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Oxytocin has been shown to increase trust, decrease anxiety and affect learning as has been observed in conditioning paradigms. Trust, anxiety and learning are important factors that influence placebo effects. In this study we investigated whether oxytocin can increase placebo analgesia, decrease nocebo hyperalgesia, and influence extinction processes of both. Eighty male volunteers were assigned to a 40 IU of oxytocin nasal spray group, or to a placebo control group. Placebo analgesia and nocebo hyperalgesia were induced by a conditioning procedure in combination with verbal suggestions. The results demonstrate that the conditioning procedure successfully elicited significant placebo analgesia and nocebo hyperalgesia responses (p < .001). Furthermore, extinction was observed (p < .001), although placebo and nocebo responses did not return to baseline and remained significant. Oxytocin did not influence placebo analgesia or nocebo hyperalgesia and had no effect on extinction. This study provides support against the placebo-boosting effects of oxytocin and was the first one to demonstrate that it also did not influence nocebo effects or extinction processes, however, these results pertain to only a male sample. As managing placebo and nocebo effects has widespread clinical implications, further research should investigate other neurobiological or behavioral pathways to boost placebo and decrease nocebo effects. Trial registration: The study protocol was preregistered on the website www.trialregister.nl under the number NTR6506. Perspective: The present study demonstrated that placebo analgesia and nocebo hyperalgesia can be successfully induced by conditioning and verbal suggestions. We could not confirm the hypothesis that oxytocin affects either of these phenomena. Other pharmacological agents and behavioral manipulations for increasing placebo and decreasing nocebo effects should be investigated.
Learn More >The classification of chronic visceral pain is complex, resulting from persistent inflammation, vascular (ischemic) mechanisms, cancer, obstruction or distension, traction or compression, and combined mechanisms, as well as unexplained functional mechanisms. Despite the prevalence, treatment options for chronic visceral pain are limited. Given this unmet clinical need, the development of novel analgesic agents, with defined targets derived from preclinical studies, is urgently needed. While various animal models have played an important role in our understanding of visceral pain, our knowledge is far from complete. Due to the complexity of visceral pain, this document will focus on chronic abdominal pain, which is the major complaint in patients with disorders of the gut-brain interaction, also referred to as functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Models for IBS are faced with challenges including a complex clinical phenotype, which is comorbid with other conditions including anxiety, depression, painful bladder syndrome, and chronic pelvic pain. Based upon the multifactorial nature of IBS with complicated interactions between biological, psychological, and sociological variables, no single experimental model recapitulates all the symptoms of IBS. This position paper will contextualize chronic visceral pain using the example of IBS and focus on its pathophysiology while providing a critical review of current animal models that are most relevant, robust, and reliable in which to screen promising therapeutics to alleviate visceral pain and delineate the gaps and challenges with these models. We will also highlight, prioritize, and come to a consensus on the models with the highest face/construct validity.
Learn More >The main aim of this work was to identify and to share the lessons learned from the negative outcome of the mirogabalin ALDAY phase 3 clinical program in pain associated with fibromyalgia. These lessons are important to improve planning and design of future phase 3 programs in fibromyalgia. A systematic review from Cochrane Library, Medline, Embase, clinicaltrials.gov, pharmaceutical companies and regulatory agencies' websites, was carried out starting from the development of gabapentin, the first α2δ ligand studied for the treatment of neuropathic pain and ending with the mirogabalin program. Based on the outcome of the main fibromyalgia programs, several differences in design, primary endpoint choice, magnitude of placebo response, presence of an active comparator, and size of the entire clinical program were identified. This analysis focused on the negative primary results of the mirogabalin ALDAY program and identified several contributing factors. Above all, the magnitude of placebo response and the unprecedented size of the program were identified. The number of study visits and procedures was also high and highly demanding for all subjects involved in ALDAY. In terms of main lessons learned from ALDAY, the first was the need for a comprehensive patient-focused strategy to preliminarily identify the challenges of fibromyalgia based on patient perspective and study complexity. Second, there was a need for a harmonized, truly patient-centric, global regulatory guidance accepted by regulatory agencies. Third, ALDAY proved that a phase 2 proof of concept, dose ranging study is necessary before commencing any phase 3 program in fibromyalgia.
Learn More >Patients with temporomandibular disorders (TMDs) often experience persistent facial pain. However, the treatment of TMD pain is still inadequate. In recent years, the disturbance of gut microbiota has been shown to play an important role in the pathogenesis of different neurological diseases including chronic pain. In the present study, we investigated the involvement of gut microbiota in the development of temporomandibular joint (TMJ) inflammation. Intra-temporomandibular joint injection of complete Freund's adjuvant (CFA) was employed to induce TMJ inflammation. Resveratrol (RSV), a natural bioactive compound with anti-inflammatory property, was used to treat the CFA-induced TMJ inflammation. We observed that CFA injection not only induces persistent joint pain, but also causes the reduction of short-chain fatty acids (SCFAs, including acetic acid, propionic acid and butyric acid) in the gut as well as decreases relevant gut bacteria Bacteroidetes and Lachnospiraceae. Interestingly, systemic administration of RSV (i.p.) dose-dependently inhibits CFA-induced TMJ inflammation, reverses CFA-caused reduction of SCFAs and these gut bacteria. Moreover, CFA injection causes blood-brain barrier (BBB) leakage, activates microglia and enhances tumor necrosis factor alpha (TNFα) release in the spinal trigeminal nucleus caudalis (Sp5C). The RSV treatment restores the BBB integrity, inhibits microglial activation and decreases the release of TNFα in the Sp5C. Furthermore, fecal microbiota transplantation with feces from RSV-treated mice significantly diminishes the CFA-induced TMJ inflammation. Taken together, our results suggest that gut microbiome perturbation is critical for the development of TMJ inflammation and that recovering gut microbiome to normal levels could be a new therapeutic approach for treating such pain.
Learn More >Despite the high prevalence of neck pain, few studies have addressed the pharmacological treatment of this condition. We evaluated the effectiveness of tapentadol prolonged-release (PR) in patients with or without a neuropathic pain component, with a focus on functional movements, disability and Quality of Life (QoL). Observational, retrospective study. Ninety-four adult patients with severe neck pain not responsive to opioid step III treatment. The primary endpoint was a ≥30% improvement of pain intensity at 4 weeks (W4). Several secondary outcomes were evaluated, including neck disability index (NDI), range of motion (ROM), and QoL. Patients received tapentadol PR at the starting dose of 100 mg/day. Dose titration was allowed in 50 mg increments, up to 500 mg daily. At W4, the primary endpoint of ≥30% improvement of pain was reported in 70% (n = 35; 95% confidence interval [CI]: 55-82%) of patients with a neuropathic pain component and in 69% (n = 20; 95% CI: 49-85%) of those without a neuropathic component. The percentage of patients reporting a neuropathic pain component significantly decreased from baseline (64.2%) to W4 (27.8%). NDI significantly improved in both groups at W12. ROM significantly improved in all three planes of motion (P < 0.01), with no difference between the two groups. Interference of pain with sleep and QoL also improved. The reduction in pain provided by tapentadol is associated with functional recovery, which may in turn be linked to an improvement in QoL.
Learn More >The major symptoms of irritable bowel syndrome (IBS) are changes in bowel habits and abdominal pain. Psychological stress is the major pathophysiological components of IBS. Corticotropin-releasing factor (CRF) is a well-known integrator in response to psychological stress. In this study, a novel CRF1 receptor antagonist T-3047928 was evaluated in stress-induced IBS models of rats to explore its potency for IBS.
Learn More >Cortical spreading depression (CSD) is a wave of transient network hyperexcitability leading to long lasting depolarization and block of firing, which initiates focally and slowly propagates in the cerebral cortex. It causes migraine aura and it has been implicated in the generation of migraine headache. Cortical excitability can be modulated by cholinergic actions, leading in neocortical slices to the generation of rhythmic synchronous activities (UP/DOWN states). We investigated the effect of cholinergic activation with the cholinomimetic agonist carbachol on CSD triggered with 130 mM KCl pulse injections in acute mouse neocortical brain slices, hypothesizing that the cholinergic-induced increase of cortical network excitability during UP states could facilitate CSD. We observed instead an inhibitory effect of cholinergic activation on both initiation and propagation of CSD, through the action of muscarinic receptors. In fact, carbachol-induced CSD inhibition was blocked by atropine or by the preferential M1 muscarinic antagonist telenzepine; the preferential M1 muscarinic agonist McN-A-343 inhibited CSD similarly to carbachol, and its effect was blocked by telenzepine. Recordings of spontaneous excitatory and inhibitory post-synaptic currents in pyramidal neurons showed that McN-A-343 induced overall a decrease of the excitatory/inhibitory ratio. This inhibitory action may be targeted for novel pharmacological approaches in the treatment of migraine with muscarinic agonists.
Learn More >Understanding molecular alterations associated with peripheral inflammation is a critical factor in selectively controlling acute and persistent pain. The present report employs in situ hybridization of the two opioid precursor mRNAs coupled with quantitative measurements of two peptides derived from the prodynorphin and proenkephalin precursor proteins: dynorphin A 1-8 and [Met]-enkephalin-Arg-Gly-Leu (MERGL). In dorsal spinal cord ipsilateral to the inflammation, dynorphin A 1-8 was elevated after inflammation, and persisted as long as the inflammation was sustained. Qualitative identification by HPLC and gel permeation chromatography revealed the major immunoreactive species in control and inflamed extracts to be dynorphin A 1-8. In situ hybridization in spinal cord after administration of the inflammatory agent, carrageenan, showed increased expression of prodynorphin (Pdyn) mRNA somatotopically in medial superficial dorsal horn neurons. The fold increase in preproenkephalin mRNA (Penk) was comparatively lower, although the basal expression is substantially higher than Pdyn. While Pdyn is not expressed in the dorsal root ganglion (DRG) in basal conditions, it can be induced by nerve injury, but not by inflammation alone. A bioinformatic meta-analysis of multiple nerve injury datasets confirmed Pdyn upregulation in DRG across different nerve injury models. These data support the idea that activation of endogenous opioids, notably dynorphin, is a dynamic indicator of persistent pain states in spinal cord and of nerve injury in DRG. [218/200] PERSPECTIVE: This is a systematic, quantitative assessment of dynorphin and enkephalin peptides and mRNA in dorsal spinal cord and dorsal root ganglia neurons in response to peripheral inflammation and axotomy. These studies form the foundational framework for understanding how endogenous spinal opioid peptides are involved in nociceptive circuit modulation. (48/50).
Learn More >The prevalence of neuropathic pain in the older population has been reported to be very high and is most commonly localized to a circumscribed area. Treatment failure is frequent in neuropathic pain and is accompanied by central side effects with recommended oral drugs acting on the central nervous system. A number of topical pharmaceuticals are available on prescription and also sold over the counter. This review in persons aged older than 60 years shows the efficacy of lidocaine 5% and capsaicin 8% for localized neuropathic pain while results with other pharmaceuticals are rather inconsistent. Local application of drugs has a very limited systemic effect and the pharmacological advantages of local over systemic treatment are particularly interesting in older persons who often have comorbidities and take multiple medications. However, more information is needed on the efficacy and safety of lidocaine 5% and capsaicin 8% in older old persons and on the long-term effects of these pharmaceuticals. These studies should also pave the way for research and development in the field of topical analgesics with a satisfactory level of evidence-based medicine.
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