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Genetics studies on the placebo hypoalgesic effect highlight a promising link between single nucleotide polymorphisms (SNPs) in the dopamine, opioid, and endocannabinoid genes and placebo hypoalgesia. However, epistasis and replication studies are missing. In this study, we expanded on previous findings related to the 3 SNPs in the opioid receptor mu subunit (OPRM1 rs1799971), catechol-O-methyltransferase (COMT rs4680), and fatty acid amide hydrolase (FAAH rs324420) genes associated with placebo hypoalgesia and tested the effect of a 3-way interaction on placebo hypoalgesia. Using 2 well-established placebo procedures (verbal suggestion and learning paradigm), we induced significant placebo hypoalgesic effects in 160 healthy participants. We found that individuals with OPRM1 AA combined with FAAH Pro/Pro and those carrying COMT met/met together with FAAH Pro/Pro showed significant placebo effects. Participants with COMT met/val alleles showed significant placebo effects independently of OPRM1 and FAAH allele combinations. Finally, the model that included the placebo procedure and genotypes predicted placebo responsiveness with a higher accuracy (area under the curve, AUC = 0.773) as compared to the SNPs alone indicating that genetic variants can only partially explain the placebo responder status. Our results suggest that the endogenous mu-opioid system with a larger activation in response to pain in the met/val allele carriers as well as the synergism between endogenous mu-opioid system and cannabinoids might play the most relevant role in driving hypoalgesic responses. Future epistasis studies with larger sample sizes will help us to fully understand the complexity of placebo effects and explain the mechanisms that underlie placebo responsiveness.
This study investigated the analgesic effects of two doses (15 and 65 mg) of PF-06372865, a novel α2/α3/α5 gamma-aminobutyric acid A (GABA) subunit selective partial positive allosteric modulator (PAM), compared with placebo and pregabalin (300 mg) as a positive control.
Persistent post-surgical pain is defined as pain localized to the area of surgery of at least 2-month duration and is unfortunately a common complication after breast cancer surgery. While there is insufficient evidence to support any preventative strategy, prior literature suggests possible efficacy of intravenous lidocaine and perioperative pregabalin in preventing persistent pain after surgery. To determine feasibility of conducting a larger definitive trial, we conducted a multicenter 2-by-2 factorial randomized placebo-controlled pilot trial of 100 female patients undergoing breast cancer surgery. Patients were randomized to receive an intraoperative lidocaine infusion (1.5 mg/kg bolus followed by 2 mg/kg/hr) or placebo and perioperative pregabalin (300 mg preoperatively, 75 mg twice daily for nine days) or placebo. All feasibility criteria were surpassed; recruitment of 100 patients within 42-weeks, follow-up rate of 100%, and study-drug compliance of ≥80%. At 3-months, 53% of patients reported persistent neuropathic pain. While there was no interaction between lidocaine and pregabalin, lidocaine reduced the development of persistent neuropathic pain (43.1% vs 63.3%; RR 0.68, 95% CI 0.47-1.0). Pregabalin did not reduce persistent pain (60% vs 46%; RR 1.3, 95% CI 0.90 to 1.90) and neither pregabalin nor lidocaine impacted acute postoperative pain, opioid consumption, pain interference, or quality of life. Our pilot trial successfully demonstrated feasibility and provided promising data for conducting further trials of intraoperative lidocaine infusions in breast cancer surgeries. Clinical trial number: NCT02240199 Perspectives: This article reports the findings of a pilot randomized controlled trial evaluating the effects of perioperative pregabalin and intraoperative lidocaine infusions in patients undergoing breast cancer surgery. This trial demonstrated feasibility of conducting a larger trial and provided promising data that these interventions may reduce the development of persistent pain.
Native Americans (NAs) have a higher prevalence of chronic pain than any other U.S. racial/ethnic group; however, little is known about the mechanisms for this pain disparity. This study used quantitative sensory testing (QST) to assess pain experience in healthy, pain-free adults (N=137 NAs [87 female], N=145 non-Hispanic whites [NHW; 68 female]) following painful electric, heat, cold, ischemic, and pressure stimuli. Following each stimulus, ratings of pain intensity, sensory pain, affective pain, pain-related anxiety, and situation-specific pain catastrophizing were assessed. Results suggested that NAs reported greater sensory pain in response to suprathreshold electric and heat stimuli, greater pain-related anxiety to heat and ischemic stimuli, and more catastrophic thoughts in response to electric and heat stimuli. Sex differences were also noted; however, with the exception of catastrophic thoughts to cold, these were not moderated by race/ethnicity. Together, findings suggest NAs experience heightened sensory, anxiety, and catastrophizing reactions to painful stimuli. This could place NAs at risk for future chronic pain and could ultimately lead to a vicious cycle that maintains pain (e.g., pain→anxiety/catastrophizing→pain). PERSPECTIVE: Native Americans experienced heightened sensory, anxiety, and catastrophizing reactions in response to multiple pain stimuli. Given the potential for anxiety and catastrophic thoughts to amplify pain, this may place them at risk for pain disorders and could lead to a vicious cycle that maintains pain.
We evaluated the frequency of six commonly reported adult migraine premonitory symptoms in children and adolescents with episodic and chronic migraine and elicited psychological or behavioral comorbidities that may be associated with these symptoms.
Many of those aging with HIV suffer from distal neuropathic pain (DNP) due to HIV-associated sensory neuropathy (HIV-SN). Prior studies have linked chronic pain conditions to a variant of the catechol-O-methyltransferase (COMT), ValMet. This variant confers reduced enzymatic activity and results in higher synaptic dopamine levels. Here we examined the role of ValMet as a predictor of DNP in HIV-SN.
As new migraine prevention treatments are developed, the onset of a preventive effect, how long it is maintained and whether patients initially non-responsive develop clinically meaningful responses with continued treatment can be assessed.
This study was performed to test whether the risk of developing chronic widespread pain (CWP) in those with regional pain was augmented in those with symptoms of neuropathic pain (NP). Persons free of CWP completed the Douleur Neuropathique 4 (scores ≥3 indicating NP); demographics; Hospital Anxiety and Depression scale; Pittsburgh Sleep Quality Index; and pain medications. Participants were classified as having no pain, regional pain with no symptoms of NP ((Equation is included in full-text article.)), or regional pain with symptoms of NP (NP). At the 12-month follow-up, participants with CWP were identified. Logistic regression estimated the odds ratio, with 95% confidence intervals, of CWP in the (Equation is included in full-text article.)and NP groups compared with no pain, and NP compared with (Equation is included in full-text article.). Partial population attributable risks estimated the proportion of CWP attributable to baseline (Equation is included in full-text article.)or NP exposure. One thousand one hundred sixty-two participants completed the baseline DN4 and provided pain data at follow-up: 523 (45.0%) had no baseline pain, 562 (48.4%) (Equation is included in full-text article.), and 77 (6.6%) NP. One hundred fifty-three (13.2%) had CWP at 12 months: 19 (3.6%) no pain, 108 (19.2%) (Equation is included in full-text article.), and 26 (33.8%) NP. (Equation is included in full-text article.)(2.9 [1.9-4.3]) and NP (2.1 [1.1-4.0]) predicted CWP after adjusting for demographics, Hospital Anxiety and Depression scale, Pittsburgh Sleep Quality Index, and medications. The partial population attributable risk was 41.3% (25.2-54.0) for (Equation is included in full-text article.)and 6.0% (0.1-11.6) for NP. The NP group were not more likely to develop CWP when compared directly with (Equation is included in full-text article.)(1.5 [0.8-2.8]). Neuropathic pain was relatively rare and predicted a small number of new-onset CWP cases. Using these estimates, treatments targeting NP would at best prevent 6% of CWP cases.
Often, persistent post-traumatic headache and migraine are phenotypically similar. However, the similarities and differences in the neuropathological underpinnings of persistent post-traumatic headache and migraine require further understanding. We used diffusion tensor imaging (DTI) and a novel method for detecting subtle changes in fibertract integrity by measuring node-by-node parameters along each tract to compare fibertract profiles between those with migraine and those with persistent post-traumatic headache, and compared both cohorts to a group of controls.
To describe long-term treatment patterns in migraine patients initiating prophylactic therapy and to evaluate acute medication use and adverse events associated with opioids.