Chronic Phantom Limb Pain: The Effects of Calcitonin, Ketamine, and Their Combination on Pain and Sensory Thresholds

Eichenberger, Urs; Neff, Frank C.; Sveticic, Gorazd; Bjørgo, Steinar; Petersen-Felix, Steen; Arendt‐Nielsen, Lars; Curatolo, Michele

doi:10.1213/ane.0b013e3181685014

Cited by 154 publications

(123 citation statements)

References 31 publications

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“…Ketamine has been used clinically as an acute anesthetic for Ͼ40 years, and it also has analgesic effects on chronic pain including neuropathic pain in humans and animals (Parsons et al, 1993;Eichenberger et al, 2008). Racemic ketamine contains the optical isomers, S-and R-ketamine, which show stereoselectivity.…”

Section: Introductionmentioning

confidence: 99%

Microglial Ca²⁺-Activated K⁺Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

Hayashi¹,

Kawaji²,

Sun³

et al. 2011

J. Neurosci.

110

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Ketamine is an important analgesia clinically used for both acute and chronic pain. The acute analgesic effects of ketamine are generally believed to be mediated by the inhibition of NMDA receptors in nociceptive neurons. However, the inhibition of neuronal NMDA receptors cannot fully account for its potent analgesic effects on chronic pain because there is a significant discrepancy between their potencies. The possible effect of ketamine on spinal microglia was first examined because hyperactivation of spinal microglia after nerve injury contributes to neuropathic pain. Optically pure S-ketamine preferentially suppressed the nerve injury-induced development of tactile allodynia and hyperactivation of spinal microglia. S-Ketamine also preferentially inhibited hyperactivation of cultured microglia after treatment with lipopolysaccharide, ATP, or lysophosphatidic acid. We next focused our attention on the Ca 2ϩ -activated K ϩ (K Ca ) currents in microglia, which are known to induce their hyperactivation and migration. S-Ketamine suppressed both nerve injury-induced large-conductance K Ca (BK) currents and 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619)-induced BK currents in spinal microglia. Furthermore, the intrathecal administration of charybdotoxin, a K Ca channel blocker, significantly inhibited the nerve injury-induced tactile allodynia, the expression of P2X 4 receptors, and the synthesis of brainderived neurotrophic factor in spinal microglia. In contrast, NS1619-induced tactile allodynia was completely inhibited by S-ketamine. These observations strongly suggest that S-ketamine preferentially suppresses the nerve injury-induced hyperactivation and migration of spinal microglia through the blockade of BK channels. Therefore, the preferential inhibition of microglial BK channels in addition to neuronal NMDA receptors may account for the preferential and potent analgesic effects of S-ketamine on neuropathic pain.

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Section: Introductionmentioning

confidence: 99%

Microglial Ca²⁺-Activated K⁺Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

Hayashi¹,

Kawaji²,

Sun³

et al. 2011

J. Neurosci.

110

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“…The experimental study, in contrast to clinical experience, showed a rapid analgesic onset (approximately 80 minutes) and a short duration (up to 180 minutes). The effect of CT (IV 200 IE) in patients with chronic phantom pain did not show any modulation of pain thresholds to electrical (temporal summation), thermal, and pressure stimulation, 32 indicating that the pain parameters evaluated may not represent the possible pain mechanisms affected by CT. Experimental pain models, such as pressure algometry, have been used in clinical studies.…”

Section: Clinical Settingmentioning

confidence: 93%

“…There is one human experimental clinical study on chronic phantom limb pain 32 where CT, CT and ketamine in combination, or ketamine alone was given. Together with the clinical pain parameters some experimental pain …”

Section: Compounds Interacting With the Analgesic Effect Of Calcitoninmentioning

confidence: 99%

Role of calcitonin in management of musculoskeletal pain

et al. 2009

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Calcitonin was discovered more than 40 years ago and the scientific community continues to debate the primary and secondary pharmacological actions of calcitonin. Presently calcitonin is accepted by agencies only for treatment of osteoporosis, but many studies have indicated an effect on pain in many different experimental settings both pre-clinically and clinically. The effects of calcitonin on clinical pain conditions have received increasing attention in the past decades, although a consensus on mode of action and potential indications still has to be reached. Several key advances in the pain field may enable a deeper understanding of the putative analgesic effects of calcitonin. Most studies have focused on the effect of calcitonin on musculoskeletal pain problems. Ample lines of independent evidence suggest that calcitonin exerts putative analgesic effects. Well-designed clinical trials, particularly in the field of musculoskeletal pain, are needed to validate fragmented evidence of analgesic actions. This in combination with advanced mechanism-based pain assessment tools can provide new insight into the role of calcitonin, alone or in combination with other compounds, in management of pain.

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“…There was also significant improvement 24 h post-infusion of the effect of pain on their general activity and enjoyment of life over the placebo group. Ketamine administered intravenously in doses ranging from 7 mcg/kg/min to 0.4 mg/kg for 45-60 min also showed efficacy in decreasing residual limb and phantom pain in two randomized, double-blind crossover studies [83,84].…”

Section: Literature On Ketamine Use In Ischemic Limb Pain and Phantommentioning

confidence: 97%

The Use of Ketamine in Neuropathic Pain

O’Brien

Pangarkar

Prager

2014

Curr Phys Med Rehabil Rep

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Hyperactivity of N-methyl-D-aspartate (NMDA) receptors may be one of the factors in the genesis of neuropathic pain (NP). Ketamine is a dissociative anesthetic and analgesic that is the most potent NMDA receptor antagonist currently available for human use. There is a growing body of literature for three decades suggesting efficacy of subanaesthetic doses of ketamine in the treatment of NP, particularly the pain in complex regional pain syndromes. The primary limitations of ketamine use are secondary to psychotomimetic and, to a lesser extent, sympathetic activation. The purpose of this article is to review the history, pharmacology, pharmacodynamics, clinical benefits, and limitations of ketamine for treatment of NP. Methods of administration and management of adverse effects are highlighted based on the clinical experience of the authors.

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Chronic Phantom Limb Pain: The Effects of Calcitonin, Ketamine, and Their Combination on Pain and Sensory Thresholds

Cited by 154 publications

References 31 publications

Microglial Ca²⁺-Activated K⁺Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

Microglial Ca²⁺-Activated K⁺Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

Role of calcitonin in management of musculoskeletal pain

The Use of Ketamine in Neuropathic Pain

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Chronic Phantom Limb Pain: The Effects of Calcitonin, Ketamine, and Their Combination on Pain and Sensory Thresholds

Cited by 154 publications

References 31 publications

Microglial Ca2+-Activated K+Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

Microglial Ca2+-Activated K+Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

Role of calcitonin in management of musculoskeletal pain

The Use of Ketamine in Neuropathic Pain

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Product

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Microglial Ca²⁺-Activated K⁺Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

Microglial Ca²⁺-Activated K⁺Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain