Prescription patterns and predictors of unmet pain relief in patients with difficult-to-treat osteoarthritis in the Nordics: analyses from the BISCUITS study.

OBJECTIVES: Osteoarthritis (OA) is one of the leading causes of disability worldwide. Pain is the most important symptom in OA, driving medical care, disability, reduced functionality, and decreased quality of life. The objective of this study was to describe prescription patterns of difficult-to-treat OA and explore possible predictors of unmet pain relief in Nordic patients. METHODS: This observational cohort study included patients with a confirmed diagnosis of OA (index date) in specialty care in Sweden, Norway, Finland and Denmark between 1 January 2011 and 31 December 2012 who were followed for up to 5 years. Four subgroups were pre-defined to characterize difficult-to-treat OA: (1) ≥2 chronic comorbidities in the 3-year pre-index period; (2) top 10% of healthcare resource users, 1-year post-index; (3) ≥3 types of prescription pain medications during pre-index period to first year post-index, with ≥30 days between types; (4) having a contraindication to a nonsteroidal anti-inflammatory drug (NSAID). Patient characteristics, prescription patterns and predictors of unmet pain relief (defined as persistent opioid use, using several types of opioids or long-term NSAID use) were analyzed. RESULTS: We identified 288,174 OA patients and the average age was 63.5 years at time of diagnosis and 58% of them were female. After 5 years, 35-50% of the patients defined as 'difficult-to-treat' had ≥1 prescription of opioids, compared to 20-25% of all OA patients (p-value <0.05). Comorbidities and disability pension were strong predictors of unmet pain relief (p-value <0.001). CONCLUSIONS: This study shows a substantial use of pain medications (NSAID and opioids) in difficult-to-treat OA patients. These findings suggest that pain may be inadequately managed in a considerable number of patients with OA, particularly those with contraindications to an NSAID. A high comorbid and socioeconomic burden are relevant risk factors among patients who continue to use opioids for a long period of time.

3-Oxoisoindoline-1-carboxamides: potent, state-dependent blockers of voltage-gated sodium channel Na(V)1.7 with efficacy in rat pain models.

The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure-activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.

Phenotyping of sensory and sympathetic ganglion neurons of a galanin-overexpressing mouse--possible implications for pain processing.

The distribution of galanin was studied in the lumbar 5 dorsal root ganglia (DRGs) and spinal cord, superior cervical ganglia (SCGs), and skin of transgenic mice overexpressing galanin under the dopamine beta-hydroxylase (DBH) promoter (GalOE-DBH mice) and in wild type (WT) mice. The DRGs and spinal cord were analysed before and after a unilateral, complete transection (axotomy) of the sciatic nerve and after dorsal rhizotomy. Both galanin protein and transcript were studied by, respectively, immunohistochemistry and in situ hybridization. Increased galanin expression was observed in several small, medium-sized and large DRG neuron profiles (NPs) in the naïve transgenic mouse, frequently in neurons lacking calcitonin gene-related peptide (CGRP) and isolectin B4-binding. This lack of coexistence was particularly evident in the medium-sized/large NPs. In the dorsal horn of the spinal cord, no differences were detected between GalOE-DBH and WT mice, both displaying a strong galanin-positive neuropil in the superficial laminae of the dorsal horn, but the transgenic mice showed a more abundant galanin-positive innervation of the ventral horn. A 12-day dorsal rhizotomy, surprisingly, failed to alter the galanin staining patterns in the dorsal (and ventral) dorsal horn. Unilateral axotomy induced upregulation of galanin in DRG NPs of all sizes in both types of mouse. In the hindpaw skin, a profuse galanin-positive fiber plexus was observed in sweat glands and around blood vessels of the transgenic mice, being much more restricted in WT mice. Finally, GalOE mice exhibited a strong galanin-like immunoreactivity in most SCG NPs. The overexpression of the peptide in DRGs and SCGs was paralleled by increased mRNA levels. The present results show that overexpression of galanin under the control of the DBH promoter does not only occur, as expected in these mice, in noradrenline/adrenaline neurons but also in DRG neurons, particularly in large and medium-sized NPs. To what extent and how this overexpression pattern is related to the previously shown elevated pain threshold under normal and lesion conditions is discussed [Grass, S., Crawley, J.N., Xu, X.J., Wiesenfeld-Hallin, Z., 2003a. Reduced spinal cord sensitization to C-fibre stimulation in mice over-expressing galanin. Eur. J. Neurosci. 17, 1829-1832; Hygge-Blakeman, K., Brumovsky, P., Hao, J.X., Xu, X.J., Hökfelt, T., Crawley, J.N., Wiesenfeld-Hallin, Z., 2004. Galanin over-expression decreases the development of neuropathic pain-like behaviour in mice after partial sciatic nerve injury. Brain Res. 1025, 152-158].

Galanin over-expression decreases the development of neuropathic pain-like behaviors in mice after partial sciatic nerve injury.

The neuropeptide galanin may have a role in modulation of nociception, particularly after peripheral nerve injury. Here we assessed the development of neuropathic pain-like behaviors in mice overexpressing galanin under the dopamine beta-hydroxylase promoter. Unoperated galanin over-expressing mice exhibited a moderately reduced sensitivity to noxious heat. Both galanin over-expressing mice and wild-type controls developed mechanical and heat hypersensitivity after photochemically induced partial sciatic nerve ischemic injury. The magnitude and persistence of such pain-like behaviors were significantly less, and recovery was faster in galanin over-expressing mice compared to wild types. However, the recovery from toe-spread deficits did not differ between galanin over-expressing and wild-type mice after a crush injury to the sciatic nerve. Thus, early recovery in pain-like response is unlikely to result from accelerated regeneration in the galanin over-expressing mice. Immunohistochemical analysis showed that galanin is over-expressed both in small and large dorsal root ganglion cells in the transgene mouse, whereas large galanin-positive neurons were never seen in wild-type mice. The present results in general support an inhibitory role of galanin in nociception and indicate that increased availability of galanin in spinal dorsal horn at the time or shortly after nerve injury may reduce the development of pain-like behaviors in mice.