The effect of a combination of gabapentin and donepezil in an experimental pain model in healthy volunteers: Results of a randomized controlled trial

Boyle, Yvonne; Fernando, Disala; Kurz, Hazel; Miller, Sam; Zucchetto, Mauro; Storey, James R.

doi:10.1016/j.pain.2014.09.003

Cited by 24 publications

(18 citation statements)

References 25 publications

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“…In part II, pregabalin showed positive effects on cold pressor (PDT and PTT), electrical single stimulus (PTT), CPM (PDT) and thermal heat pain in normal skin. Alpha‐2δ ligands have previously been shown to affect pain in human pain models; gabapentin showed positive effects on pain in an electrical hyperalgesia model in healthy subjects . Conversely, gabapentin failed to show effects on heat PDT in healthy subjects .…”

Section: Discussionmentioning

confidence: 99%

The use of a battery of pain models to detect analgesic properties of compounds: a two‐part four‐way crossover study

Okkerse

Amerongen

Kam

et al. 2017

Brit J Clinical Pharma

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AIMThe aim was to investigate the ability of a battery of pain models to detect analgesic properties of commonly used analgesics in healthy subjects. METHODSThe battery consisted of tests eliciting electrical, mechanical and thermal (contact heat and cold pressor)-pain and included a UVB model, the thermal grill illusion and a paradigm of conditioned pain modulation. Subjects were administered fentanyl 3 μg kg -1 , phenytoin 300 mg, (S)-ketamine 10 mg and placebo (part I), or imipramine 100 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo (part II). Pain measurements were performed at baseline and up to 10 h post-dose. Endpoints were analysed using a mixed model analysis of variance. RESULTSSixteen subjects (8 female) completed each part. The pain tolerance threshold (PTT) for electrical stimulation was increased (all P < 0.05) compared to placebo for (S)-ketamine (+10.1%), phenytoin (+8.5%) and pregabalin (+10.8%). The PTT for mechanical pain was increased by pregabalin (+14.1%). The cold pressor PTT was increased by fentanyl (+17.1%) and pregabalin (+46.4%). Normal skin heat pain detection threshold was increased by (S)-ketamine (+3.3%), fentanyl (+2.8%) and pregabalin (+4.1%). UVB treated skin pain detection threshold was increased by fentanyl (+2.6%) and ibuprofen (+4.0%). No differences in conditioned pain modulation were observed. CONCLUSIONThis study shows that these pain models are able to detect changes in pain thresholds after administration of different classes of analgesics in healthy subjects. The analgesic compounds all showed a unique profile in their effects on the pain tasks administered. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2017) 83 976-990 976

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Section: Discussionmentioning

confidence: 99%

The use of a battery of pain models to detect analgesic properties of compounds: a two‐part four‐way crossover study

Okkerse

Amerongen

Kam

et al. 2017

Brit J Clinical Pharma

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“…99,107 Area of allodynia was reduced. 108,109 Contrasting effects were also seen after sural nerve stimulation. 108,110 The continuous electrical stimulation model induces both central sensitisation and continuous C-fibre mediated pain.…”

Section: Effect On Inflammation and Postoperative Pain Modelsmentioning

confidence: 90%

“…108,109 Contrasting effects were also seen after sural nerve stimulation. 108,110 The continuous electrical stimulation model induces both central sensitisation and continuous C-fibre mediated pain. Gabapentin increased the current strength required to induce pain and reduced area of secondary hyperalgesia but did not influence pain detection threshold in area of hyperalgesia.…”

Section: Effect On Inflammation and Postoperative Pain Modelsmentioning

confidence: 90%

“…114 Significant number of healthy subjects in experimental studies experienced adverse effects, particularly with increasing dosage. 99,103,104,108,109 Gabapentinoids are often utilised in enhanced recovery pathways, particularly for hip and knee replacement surgery. These procedures are often performed in the elderly, who may be more vulnerable to the potential side effects of gabapentinoids.…”

Section: Continuedmentioning

confidence: 99%

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Analgesic mechanisms of gabapentinoids and effects in experimental pain models: a narrative review

Chincholkar

2018

British Journal of Anaesthesia

138

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The focus of perioperative pain management should be to attempt to minimise the nociceptive input and reduce the risk of transition to central sensitisation. Gabapentinoids are being increasingly used as adjuncts for management of perioperative pain. Although gabapentinoids are classed as calcium channel blockers, their mechanisms of action are poorly understood. The analgesic effect in neuropathic pain is well evidenced but the role in postoperative pain is less certain. Medline and EMBASE database searches were conducted to identify studies relating to mechanisms of action and effects in experimental animal models of inflammatory and postoperative pain and human models of experimental pain. The effects of gabapentinoids may be attributed to depression of dorsal horn sensitivity through a multitude of mechanisms. They inhibit calcium mediated neurotransmitter release through effects on α2δ-1 subunits. They inhibit forward trafficking of α2δ-1 from the dorsal root ganglion, their recycling from endosomal compartments, thrombospondin mediated processes and stimulate glutamate uptake by excitatory amino acid transporters. Mechanisms not directly related to neurotransmitter release at dorsal horn include inhibition of descending serotonergic facilitation, stimulation of descending inhibition, anti-inflammatory actions, and influence on the affective component of pain. Gabapentinoids are effective analgesics in most animal models of inflammation and postoperative pain but effects in human models are variable.

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“…Somewhat surprisingly, it has proven difficult in patient populations to demonstrate consistently an antinociceptive action of gabapentinoids in tests of mechanical sensitivity, which is presumed to reflect an action at the spinal cord. In fact, there are very few randomized control trials that examined this question; some found an antiallodynic action of systemic GP, 1 , 5 , 6 whereas other studies did not. 26 Interestingly, in the latter study, the patients in whom pregabalin was effective (against pain of HIV neuropathy) were the most sensitive in a test of pin-prick hyperalgesia.…”

Section: Discussionmentioning

confidence: 99%

Pain relief by supraspinal gabapentin requires descending noradrenergic inhibitory controls

Juarez-Salinas

Bráz

Hamel

2018

PR9

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Introduction:Gabapentin regulates pain processing by direct action on primary afferent nociceptors and dorsal horn nociresponsive neurons. Through an action at supraspinal levels, gabapentin also engages descending noradrenergic inhibitory controls that indirectly regulate spinal cord pain processing. Although direct injection of gabapentin into the anterior cingulate cortex provides pain relief independent of descending inhibitory controls, it remains unclear whether that effect is representative of what occurs when gabapentin interacts at multiple brain loci, eg, after intracerebroventricular (i.c.v.) injection.Methods:We administered gabapentin i.c.v. in a mouse model of chemotherapy (paclitaxel)-induced neuropathic pain. To distinguish spinal from supraspinally processed features of the pain experience, we examined mechanical hypersensitivity and assessed relief of pain aversiveness using an analgesia-induced conditioned place preference paradigm.Results:Paclitaxel-treated mice showed a preference for a 100-μg i.c.v. gabapentin-paired chamber that was accompanied by reduced mechanical allodynia, indicative of concurrent engagement of descending controls. As expected, the same dose in uninjured mice did not induce place preference, demonstrating that gabapentin, unlike morphine, is not inherently rewarding. Furthermore, a lower dose of supraspinal gabapentin (30 μg), which did not reverse mechanical allodynia, did not induce conditioned place preference. Finally, concurrent injections of i.c.v. gabapentin (100 μg) and intrathecal yohimbine, an α2-receptor antagonist, blocked preference for the gabapentin-paired chamber.Conclusion:We conclude that pain relief, namely a reduction of pain aversiveness, induced by supraspinal gabapentin administered by an i.c.v. route is secondary to its activation of descending noradrenergic inhibitory controls that block transmission of the “pain” message from the spinal cord to the brain.

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The effect of a combination of gabapentin and donepezil in an experimental pain model in healthy volunteers: Results of a randomized controlled trial

Cited by 24 publications

References 25 publications

The use of a battery of pain models to detect analgesic properties of compounds: a two‐part four‐way crossover study

The use of a battery of pain models to detect analgesic properties of compounds: a two‐part four‐way crossover study

Analgesic mechanisms of gabapentinoids and effects in experimental pain models: a narrative review

Pain relief by supraspinal gabapentin requires descending noradrenergic inhibitory controls

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