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Prolonged exposure to opioids results in analgesic tolerance, drug overdose, and death. The mechanism underlying morphine analgesic tolerance still remains unresolved. We show that morphine analgesic tolerance was significantly attenuated in germfree (GF) and in pan-antibiotic-treated mice. Reconstitution of GF mice with naïve fecal microbiota reinstated morphine analgesic tolerance. We further demonstrated that tolerance was associated with microbial dysbiosis with selective depletion in and Probiotics, enriched with these bacterial communities, attenuated analgesic tolerance in morphine-treated mice. These results suggest that probiotic therapy during morphine administration may be a promising, safe, and inexpensive treatment to prolong morphine's efficacy and attenuate analgesic tolerance. We hypothesize a vicious cycle of chronic morphine tolerance: morphine-induced gut dysbiosis leads to gut barrier disruption and bacterial translocation, initiating local gut inflammation through TLR2/4 activation, resulting in the activation of proinflammatory cytokines, which drives morphine tolerance.
Learn More >To investigate whether the two briefest validated ICF-based (International Classification of Functioning, Disability and Health) tools can detect differences between different spinal conditions.
Learn More >Therapeutic interventions for neuropathic pain (NP), such as the NMDA-antagonist ketamine, can vary widely in effectiveness; Here, we conducted a longitudinal functional MRI study to test the hypothesis that the pain relieving effect of ketamine is due to reversal of abnormalities in regional low frequency brain oscillations (LFOs) and abnormal cross-network functional connectivity (FC) of the dynamic pain connectome. We found that: 1) ketamine decreased regional LFOs in the posterior cingulate cortex (PCC) of the default mode network (DMN), 2) a machine learning algorithm demonstrated that treatment-induced brain changes could be used to make generalizable inferences about pain relief, 3) treatment responders exhibited a significant decrease in cross-network static FC between the PCC and regions of the sensorimotor (SM) and salience networks following treatment, 4) the degree of reduced cross-network FC was correlated with the amount of pain relief, and 5) ketamine treatment did not produce significant differences in static or dynamic FC within the ascending nociceptive- or descending antinociceptive pathway. These findings support the proposition that regional LFOs contribute to cross-network connectivity that underlie the effectiveness of ketamine to produce significant relief of neuropathic pain. Together with our recent findings that pre-treatment dynamic FC of the descending antinociceptive pathway can predict ketamine treatment outcomes, these new findings indicate that pain relief from ketamine arises from a combination of a strong and flexible pre-treatment FC of the descending antinocieptive pathway together with plasticity (reduction) of cross-network connectivity of the DMN with SM and salience networks.
Learn More >The purpose of this randomized controlled trial is to determine whether the quantity of opioid pills prescribed at discharge is associated with the number of opioid pills consumed or unused by patients after primary hip and knee arthroplasty within 30 days after discharge.
Learn More >The opioid risk tool (ORT) is a commonly employed measure of risk of aberrant drug related behaviors (ADRB) in patients with chronic pain prescribed opioid therapy. In this study the discriminant predictive validity of the ORT was evaluated in a unique cohort of patients with chronic nonmalignant pain (CNMP) on long-term opioid therapy (LTOT) that displayed no evidence of developing an opioid use disorder (OUD) and a sample of patients with CNMP that developed an OUD after commencing opioid therapy. Results revealed that the original ORT was able to discriminate between patients with and without OUDs (OR=1.624; CI 95%: 1.539-1.715, p< 0.001). A weighted ORT eliminating the gender specific history of preadolescent sexual abuse item revealed comparable results (OR= 1.648; CI 95%: 1.539-1.742, p< 0.001). A revised unweighted ORT (ORT-OUD) removing the history of preadolescent sexual abuse item was notably superior in predicting the development of OUD in patients with CNMP on LTOT (OR= 3.085; CI 95%: 2.725-3.493, p< 0.001) with high specificity (0.851; CI 95%: 0.811-0.885), sensitivity (0.854; 95% CI: 0,799-0.898), positive (0.757; CI 95%: 0.709-0.799) and negative (0.914; CI 95%: 0.885-0.937) predictive values. Perspective: The revised ORT (ORT-OUD) is the first tool developed on a unique cohort to predict the risk of developing an OUD in patients with CNMP receiving opioid therapy, as opposed to ADRB that can reflect a number of other issues. The ORT-OUD has clinical utility in providing clinicians a simple, validated method to rapidly screen for the risk of developing OUD in patients on or being considered for opioid therapy.
Learn More >Fabry disease (FD) is an X-linked lysosomal storage disorder associated with pain triggered by heat or febrile infections. We modelled this condition by measuring the cytokine expression of peripheral blood mononuclear cells (PBMC) from FD patients in vitro upon stimulation with heat and lipopolysaccharide (LPS). We enrolled 67 FD patients and 37 healthy controls. We isolated PBMC, assessed their gene expression of selected pro- and anti-inflammatory cytokines, incubated them with heat, LPS, globotriaosylceramide (Gb3), and tumor necrosis factor-α (TNF), and measured TNF secretion in the supernatant and intracellular Gb3 accumulation, respectively. We found increased TNF, interleukin (IL-)1β, and toll-like receptor 4 (TLR4) gene expression in FD men (p < .05 to p < .01). TNF and IL-10 were higher, and IL-4 was lower in the subgroup of FD men with pain compared to controls (p < .05 to p < .01). Hereby, TNF was only increased in FD men with pain and classical mutations (p < .05) compared to those without pain. PBMC from FD patients secreted more TNF upon stimulation with LPS (p < .01) than control PBMC. Incubation with Gb3 and an additional α-galactosidase A inhibitor did not further increase TNF secretion, but incubation with TNF greatly increased the Gb3 load in FD PBMC compared to controls (p < .01). Also, LPS incubation and heat challenge (40 °C) increased Gb3 accumulation in PBMC of patients compared to baseline (p < .05 each), while no alterations were observed in control PBMC. Our data show that TNF holds a crucial role in the pathophysiology of FD associated pain, which may open a novel perspective for analgesic treatment in FD pain.
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