of the endocannabinoid system. We show that administration of a single oral dose of 20 mg THC to 30 healthy volunteers resulted in higher circulating concentrations of anandamide, 2-AG, palmitoyl ethanolamide, and oleoylethanolamide at 2 and 3 hours after administration as compared with placebo. At 2 hours after THC administration, changes in oleoylethanolamide plasma concentrations from baseline were linearly related to the THC plasma concentrations. In rats, treatment with the CB1/CB2 agonist WIN 55,212 also increased plasma endocannabinoid concentrations. However, this was associated with a decrease of ethanolamide endocannabinoids in specific brain regions including spinal cord, cortex, and hypothalamus; whereas 2-arachidonoyl glycerol increased in the cortex. Thus, administration of THC to human volunteers influenced the concentrations of circulating endocannabinoids, which was mimicked by WIN-55,212 in rats, suggesting that exogenous cannabinoids may lead to changes in the endocannabinoid system that can be detected in plasma.

EEG responses to standardised noxious stimulation during clinical anaesthesia: a pilot study.

Background: During clinical anaesthesia, the administration of analgesics mostly relies on empirical knowledge and observation of the patient's reactions to noxious stimuli. Previous studies in healthy volunteers under controlled conditions revealed EEG activity in response to standardised nociceptive stimuli even at high doses of remifentanil and propofol. This pilot study aims to investigate the feasibility of using these standardised nociceptive stimuli in routine clinical practice. Methods: We studied 17 patients undergoing orthopaedic trauma surgery under general anaesthesia. We evaluated if the EEG could track standardised noxious phase-locked electrical stimulation and tetanic stimulation, a time-locked surrogate for incisional pain, before, during, and after the induction of general anaesthesia. Subsequently, we analysed the effect of tetanic stimulation on the surgical pleth index as a peripheral, vegetative, nociceptive marker. Results: We found that the phase-locked evoked potentials after noxious electrical stimulation vanished after the administration of propofol, but not at low concentrations of remifentanil. After noxious tetanic stimulation under general anaesthesia, there were no consistent spectral changes in the EEG, but the vegetative response in the surgical pleth index was statistically significant (Hedges' g effect size 0.32 [95% confidence interval 0.12-0.77], P=0.035). Conclusion: Our standardised nociceptive stimuli are not optimised for obtaining consistent EEG responses in patients during clinical anaesthesia. To validate and sufficiently reproduce EEG-based standardised stimulation as a marker for nociception in clinical anaesthesia, other pain models or stimulation settings might be required to transfer preclinical studies into clinical practice. Clinical trial registration: DRKS00017829.

Electroencephalography-Based Effects of Acute Alcohol Intake on the Pain Matrix.

The effects of acute and chronic intakes of high doses of alcohol on pain perception are well known, ranging from short-term analgesic effects to long-term sensitization and polyneuropathies. The short-term analgesic effects of ethanol consumption on subjective pain perception have been well studied in the literature. Recent advances in neuroimaging allow for an insight into pain-related structures in the brain, fostering the mechanistic understanding of the processing of nociceptive input and pain. We aimed to utilize EEG, combined with standardized noxious mechanical/thermal stimulation and subjective pain testing, to research the effects of acute alcohol intake on nociceptive processing and pain perception. We recruited 12 healthy subjects in an unblinded cross-over study design and aimed at achieving a blood alcohol level of 0.1%. Our data revealed a significant reduction in subjective pain ratings to noxious thermal and mechanical stimuli after alcohol ingestion. Our EEG data revealed suppressing effects on the cortical structures responsible for processing pain, the "pain matrix". We conclude that in addition to its analgesic effects, as expressed by the reduction in subjective pain, alcohol has a further impact on the "pain matrix" and directly affects the salience to a nociceptive stimulus.

An HPA-1a-positive platelet-depleting agent for prevention of fetal and neonatal alloimmune thrombocytopenia: a randomized, single-blind, placebo-controlled, single-center, phase 1/2 proof-of-concept study.

BACKGROUND: Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a rare and potentially life-threatening bleeding disorder of the fetus/newborn. Antibodies against human platelet antigen 1a (HPA-1a) are associated with the most frequent FNAIT cases. There are no approved therapies for FNAIT prevention or treatment. RLYB211 is a polyclonal HPA-1a hyperimmune IgG being developed to prevent FNAIT. OBJECTIVES: To investigate whether a single dose of anti-HPA-1a (1000 IU) could markedly accelerate the elimination of HPA-1ab platelets transfused into healthy, HPA-1a-negative participants as compared with placebo. METHODS: This randomized, single-blind, placebo-controlled, single-center, phase 1/2 proof-of-concept study (EudraCT: 2019-003459-12) included HPA-1a- and HLA-A2-negative healthy men. Cohort 1 received intravenous RLYB211 or placebo 1 hour after transfusion of HPA-1ab platelets. Cohort 1B received RLYB211 or placebo, followed by platelet transfusion 1 week later. Primary endpoint was the half-life of transfused platelets in circulation after administration of RLYB211 or placebo, determined by flow cytometry. Proof of concept was ≥90% reduction of half-life relative to placebo. RESULTS: Twelve participants were allocated to cohort 1 or 1B and randomized to receive RLYB211 (n = 9) or placebo (n = 3). RLYB211 markedly accelerated the elimination of HPA-1ab platelets in all participants vs placebo. In cohort 1B, this effect was observed 7 days after RLYB211 administration. Two treatment-emergent adverse events were possibly related to treatment, both in RLYB211-treated participants. No participants developed HPA-1a antibodies at 12 or 24 weeks. CONCLUSION: These data support the hypothesis that anti-HPA-1a could be used as prophylaxis in women at risk of having an FNAIT-affected pregnancy.

Separating brain processing of pain from that of stimulus intensity.

Regions of the brain network activated by painful stimuli are also activated by nonpainful and even nonsomatosensory stimuli. We therefore analyzed where the qualitative change from nonpainful to painful perception at the pain thresholds is coded. Noxious stimuli of gaseous carbon dioxide (n = 50) were applied to the nasal mucosa of 24 healthy volunteers at various concentrations from 10% below to 10% above the individual pain threshold. Functional magnetic resonance images showed that these trigeminal stimuli activated brain regions regarded as the "pain matrix." However, most of these activations, including the posterior insula, the primary and secondary somatosensory cortex, the amygdala, and the middle cingulate cortex, were associated with quantitative changes in stimulus intensity and did not exclusively reflect the qualitative change from nonpainful to pain. After subtracting brain activations associated with quantitative changes in the stimuli, the qualitative change, reflecting pain-exclusive activations, could be localized mainly in the posterior insular cortex. This shows that cerebral processing of noxious stimuli focuses predominately on the quantitative properties of stimulus intensity in both their sensory and affective dimensions, whereas the integration of this information into the perception of pain is restricted to a small part of the pain matrix.

Sensory testing and topical capsaicin can characterize patients with rheumatoid arthritis.

BACKGROUND AND OBJECTIVES: Our study aimed at examining the long-time inflammatory effects of rheumatoid arthritis (RA) as chronic immune-mediated disease on pain sensation and neuropathy development compared to healthy subjects (HS). METHODS: We used the quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain and Electroencephalography (EEG)-based contact heat evoked potentials (CHEPs) before and after topical capsaicin application. We recruited 16 RA patients in remission or low disease activity state (mean age: 59.38 years [± 10.18]) and 16 healthy subjects (mean age: 56.69 years [± 8.92]). RESULTS: The application of capsaicin cream on the thigh provoked a stronger effect in HS for both mechanical and heat pain thresholds (MPT and HPT, resp.), according to the area under the receiver operation characteristic (AUROC) (HS: HPT: 0.8965, MPT: 0.7402; RA: HPT: 0.7012, MPT: 0.6113). We observed contrary effects regarding changes in CHEPs (HS: g*max = - 0.65; RA patients: g*max = 0.72). CONCLUSION: As the overall effect of topical capsaicin application was higher in HS for QST, we suggest the existence of a sensitization of TRPV1 channels in RA patients caused by long-time chronical inflammation, despite a lack of clinical signs of inflammation due to adequate treatment. The effect in CHEPs probably uncovers neuropathic symptoms. The effect of topical capsaicin on HPTs and CHEPs can act as a marker for the extent of sensitization and the development of neuropathic symptoms. Further studies are needed to prove if our proposed method can act as a marker for the success of anti-inflammatory treatment. Key Points • The effect of topical capsaicin may represent the extent of TRPV1 sensitization in rheumatoid arthritis. • The effect of topical capsaicin on the amplitude level of CHEPs can unmask neuropathic symptoms. • The effect of topical capsaicin on CHEPs and HPTs can show the long-term consequences and the treatment success of RA patients in remission.

Application of Referencing Techniques in EEG-Based Recordings of Contact Heat Evoked Potentials (CHEPS).

Evoked potentials in the amplitude-time spectrum of the electroencephalogram are commonly used to assess the extent of brain responses to stimulation with noxious contact heat. The magnitude of the N- and P-waves are used as a semi-objective measure of the response to the painful stimulus: the higher the magnitude, the more painful the stimulus has been perceived. The strength of the N-P-wave response is also largely dependent on the chosen reference electrode site. The goal of this study was to examine which reference technique excels both in practical and theoretical terms when analyzing noxious contact heat evoked potentials (CHEPS) in the amplitude-time spectrum. We recruited 21 subjects (10 male, 11 female, mean age of 55.79 years). We applied seven noxious contact heat stimuli using two temperatures, 51°C, and 54°C, to each subject. During EEG analysis, we aimed to identify the referencing technique which produces the highest N-wave and P-wave amplitudes with as little artifactual influence as possible. For this purpose, we applied the following six referencing techniques: mathematically linked A1/A2 (earlobes), average reference, REST, AFz, Pz, and mathematically linked PO7/PO8. We evaluated how these techniques impact the N-P amplitudes of CHEPS based on our data from healthy subjects. Considering all factors, we found that mathematically linked earlobes to be the ideal referencing site to use when displaying and evaluating CHEPS in the amplitude-time spectrum.

A data science approach to the selection of most informative readouts of the human intradermal capsaicin pain model to assess pregabalin effects.

Persistent and, in particular, neuropathic pain is a major healthcare problem with still insufficient pharmacological treatment options. This triggered research activities aimed at finding analgesics with a novel mechanism of action. Results of these efforts will need to pass through the phases of drug development, in which experimental human pain models are established components e.g. implemented as chemical hyperalgesia induced by capsaicin. We aimed at ranking the various readouts of a human capsaicin-based pain model with respect to the most relevant information about the effects of a potential reference analgesic. In a placebo-controlled, randomized cross-over study, seven different pain-related readouts were acquired in 16 healthy individuals before and after oral administration of 300 mg pregabalin. The sizes of the effect on pain induced by intradermal injection of capsaicin were quantified by calculating Cohen's d. While in four of the seven pain-related parameters, pregabalin provided a small effect judged by values of Cohen's d exceeding 0.2, an item categorization technique implemented as computed ABC analysis identified the pain intensities in the area of secondary hyperalgesia and of allodynia as the most suitable parameters to quantify the analgesic effects of pregabalin. Results of this study provide further support for the ability of the intradermal capsaicin pain model to show analgesic effects of pregabalin. Results can serve as a basis for the designs of studies where the inclusion of this particular pain model and pregabalin is planned.

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 continuous theta-burst stimulation of the primary motor and secondary somatosensory areas on the central processing and the perception of trigeminal nociceptive input in healthy volunteers.

Noninvasive modulation of the activity of pain-related brain regions by means of transcranial magnetic stimulation promises an innovative approach at analgesic treatments. However, heterogeneous successes in pain modulation by setting reversible "virtual lesions" at different brain areas point at unresolved problems including the optimum stimulation site. The secondary somatosensory cortex (S2) has been previously identified to be involved in the perception of pain-intensity differences. Therefore, impeding its activity should impede the coding of the sensory component of pain intensity, resulting in a flattening of the relationship between pain intensity and physical stimulus strength. This was assessed using inactivating spaced continuous theta-burst stimulation (cTBS) in 18 healthy volunteers. In addition, cTBS was applied on the primary motor cortex (M1) shown previously to yield moderate and variable analgesic effects, whereas sham stimulation at both sites served as placebo condition. Continuous theta-burst stimulation flattened the relationship between brain activation and stimulus strength, mainly at S2, the insular cortex, and the postcentral gyrus (16 subjects analyzed). However, these effects were observed after inactivation of M1 while this effect was not observed after inactivation of S2. Nevertheless, both the M1 and the S2-spaced cTBS treatment were not reflected in the ratings of the nociceptive stimuli of different strengths (17 subjects analyzed), contrasting with the clear coding of stimulus strength by these data. Hence, while modulating the central processing of nociceptive input, cTBS failed to produce subjectively relevant changes in pain perception, indicating that the method in the present implementation is still unsuitable for clinical application.

Abuse-Deterrent Opioid Formulations: Pharmacokinetic and Pharmacodynamic Considerations.

Abuse-deterrent formulations (ADFs) are technologically sophisticated pharmaceutical formulations that impede manipulation and extraction of opioids and/or provoke unpleasant effects when they are taken in excessive quantity. This is implemented by creating physical barriers, inseparably combining the opioid with an opioid antagonist or adding aversive agents to the formulation. These pharmaceutical changes may potentially alter the pharmacokinetics and consequently the pharmacodynamics of the opioid. In this review, comparative evidence on pharmacokinetic differences between abuse-deterrent and classical formulations of the same opioids is summarized; furthermore, pharmacodynamic differences, with a focus on analgesia and abuse-related symptoms, are addressed. Most of the 12 studies comparing opioid pharmacokinetics have judged the physically intact ADF as being bioequivalent to the corresponding classical formulation. Pharmacokinetic differences have, however, been reported with physically manipulated ADFs and have ranged from moderate deviations from bioequivalence to complete changes in the pharmacokinetic profile (e.g. from a sustained-release formulation to a fast-release formulation). Pharmacodynamic effects were assessed in 14 comparative studies, which reported that intact ADFs usually provided clinically equivalent analgesia and clear advantages with respect to their addiction potential. However, withdrawal symptoms could be induced by the ADFs, although rarely and, in particular, when the ADFs had been physically altered. This evidence suggests that opioid ADFs are a working concept resulting in mostly minor pharmacokinetic and pharmacodynamic differences in comparison with classical formulations; however, they may deviate from this equivalence when physically altered.