Human Studies

The transient receptor potential (TRP) ion channel TRPM3 functions as a noxious heat sensor and plays a key role in acute pain sensation and inflammatory hyperalgesia in rodents. Despite its potential as novel analgesic drug target, little is known about the expression, function and modulation of TRPM3 in the human somatosensory system.

Trigeminal neuralgia is defined by its clinical characteristics of paroxysmal unilateral facial pain in a well-defined territory. Distribution of the pain may be in one or several of the cutaneous and/or mucous territories of the three divisions with V2 pain being the most frequent territory followed by V3 and V1. Factors determining the distribution of pain have not yet been systematically investigated. It is now well recognized that vascular compression factor is a predominant aetiology of classical trigeminal neuralgia. In this study we aimed to find whether there is a relation between the location of the vascular compression and the peripheral distribution of the pain. Patients with classical trigeminal neuralgia in whom microvascular decompression was performed were included. Data recorded pertained to the nature of the conflict, its degree and, most importantly, location around the root: supero-median, supero-lateral or inferior. Equally, clinical data for the distribution of pain were recorded. Most of the patients 318 (89.3%) had the compression coming from above, i.e. 220 (61.7%) had compression from a supero-medial direction and 98 (27.5%) from a supero-lateral direction; inferior compression was present in 38 patients (10.7%). Distribution of the pain was significantly different according to the location of the conflict (P = 0.0005, Fisher Exact test). Odds ratios were computed for each location of compression and painful territory involved. According to the overall distribution of pain, patients with supero-medial compression had an odds ratio of 2.7 [95% confidence interval (CI) 1.66-4.41] of manifesting with V1 pain. Conversely V3 pain was less likely to occur with supero-median compression than the other types of pain (odds ratio 0.53, 95% CI 0.34-0.83). Inferior compression on the other hand was more likely to manifest with V3 pain with an odds ratio of 2.56 (95% CI 1.21-5.45). Overall V2 pain had an odds ratio close to 1 regardless of the type of compression. These findings suggest an association between the location of the neurovascular conflict with its resulting insult and the distribution of pain supporting a somatotopic view of the organization of the trigeminal root and a role of the conflict in the clinical manifestation of trigeminal neuralgia.

Prescribers are often confronted with the decision to escalate opioid doses to achieve adequate analgesia. Understanding the impact of dose escalation on pain intensity is warranted. Using a retrospective cohort study design, Veterans with chronic pain and chronic opioid therapy were identified. Opioid dose escalators (>20% increase in average morphine milligram equivalent [MME] daily dose) were compared to dose maintainers (±20% change in average MME daily dose) assessed over two consecutive 6 month windows. Pain intensity was measured by the Numeric Rating Scale (NRS). The primary analyses used linear repeated measures models among a 1:1 matched sample of escalators and maintainers matched on propensity score and within ±180 days of the index date. Sensitivity analyses were conducted using adjusted linear repeated measures models with and without incorporating stabilized inverse probability of treatment weighting (SIPTW). There were 32,420 dose maintainers and 20,767 dose escalators identified with 19,358 (93%) matched pairs. Pain scores were persistently higher among dose escalators at each 90 day time period after the index date (0-90 Days After Index Date: Dose Escalators:4.68, 95%CI: 4.64, 4.72 Dose Maintainers:4.32, 95%CI: 4.28, 4.36, p<0.0001; 91-180 Days After Index Date: Dose Escalators:4.53, 95%CI: 4.49, 4.57; Dose Maintainers:4.25, 95%CI: 4.22, 4.29, p<0.0001) but were not different in the 90 days prior to the index date (Dose Escalators:4.64, 95%CI: 4.61, 4.68; Dose Maintainers:4.59, 95%CI: 4.55, 4.63, p=0.0551). Sensitivity analyses provided similar results as the primary analyses. Opioid dose escalation among patients with chronic pain is not associated with improvements in NRS pain scores.

Some individuals with chronic pain experience improvement in their pain with treatment, whereas others do not. The neurobiological reason is unclear, but an understanding of brain structure and functional patterns may provide insights into pain's responsivity to treatment. In this investigation, we used magnetic resonance imaging (MRI) techniques to determine grey matter density alterations on resting functional connectivity (RFC) strengths between pain responders and nonresponders in patients with complex regional pain syndrome. Brain metrics of pediatric patients at admission to an intensive pain rehabilitative treatment program were evaluated. Pain responders reported significant pain improvement at discharge and/or follow-up whereas nonresponders reported no improvements in pain, increases in pain, or emergence of new pain symptoms. The pain (responder/nonresponder) groups were compared with pain-free healthy controls to examine predictors of pain responder status via brain metrics. Our results show: (1) on admission, pain nonresponders had decreased grey matter density (GMD) within the nucleus accumbens (NAc) and reduced RFC strength between the NAc and the dorsolateral prefrontal cortex vs. responders; (2) Connectivity strength was positively correlated with change in pain intensity from admission to discharge; (3) Compared with pain-free controls, grey matter and RFC differences emerged only among pain nonresponders; and (4) Using a discriminative model, combining GMD and RFC strengths assessed at admission showed the highest prediction estimate (87%) on potential for pain improvement, warranting testing in a de novo sample. Taken together, these results support the idea that treatment responsiveness on pain is underpinned by concurrent brain structure and resting brain activity.

Choosing perioperative suitable treatments requires reliable and valid outcome measurements. The International Pain Outcome (IPO) questionnaire has been widely used for quality improvement and research purposes within the PAIN-OUT network that has collected more than 550,000 data sets of postoperative patients in 200 hospitals worldwide. Our aim is to confirm psychometric properties of the Spanish version of the IPO questionnaire and its invariance by pain predictors.

Temporomandibular disorder (TMD) is one of the most common orofacial pain conditions. Alteration in immune functioning is one promising biological mechanism underlying pain in TMD. However, there is a gap in the understanding of molecular bases contributing to altered immune functioning in these patients.