Intrathecal Baclofen in Pain Management

Slonimski, Marc; Abram, Stephen E.; Zuniga, Robert

doi:10.1097/00115550-200405000-00014

Cited by 65 publications

(28 citation statements)

References 53 publications

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“…Baclofen, a γ‐aminobutyric acid (GABA) B agonist, acts on the spinal GABA‐B receptor that can regulate the response to acute high‐intensity input, the facilitated pain state associated with tissue injury, and the component of the hyperalgesia and allodynia resulting from nerve or spinal injury. The drug produces powerful antinociceptive effects in experimental animal models at doses that produce few or no motor‐blocking effects (103).…”

Section: Other Nonopioid Agents Used Intrathecallymentioning

confidence: 99%

“…It has been increasingly used for the treatment of children (107) with cerebral palsy or adults with severe spasticity due to spinal cord injuries or multiple sclerosis that does not respond to oral therapy (103,108,109). Baclofen is rarely used as an analgesic drug in patients without spasticity, but recent evidence suggests that the drug, given IT, may have therapeutic value in the management of patients even without spasticity (103). In one study ( N = 48), IT baclofen was administered as an adjunct treatment in patients with neuropathic pain of peripheral origin who responded poorly to SCS (105).…”

Section: Other Nonopioid Agents Used Intrathecallymentioning

confidence: 99%

See 1 more Smart Citation

Polyanalgesic Consensus Conference 2007: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel

Deer¹,

Krames²,

Hassenbusch³

et al. 2007

Neuromodulation: Technology at the Neural Interface

220

248

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Section: Other Nonopioid Agents Used Intrathecallymentioning

confidence: 99%

Section: Other Nonopioid Agents Used Intrathecallymentioning

confidence: 99%

Polyanalgesic Consensus Conference 2007: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel

Deer¹,

Krames²,

Hassenbusch³

et al. 2007

Neuromodulation: Technology at the Neural Interface

220

248

View full text Add to dashboard Cite

“…5). The model shows the potential importance of the neurochemical mechanism identified herein as this component appears as a possible link between the spinal SP-rNK1 system and activities of NMDA receptor and GABA A receptors that are crucial for sensory processes (2,18,19). We do not contend that the model proposed is an exhaustive one.…”

Section: Discussionmentioning

confidence: 84%

“…Consequently, by decreasing locally 3␣,5␣-THP concentration in the spinal sensory circuit, the SP-rNK1 system may indirectly interfere with the GABAergic transmission, which is pivotal for the regulation of nociceptive mechanisms (17)(18)(19). The fact that 3 h were sufficient for SP at 10 Ϫ6 M to provoke a Ϫ70% reduction in the amount of 3␣,5␣-THP released in the DH suggests the existence of a down-regulatory mechanism of 3␣,5␣-THP formation during the acute phase of pain processing, which may decrease the GABAergic tone and facilitate the occurrence of spinal hyperexcitability and hyperalgesia.…”

Section: Discussionmentioning

confidence: 99%

“…Investigations of rats submitted to neuropathic pain provoked by sciatic nerve ligature allowed the observation of hyperproduction of 3␣,5␣-THP in spinal sensory networks under the painful state (16). Because 3␣,5␣-THP is a potent stimulator of GABA A receptors, which play a pivotal role in the modulation of pain sensation (12,13,(17)(18)(19), increase of 3␣,5␣-THP formation in the DH appeared to be an endogenous mechanism triggered by neuropathic animals to cope with the chronic pain (16). Therefore, we found it important to determine neuroanatomical and functional interactions between the spinal SP-rNK1 system controlling pain transmission and the process of progesterone conversion into 5␣-DHP and 3␣,5␣-THP occurring in DH neurons, to clarify neurochemical pathways involved in nociception.…”

mentioning

confidence: 99%

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Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception

Patte‐Mensah

Kibaly

Mensah‐Nyagan

2005

Proc. Natl. Acad. Sci. U.S.A.

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A crucial biochemical reaction in vertebrates is progesterone conversion into neuroactive metabolites such as dihydroprogesterone (5␣-DHP) and tetrahydroprogesterone (3␣,5␣-THP), which regulate several neurobiological processes, including stress, depression, neuroprotection, and analgesia. 3␣,5␣-THP is a potent stimulator of type A receptors of GABA, the main inhibitory neurotransmitter. Here, we show that in the spinal sensory circuit progesterone conversion into 5␣-DHP and 3␣,5␣-THP is inhibited dose-dependently by substance P (SP), a major mediator of painful signals. We developed a triple-labeling approach coupled with multichannel confocal microscope analysis, which revealed that, in the spinal cord (SC), SP-releasing afferents project on sensory neurons expressing simultaneously neurokinin 1 receptors (rNK1) and key enzymes catalyzing progesterone metabolism. Evidence for a potent inhibitory effect of SP on 5␣-DHP and 3␣,5␣-THP formation in the SC was provided by combining pulse-chase experiments using neurosteroid ͉ pain ͉ spinal cord ͉ steroids ͉ nervous system T he spinal cord (SC) is a pivotal structure controlling many neurophysiological activities, including somatosensory transmission, locomotion, reflexes, and neurovegetative functions. Primary sensory inputs arising from receptors in various areas of the body are integrated in multisynaptic relays in the SC that convey these inputs toward the brain (1, 2). A variety of molecules, including glutamate, substance P (SP), neurotrophins, calcitonin-gene related peptide, and adenosine triphosphate, are thought to be involved in the central transmission of sensory messages (2, 3). Among these neuromodulators, SP, the role of which is clearly established and well documented, is considered as a key neuropeptide mediating nociceptive message transmission from peripheral afferents to sensory neurons located in the SC dorsal horn (DH) (4-6). In particular, it has been shown that projection neurons in lamina I of rat DH expressing neurokinin 1 receptors (rNK1s) are selectively innervated by SP-containing afferents and respond to noxious stimulation (7). Direct structural-functional evidence for SP-mediated nociceptive transmission has also been provided in cats by multidisciplinary studies that combined various approaches, including intracellular recording from DH neurons in vivo, characterization of these neurons on the basis of their responses to peripheral noxious stimulation, cellular labeling by horseradish peroxidase, and electron microscopic identification of synaptic contacts (6-9). Moreover, intrathecal injection of SP conjugated to the cytotoxin saporin selectively destroyed DH neurons bearing rNK1 and strongly reduced hyperalgesia after capsaicin treatment, indicating that spinal rNK1 neurons are important for the development of hyperalgesia (4, 5). However, intracellular changes or neurochemical modifications that spinal rNK1 neurons undergo during nociception are poorly characterized. This situation hampers the understanding of spinal mechanisms in...

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Single‐ and Multiple‐Dose Safety, Tolerability, and Pharmacokinetic Profiles of ASP8062: Results From 2 Phase 1 Studies

Walzer

Marek

et al. 2020

Clinical Pharm in Drug Dev

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ASP8062 is an orally active γ‐amino‐butyric acid type B (GABAB) receptor positive allosteric modulator currently in phase 2 development. Safety and pharmacokinetic (PK) profiles of ASP8062 were evaluated in 2 studies in healthy subjects. The first study (a first‐in‐human study) evaluated single ascending doses (SAD) of ASP8062. The second study was composed of 2 parts: part 1 evaluated multiple ascending doses (MAD) of ASP8062 for 14 days, and part 2 was a single‐dose arm to assess the PK of ASP8062 in cerebrospinal fluid (CSF). Fifty‐six men (SAD) and 56 subjects (24 women and 32 men; MAD) were enrolled. Across the SAD dosing range, area under the concentration‐time curve was dose proportional; increases in maximum plasma concentration appeared linear but were slightly less than dose proportional. Time to maximal concentration and half‐life were 1‐4 hours and ∼40‐50 hours, respectively; no food effect was observed. ASP8062 PK properties at steady state were similar to those following a single dose. Steady state was achieved by ∼day 9 with ∼2‐fold accumulation, and ASP8062 was detected in CSF. ASP8062 was well tolerated; no clear evidence of ASP8062's effects on safety, cognition, drug withdrawal, or suicidal ideation/behavior was observed. These data support the development of ASP8062 in indications where the GABAB receptor is a target.

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Intrathecal Baclofen in Pain Management

Cited by 65 publications

References 53 publications

Polyanalgesic Consensus Conference 2007: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel

Polyanalgesic Consensus Conference 2007: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel

Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception

Single‐ and Multiple‐Dose Safety, Tolerability, and Pharmacokinetic Profiles of ASP8062: Results From 2 Phase 1 Studies

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