An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee

Huggins, John P.; Smart, Trevor S.; Langman, Stephen; Taylor, Louise; Young, Tim

doi:10.1016/j.pain.2012.04.020

Cited by 345 publications

(286 citation statements)

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“…Despite the wealth of pre-clinical data on alternative EC-mediated compounds, the only major clinical trial conducted utilising an EC-directed compound looked at the ability of the selective FAAH inhibitor PF-04457845 to produce analgesia in an osteoarthritic patient population (128) . Despite significant elevations in plasma AEA, no analgesic effect was observed.…”

Section: Cannabinoids and Endocannabinoids In Clinical Trialsmentioning

confidence: 99%

Endocannabinoid system and pain: an introduction

Burston

Woodhams

2013

Proc. Nutr. Soc.

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The endocannabinoid (EC) system consists of two main receptors: cannabinoid type 1 receptor cannabinoid receptors are found in both the central nervous system (CNS) and periphery, whereas the cannabinoid type 2 receptor cannabinoid receptor is found principally in the immune system and to a lesser extent in the CNS. The EC family consists of two classes of well characterised ligands; the N-acyl ethanolamines, such as N-arachidonoyl ethanolamide or anandamide (AEA), and the monoacylglycerols, such as 2-arachidonoyl glycerol. The various synthetic and catabolic pathways for these enzymes have been (with the exception of AEA synthesis) elucidated. To date, much work has examined the role of EC in nociceptive processing and the potential of targeting the EC system to produce analgesia. Cannabinoid receptors and ligands are found at almost every level of the pain pathway from peripheral sites, such as peripheral nerves and immune cells, to central integration sites such as the spinal cord, and higher brain regions such as the periaqueductal grey and the rostral ventrolateral medulla associated with descending control of pain. EC have been shown to induce analgesia in preclinical models of acute nociception and chronic pain states. The purpose of this review is to critically evaluate the evidence for the role of EC in the pain pathway and the therapeutic potential of EC to produce analgesia. We also review the present clinical work conducted with EC, and examine whether targeting the EC system might offer a novel target for analgesics, and also potentially disease-modifying interventions for pathophysiological pain states. Pain: Endocannabinoid: AnalgesiaFrom an evolutionary standpoint, pain can be considered a necessary evil, providing a potent warning system to protect an individual from present and future harm. However, not all pain is part of this adaptive response, e.g. persistent pain after injury healing (chronic pain) or pain arising from damage to nerve tissue (neuropathic pain). Pain is the most common complaint in those seeking a physician, and a recent study suggests that pain represents the greatest economic burden of any pathological condition in the USA, with an estimated annual cost of $565-635 billion (1) . Many chronic pain states are refractory to standard analgesics, and even in those which do respond, pain control can be incomplete or only short-term in nature. Of the imperfect currently available analgesics, the most efficacious are the opioids which exploit an endogenous pain control pathway within the central nervous system. However, opioids have significant issues with tolerance, dependence, respiratory depression and opioid-induced hyperalgesia (2) . Over the past few decades, the existence of a second endogenous anti-nociceptive pathway has been revealed: the endocannabinoid (EC) system. *Corresponding author: J. J. Burston, fax +44 (0)115 823 0142, email james.burston@nottingham.ac.uk Abbreviations: 2-AG, 2-arachidonoylglycerol; ACC, anterior cingulate cortex; AEA, anandamide; CB 1 , cannab...

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Section: Cannabinoids and Endocannabinoids In Clinical Trialsmentioning

confidence: 99%

Endocannabinoid system and pain: an introduction

Burston

Woodhams

2013

Proc. Nutr. Soc.

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“…Significant biological differences between rodents and humans could lead to erroneous predictions of the activity of potential therapeutics (Fitzgerald 2009; Huggins et al. 2012; Chen et al. 2013).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

Shidahara

Ogawa

Nakamura

et al. 2016

Pharmacology Res & Perspec

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Oxaliplatin is a first‐line treatment for colorectal cancer. However, shortly following treatment, cold‐evoked hypersensitivity appears in the extremities and over time, the pain is such that oxaliplatin dosing may need to be markedly reduced or even terminated. There is currently a lack of efficacious treatments for oxaliplatin‐induced peripheral neuropathy, which is due in part to the difficulty in translating findings obtained from preclinical rodent models of chemotherapy‐induced peripheral neuropathy. Nonhuman primates (NHP) are phylogenetically closer to humans than rodents and may show drug responses that parallel those of humans. A significant decrease in tail withdrawal latency to 10°C water (“cold hypersensitivity”) was observed beginning 3 days after intravenous infusion of oxaliplatin (5 mg/kg) in Macaca fascicularis. A single treatment of duloxetine (30 mg/kg, p.o.) ameliorated oxaliplatin‐induced cold hypersensitivity, whereas pregabalin (30 mg/kg, p.o.) and tramadol (30 mg/kg, p.o.) did not. By contrast, in rats, no significant cold hypersensitivity, or increased responsiveness to acetone applied to the hind paws, was observed 3 days after the first injection of oxaliplatin (5 mg/kg, i.p., once per day, two injections). Therefore, rats were tested after six treatments of oxaliplatin, 17 days after the first treatment. All analgesics (30 mg/kg, p.o.) significantly ameliorated cold hypersensitivity in rats. The activity of analgesics in the oxaliplatin‐treated macaques parallel clinical findings. The current results indicate that the NHP could serve as a bridge species to improve translatability of preclinical findings into clinically useful treatments for oxaliplatin‐induced peripheral neuropathy.

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“…Selective FAAH inhibitors have been identified and several have been advanced for clinical development. In a proof‐of‐concept study with the FAAH inhibitor PF‐04457845 in patients with osteoarthritis, peripheral inhibition of FAAH activity was observed; however, no effect on pain perception was reported 3. Whether FAAH inhibition can be useful in other conditions remains to be evaluated.…”

mentioning

confidence: 99%

Fatty Acid Amide Hydrolase Inhibition by JNJ‐42165279: A Multiple‐Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers

Postnov

Schmidt

Pemberton

et al. 2018

Clinical Translational Sci

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Inhibition of fatty acid amide hydrolase (FAAH) potentiates endocannabinoid activity and is hypothesized to have therapeutic potential for mood and anxiety disorders and pain. The clinical profile of JNJ‐42165279, an oral selective FAAH inhibitor, was assessed by investigating the pharmacokinetics, pharmacodynamics, safety, and binding to FAAH in the brain of healthy human volunteers. Concentrations of JNJ‐42165279 (plasma, cerebrospinal fluid (CSF), urine) and fatty acid amides (FAA; plasma, CSF), and FAAH activity in leukocytes was determined in a phase I multiple ascending dose study. A positron emission tomography study with the FAAH tracer [11C]MK3168 was conducted to determine brain FAAH occupancy after single and multiple doses of JNJ‐42165279. JNJ‐42165279 administration resulted in an increase in plasma and CSF FAA. Significant blocking of brain FAAH binding of [11C]MK3168 was observed after pretreatment with JNJ‐42165279. JNJ‐42165279 produces potent central and peripheral FAAH inhibition. Saturation of brain FAAH occupancy occurred with doses ≥10 mg of JNJ‐42165279. No safety concerns were identified.

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An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee

Cited by 345 publications

References 55 publications

Endocannabinoid system and pain: an introduction

Endocannabinoid system and pain: an introduction

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

Fatty Acid Amide Hydrolase Inhibition by JNJ‐42165279: A Multiple‐Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers

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