Differential Efficacy of Ketamine in the Acute versus Chronic Stages of Complex Regional Pain Syndrome in Mice

Abstract

Background Complex regional pain syndrome (CRPS) is a painful, disabling and often chronic condition, where many patients transition from an acute phase with prominent peripheral neurogenic inflammation to a chronic phase with evident central nervous system (CNS) changes. Ketamine is a centrally-acting agent believed to work through blockade of N-methyl-D-aspartate (NMDA) receptors and is being increasingly used for the treatment of refractory CRPS, although the basis for the drug’s effects and efficacy at different stages of the syndrome remain unclear. Methods We used a mouse model of CRPS (n=8–12/group) involving tibia fracture/cast immobilization to test the efficacy of ketamine (2 mg/kg/day; 7 days) or vehicle infusion during acute (3weeks [3w] post-fracture) and chronic (7w post-fracture) stages. Results Acute phase fracture mice displayed elevated limb temperature, edema and nociceptive sensitization that were not reduced by ketamine. Fracture mice treated with ketamine during the chronic phase showed reduced nociceptive sensitization that persisted beyond completion of the infusion. During this chronic phase, ketamine also reduced latent nociceptive sensitization and improved motor function at 18 weeks post-fracture. No side effects of the infusions were identified. These behavioral changes were associated with altered spinal astrocyte activation and expression of pain-related proteins including NMDA receptor 2b (NR2b), Ca2+/calmodulin-dependent protein kinase ii (CaMK2), and brain-derived neurotrophic factor (BNDF). Conclusions Collectively, these results demonstrate that ketamine is efficacious in the chronic, but not acute stages of CRPS, suggesting that the centrally-acting drug is relatively ineffective in early CRPS when peripheral mechanisms are more critical for supporting nociceptive sensitization.

Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain

“…This suggests that (2R,6R)-HNK may reduce the central sensitization that can contribute to CRPS1 pain 20. Although with our daily intraperitoneal boluses of ketamine, 10 mg/kg for 3 days, we did not see any elevation of von Frey thresholds, in a similar study with the CRPS1 mouse tibia fracture model, slow subcutaneous infusion of ketamine at 2 mg/kg/day for 7 days starting at 7 weeks postfracture (ours was at 6 weeks postfracture) did produce sustained elevation of von Frey thresholds 12. So, ketamine infusion does have effectiveness in CRPS1 mice, but in our bolus protocol (2R,6R)-HNK was the more potent compound.…”

CRPS: what’s in a name? Taxonomy, epidemiology, neurologic, immune and autoimmune considerations

“…It is not uncommon for patients with CRPS to suffer cognitive impairment, labile personality, anxiety, and depression. While speculative, such CNS effects may result from the reduction in GABAergic or NMDA-mediated cortical neuroplasticity96, The foregoing symptoms are not necessarily permanent, but may merely be a part reflection of the acute phase of CRPS and in some cases do respond to multiple intravenous treatments with ketamine.…”

Biochemical and Pharmacological Characterization of a Mice Model of Complex Regional Pain Syndrome

“…After fracture, the hindlimb was wrapped (from metatarsals of hindpaw up to a spica formed around the abdomen) using casting tape (3M Scotchcast Plus; 3M, St Paul, Minnesota), so the hip, knee, and ankle were all immobile. 6,12 A window was left open over the dorsal paw and ankle to prevent constriction when postfracture edema develops. At the completion of casting, mice received buprenorphine subcutaneously (SC) at 0.05 mg/kg for analgesia and gentamicin SC (25 mg/kg) as an antibiotic (just in case there was a slight tear in the skin).…”

“…After a closed tibia fracture with 3 weeks of casting, mice develop increases in ipsilateral hindpaw volume (asymmetric edema) and ipsilateral hindpaw temperature (temperature asymmetry), although this resolves in a few weeks. 6,12 In addition, these animals develop severe mechanical allodynia and motor impairment that last for months. 6,12 So at least transiently, 4 of the 4 signs of the "Budapest criteria" are met in the mouse model.…”

“…6,12 In addition, these animals develop severe mechanical allodynia and motor impairment that last for months. 6,12 So at least transiently, 4 of the 4 signs of the "Budapest criteria" are met in the mouse model. 1 Our study seeks to further characterize the behavioral, pharmacological, and sensory neuron biochemistry of this mouse CRPS model.…”