Intrathecal Gabapentin to Treat Chronic Intractable Noncancer Pain

Rauck, Richard; Coffey, Robert J.; Schultz, David M.; Wallace, Mark; Webster, Lynn R.; McCarville, Sally E.; Grigsby, Eric; Page, Linda M.

doi:10.1097/aln.0b013e3182a10fbf

Cited by 51 publications

(31 citation statements)

References 33 publications

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“…Drugs such as gabapentin and pregabalin 200 (see Management) target the α 2 δ subunit of the voltage-dependent calcium channels that are overexpressed in patients with neuropathic pain. When given intrathecally, gabapentin inhibited hypersensitivity in animal models 201 but has failed to show positive results in humans 202 .…”

Section: Figurementioning

confidence: 99%

Neuropathic pain

Colloca

Ludman

Bouhassira

et al. 2017

Nat Rev Dis Primers

1,622

1,364

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Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aβ, Aδ and C fibres) and central neurons, and affects 7–10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain.

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Section: Figurementioning

confidence: 99%

Neuropathic pain

Colloca

Ludman

Bouhassira

et al. 2017

Nat Rev Dis Primers

1,622

1,364

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“…A recent clinical trial failed to show efficacy of intrathecal gabapentin in patients with chronic non-cancer pain [22], in contrast to documented efficacy with systemic administration. We previously suggested that systemic gabapentin acts primarily to produce analgesia by increasing descending noradrenergic inhibition, as witnessed by increased noradrenaline concentration in cerebrospinal fluid in patients with chronic orthopedic pain who received gabapentin compared to placebo [7].…”

Section: Discussionmentioning

confidence: 99%

“…A focus on the spinal cord as a key site of pain transmission and plasticity after nerve injury has led to the theory that gabapentin primarily acts on spinal pain mechanisms. However, a recent clinical study questioned this theory by demonstrating a complete lack of clinical efficacy of intrathecal gabapentin in patients with chronic pain [22], despite the known efficacy of oral gabapentin in this patient population. We and others have proposed a different gabapentin’s action on descending inhibition.…”

Section: Introductionmentioning

confidence: 99%

Gabapentin loses efficacy over time after nerve injury in rats: role of glutamate transporter-1 in the locus coeruleus

Kimura

Eisenach

Hayashida

2016

PAIN

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Despite being one of the first-choice analgesics for chronic neuropathic pain, gabapentin sometimes fails to provide analgesia, but the mechanisms for this lack of efficacy is unclear. Rats with nerve injury including L5-L6 spinal nerve ligation (SNL) respond uniformly and well to gabapentin, but many of these studies are performed within just a few weeks of injury, questioning their relevance to chronic neuropathic pain. In this study, intraperitoneal gabapentin showed a time-dependently reduction in antihypersensitivity after SNL, associated with downregulation of astroglial glutamate transporter-1 (GLT-1) in the locus coeruleus (LC). Consistently, SNL also time-dependently increased basal but masked gabapentin-induced noradrenergic neuronal activity in the LC. In rats 2 weeks after SNL, knock-down of GLT-1 in the LC reduced the antihypersensitivity effect of gabapentin. In rats 8 weeks after SNL, increasing GLT-1 expression by histone deacetylase inhibitor valproate restored the antihypersensitivity effect of gabapentin, associated with restored gabapentin-induced noradrenergic neuronal activity in the LC and subsequent spinal noradrenaline release. Knock-down of GLT-1 in the LC reversed the effect of valproate to restore gabapentin-induced antihypersensitivity. In addition, the antihypersensitivity effect of the intrathecal α2-adrenoceptor agonist clonidine also decreased with time after SNL injury. These results suggest that downregulation of GLT-1 in the LC and reduced spinal noradrenergic inhibition contribute to impaired analgesic efficacy from gabapentin in chronic neuropathic pain and that valproate can rescue this impaired efficacy.

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“…30 The antiallodynic effects of gabapentin was mediated by blocking surface trafficking of a2d1 and a2d2 heteromeric protein subunits of voltage-gated calcium channels in primary sensory and dorsal horn neurons, 26 which suggests a strong theoretical rationale for intrathecal administration of gabapentin, despite the recent failure of a phase 2 clinical trial. 31 When administered within appropriate therapeutic windows and in a slow titration, intrathecal ziconotide is recommended as a first-line option after conservative medical treatments have failed. 32 The adverse effects associated with off-target blockade of N-and T-type calcium channels may limit the effectiveness of these compounds; for example, ziconotide must be delivered intrathecally to limit the neurocognitive, psychiatric, and ataxic side effects that can be encountered with systematic routes of administration.…”

Section: Physiology and Pathophysiology Of The Primary Sensory Neuronmentioning

confidence: 99%

The Dorsal Root Ganglion as a Therapeutic Target for Chronic Pain

Liem

Dongen

Huygen

et al. 2016

Regional Anesthesia and Pain Medicine

100

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Chronic neuropathic pain is a widespread problem with negative personal and societal consequences. Despite considerable clinical neuroscience research, the goal of developing effective, reliable, and durable treatments has remained elusive. The critical role played by the dorsal root ganglion (DRG) in the induction and maintenance of chronic pain has been largely overlooked in these efforts, however. It may be that, by targeting this site, robust new options for pain management will be revealed. This review summarizes recent advances in the knowledge base for DRG-targeted treatments for neuropathic pain:• Pharmacological options including the chemical targeting of voltage-dependent calcium channels, transient receptor potential channels, neurotrophin production, potentiation of opioid transduction pathways, and excitatory glutamate receptors.• Ablation or modulation of the DRG via continuous thermal radiofrequency and pulsed radiofrequency treatments.• Implanted electrical neurostimulator technologies.• Interventions involving the modification of DRG cellular function at the genetic level by using viral vectors and gene silencing methods.

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Intrathecal Gabapentin to Treat Chronic Intractable Noncancer Pain

Cited by 51 publications

References 33 publications

Neuropathic pain

Neuropathic pain

Gabapentin loses efficacy over time after nerve injury in rats: role of glutamate transporter-1 in the locus coeruleus

The Dorsal Root Ganglion as a Therapeutic Target for Chronic Pain

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