Relief of Neuropathic Pain Through Epidermal Growth Factor Receptor Inhibition: A Randomized Proof-of-Concept Trial.

OBJECTIVE: Case reports and a case series have described relief of neuropathic pain (NP) after treatment with epidermal growth factor receptor inhibitors (EGFR-Is). These observations are supported by preclinical findings. The aim of this trial was to explore a potential clinical signal supporting the therapeutic efficacy of EGFR-Is in NP. METHODS: In a proof-of-concept trial using a randomized, double-blind, placebo-controlled design, 14 patients with severe, chronic, therapy-resistant NP due to compressed peripheral nerves or complex regional pain syndrome were randomized to receive a single infusion of the EGFR-I cetuximab and placebo in crossover design, followed by a single open-label cetuximab infusion. RESULTS: The mean reduction in daily average pain scores three to seven days after single-blinded cetuximab infusion was 1.73 points (90% confidence interval [CI] = 0.80 to 2.66), conferring a 1.22-point greater reduction than placebo (90% CI = -0.10 to 2.54). Exploratory analyses suggested that pain reduction might be greater in the 14 days after treatment with blinded cetuximab than after placebo. The proportion of patients who reported ≥50% reduction in average pain three to seven days after cetuximab was 36% (14% after placebo), and comparison of overall pain reduction suggests a trend in favor of cetuximab. Skin rash (grade 1-2) was the most frequent side effect (12/14, 86%). CONCLUSIONS: This small proof-of-concept evaluation of an EGFR-I against NP did not provide statistical evidence of efficacy. However, substantial reductions in pain were reported, and confidence intervals do not rule out a clinically meaningful treatment effect. Evaluation of EGFR-I against NP therefore warrants further investigation.

A Targeted Mutation Disrupting Mitochondrial Complex IV Function in Primary Afferent Neurons Leads to Pain Hypersensitivity Through P2Y1 Receptor Activation.

As mitochondrial dysfunction is evident in neurodegenerative disorders that are accompanied by pain, we generated inducible mutant mice with disruption of mitochondrial respiratory chain complex IV, by COX10 deletion limited to sensory afferent neurons through the use of an Advillin Cre-reporter. COX10 deletion results in a selective energy-deficiency phenotype with minimal production of reactive oxygen species. Mutant mice showed reduced activity of mitochondrial respiratory chain complex IV in many sensory neurons, increased ADP/ATP ratios in dorsal root ganglia and dorsal spinal cord synaptoneurosomes, as well as impaired mitochondrial membrane potential, in these synaptoneurosome preparations. These changes were accompanied by marked pain hypersensitivity in mechanical and thermal (hot and cold) tests without altered motor function. To address the underlying basis, we measured Ca2+ fluorescence responses of dorsal spinal cord synaptoneurosomes to activation of the GluK1 (kainate) receptor, which we showed to be widely expressed in small but not large nociceptive afferents, and is minimally expressed elsewhere in the spinal cord. Synaptoneurosomes from mutant mice showed greatly increased responses to GluK1 agonist. To explore whether altered nucleotide levels may play a part in this hypersensitivity, we pharmacologically interrogated potential roles of AMP-kinase and ADP-sensitive purinergic receptors. The ADP-sensitive P2Y1 receptor was clearly implicated. Its expression in small nociceptive afferents was increased in mutants, whose in vivo pain hypersensitivity, in mechanical, thermal and cold tests, was reversed by a selective P2Y1 antagonist. Energy depletion and ADP elevation in sensory afferents, due to mitochondrial respiratory chain complex IV deficiency, appear sufficient to induce pain hypersensitivity, by ADP activation of P2Y1 receptors.

EP2 receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis.

Endometriosis is an incurable gynecological disorder characterized by debilitating pain and the establishment of innervated endometriosis lesions outside the uterus. In a preclinical mouse model of endometriosis we demonstrated overexpression of the PGE2-signaling pathway (including COX-2, EP2, EP4) in endometriosis lesions, dorsal root ganglia (DRG), spinal cord, thalamus and forebrain. TRPV1, a PGE2-regulated channel in nociceptive neurons was also increased in the DRG. These findings support the concept that an amplification process occurs along the pain neuroaxis in endometriosis. We then tested TRPV1, EP2, and EP4 receptor antagonists: The EP2 antagonist was the most efficient analgesic, reducing primary hyperalgesia by 80% and secondary hyperalgesia by 40%. In this study we demonstrate reversible peripheral and central hyperalgesia in mice with induced endometriosis.

A novel model of combined neuropathic and inflammatory pain displaying long-lasting allodynia and spontaneous pain-like behaviour.

Many clinical cases of chronic pain exhibit both neuropathic and inflammatory components. In contrast, most animal models of chronic pain focus on one type of injury alone. Here we present a novel combined model of both neuropathic and inflammatory pain and characterise its distinctive properties. This combined model of chronic constriction injury (CCI) and intraplantar Complete Freund's Adjuvant (CFA) injection results in enhanced mechanical allodynia, thermal hyperalgesia, a static weight bearing deficit, and notably pronounced spontaneous foot lifting (SFL) behaviour (which under our conditions was not seen in either individual model and may reflect ongoing/spontaneous pain). Dorsal root ganglion (DRG) expression of Activating Transcription Factor-3 (ATF-3), a marker of axonal injury, was no greater in the combined model than CCI alone. Initial pharmacological characterisation of the new model showed that the SFL was reversed by gabapentin or diclofenac, typical analgesics for neuropathic or inflammatory pain respectively, but not by mexiletine, a Na(+) channel blocker effective in both neuropathic and inflammatory pain models. Static weight bearing deficit was moderately reduced by gabapentin, whereas only diclofenac reversed mechanical allodynia. This novel animal model of chronic pain may prove a useful test-bed for further analysing the pharmacological susceptibility of complicated clinical pain states.