Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients

Abstract

Central mechanisms related to referred muscle pain and temporal summation of muscular nociceptive activity are facilitated in fibromyalgia syndrome (FMS) patients. The present study assessed the effects of an NMDA-antagonist (ketamine) on these central mechanisms. FMS patients received either i.v. placebo or ketamine (0.3 mg/kg, Ketalar((R))50% decrease in pain intensity at rest by active drug on two consecutive VAS assessments). Fifteen out of 17 ketamine-responders were included in the second part of the study. Before and after ketamine or placebo, experimental local and referred pain was induced by intramuscular (i.m.) infusion of hypertonic saline (0.7 ml, 5%) into the tibialis anterior (TA) muscle. The saline-induced pain intensity was assessed on an electronic VAS, and the distribution of pain drawn by the subject. In addition, the pain threshold (PT) to i.m. electrical stimulation was determined for single stimulus and five repeated (2 Hz, temporal summation) stimuli. The pressure PT of the TA muscle was determined, and the pressure PT and pressure pain tolerance threshold were determined at three bilaterally located tenderpoints (knee, epicondyle, and mid upper trapezius). VAS scores of pain at rest were progressively reduced during ketamine infusion compared with placebo infusion. Pain intensity (area under the VAS curve) to the post-drug infusion of hypertonic saline was reduced by ketamine (-18. 4+/-0.3% of pre-drug VAS area) compared with placebo (29.9+/-18.8%, P<0.02). Local and referred pain areas were reduced by ketamine (-12. 0+/-14.6% of pre-drug pain areas) compared with placebo (126.3+/-83. 2%, P<0.03). Ketamine had no significant effect on the PT to single i.m. electrical stimulation. However, the span between the PT to single and repeated i.m. stimuli was significantly decreased by the ketamine (-42.3+/-15.0% of pre-drug PT) compared with placebo (50. 5+/-49.2%, P<0.03) indicating a predominant effect on temporal summation. Mean pressure pain tolerance from the three paired tenderpoints was increased by ketamine (16.6+/-6.2% of pre-drug thresholds) compared with placebo (-2.3+/-4.9%, P<0.009). The pressure PT at the TA muscle was increased after ketamine (42.4+/-9. 2% of pre-drug PT) compared with placebo (7.0+/-6.6%, P<0.011). The present study showed that mechanisms involved in referred pain, temporal summation, muscular hyperalgesia, and muscle pain at rest were attenuated by the NMDA-antagonist in FMS patients. It suggested a link between central hyperexcitability and the mechanisms for facilitated referred pain and temporal summation in a sub-group of the fibromyalgia syndrome patients. Whether this is specific for FMS patients or a general phenomena in painful musculoskeletal disorders is not known.

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

“…Intramuscular electrical stimulation can be used to assess the efficacy of temporal summation in muscles (Graven-Nielsen et al, 2000). Moreover, increased temporal summation is found during experimentally induced muscle hyperalgesia (Nie et al, 2006).…”

Relationships Between Skin Temperature and Temporal Summation of Heat and Cold Pain

“…Temporal summation for psychophysical and neural responses to heat is dependent on activation of unmyelinated (C) nociceptors and is dependent in part on activation of central N-methyl-D-aspartate (NMDA) receptors (Dickenson 1990;Graven-Nielsen et al 2000;Price et al 1994). Most investigations of heat pain summation have utilized triangular ramps from a Peltier device in constant contact with the skin.…”

The Use of Ketamine in Neuropathic Pain

“…Three randomized, double-blind studies have been published on the use of ketamine in fibromyalgia pain [85,87,88]. Sorensen et al [87] found that ketamine IV 0.3 mg/kg administered over 30 min resulted in a significant decrease in pain intensity during and after the test period, decreased tenderness at tender points, and increased endurance in 18 patients with fibromyalgia.…”

“…Most notably, physical functioning ability scores improved significantly in the fibromyalgia patients after ketamine infusion. GravenNielsen et al [88] studied the use of ketamine 0.3 mg/kg IV over 30 min versus placebo in 29 patients with fibromyalgia and found that of the 17 of 29 identified as ketamine responders, those patients experienced significant decrease in pain at rest, referred pain, temporal summation, and muscular hyperalgesia. Noppers et al [85] studied the use of S(?…”