The effect of PF-04457845, a potent and selective fatty acid amide hydrolase-1 (FAAH1) inhibitor, on pain due to osteoarthritis of the knee was investigated in a randomised placebo and active-controlled clinical trial. The trial involved 2 periods (separated by a 2-week washout) consisting of a 1-week wash-in phase followed by 2weeks double-blind treatment. Patients received single-blind placebo throughout the wash-in and washout periods. Patients were randomised to receive either 4mg q.d. PF-04457845 followed by placebo (or vice versa), or 500mg b.i.d. naproxen followed by placebo (or vice versa). The primary end point was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. The trial had predefined decision rules based on likelihood that PF-04457845 was better or worse than the standard of care (considered to be a 1.8 reduction in WOMAC pain score compared to placebo). A total of 74 patients were randomised to 1 of 4 treatment sequences. The mean differences (80% confidence intervals) from placebo in WOMAC pain score were 0.04 (-0.63 to 0.71) for PF-04457845 and -1.13 (-1.79 to -0.47) for naproxen, indicating that whilst naproxen seemed efficacious, PF-04457845 was not differentiated from placebo. The study was stopped at the interim analysis for futility. PF-04457845 decreased FAAH activity by >96% and substantially increased 4 endogenous substrates (fatty acid amides). PF-04457845 was well tolerated in osteoarthritis patients, and there was no evidence of cannabinoid-type adverse events. The lack of analgesic effect of FAAH1 inhibition in humans is in contrast to data from animal models. This apparent disconnect between species needs further study.

The results of this study suggest that pregabalin works in part by reducing insular glutamatergic activity, leading to a reduction of the increased functional connectivity seen between brain regions in chronic pain states. The study also supports a role for human brain imaging in the development, assessment, and personalized use of central-acting analgesics.

Abnormal processing of somatosensory inputs in the central nervous system (central sensitization) is the mechanism accounting for the enhanced pain sensitivity in the skin surrounding tissue injury (secondary hyperalgesia). Secondary hyperalgesia shares clinical characteristics with neurogenic hyperalgesia in patients with neuropathic pain. Abnormal brain responses to somatosensory stimuli have been found in patients with hyperalgesia as well as in normal subjects during experimental central sensitization. The aim of this study was to assess the effects of gabapentin, a drug effective in neuropathic pain patients, on brain processing of nociceptive information in normal and central sensitization states. Using functional magnetic resonance imaging (fMRI) in normal volunteers, we studied the gabapentin-induced modulation of brain activity in response to nociceptive mechanical stimulation of normal skin and capsaicin-induced secondary hyperalgesia. The dose of gabapentin was 1,800 mg per os, in a single administration. We found that (i) gabapentin reduced the activations in the bilateral operculoinsular cortex, independently of the presence of central sensitization; (ii) gabapentin reduced the activation in the brainstem, only during central sensitization; (iii) gabapentin suppressed stimulus-induced deactivations, only during central sensitization; this effect was more robust than the effect on brain activation. The observed drug-induced effects were not due to changes in the baseline fMRI signal. These findings indicate that gabapentin has a measurable antinociceptive effect and a stronger antihyperalgesic effect most evident in the brain areas undergoing deactivation, thus supporting the concept that gabapentin is more effective in modulating nociceptive transmission when central sensitization is present.deactivation ͉ fMRI ͉ hyperalgesia ͉ nociceptive system A fter skin injury, an increased sensitivity to mechanical stimuli occurs in a large, uninjured area surrounding the injury site (1, 2). This phenomenon is termed secondary hyperalgesia and is the consequence of neuroplastic changes leading to a state of sensitization of the central nervous system (central sensitization) (3). Secondary hyperalgesia can be experimentally induced by treating the skin with high doses of the vanilloid capsaicin (by intradermal injection or topical application).Two forms of mechanical hyperalgesia occur in the area of secondary hyperalgesia: hyperalgesia to gentle skin stroking (stroking hyperalgesia or allodynia) and hyperalgesia to punctate stimuli (punctate hyperalgesia). Although both stroking and punctate hyperalgesia are due to central sensitization, they have different psychophysical characteristics (punctate hyperalgesia is easier to establish, it encompasses a larger area and it is longer-lasting than stroking hyperalgesia). They are mediated by different primary afferents (3): stroking hyperalgesia is signaled by low-threshold mechanoreceptors (4), whereas punctate hyperalgesia is signaled by capsaicin-insensitive A-fi...

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Inhibition of fatty acid amide hydrolase‐1 (FAAH1) and the subsequent elevation of fatty acid amides has been proposed as a strategy to induce the analgesic properties of cannabinoids without the accompanying negative side effects such as impairment in cognition, motor control and predisposition to psychoses. PF‐04457845 is a potent and selective irreversible FAAH1 inhibitor which has been shown to elevate fatty acid amide concentrations in animal models and induce responses in behavioural models suggestive of analgesia. WHAT THIS STUDY ADDS • This study is the first to investigate a FAAH1 inhibitor in humans. PF‐04457845 is well tolerated following single and multiple dosing to healthy volunteers and has pharmacokinetic and pharmacodynamic properties that make nearly complete inhibition of FAAH1 possible with once daily dosing. AIMS To evaluate the pharmacology and tolerability of PF‐04457845, an orally available fatty acid amide hydrolase‐1 (FAAH1) inhibitor, in healthy subjects. METHODS Double‐blind, randomized, placebo‐controlled single and multiple rising dose studies and an open‐label, randomized, food effect study were conducted. Plasma and urine PF‐04457845 concentrations, plasma fatty acid amide concentrations and FAAH1 activity in human leucocytes were measured. Tolerability, including effects on cognitive function, were assessed. RESULTS PF‐04457845 was rapidly absorbed (median tmax 0.5–1.2 h). Exposure increased supraproportionally to dose from 0.1 to 10 mg and proportionally between 10 and 40 mg single doses. The pharmacokinetics appeared dose proportional following 14 days once daily dosing between 0.5 and 8 mg. Steady‐state was achieved by day 7. Less than 0.1% of the dose was excreted in urine. Food had no effect on PF‐04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (>97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF‐04457845. Mean fatty acid amide concentrations increased (3.5‐ to 10‐fold) to a plateau and then were maintained following PF‐04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF‐04457845 on cognitive function. PF‐04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated. CONCLUSIONS PF‐04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.

1 The modulation of the guanosine 3':5'-cyclic monophosphate (cyclic GMP)-and adenosine 3':5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase activities by the diastereomers of 8-bromoflphenyl-1,N2-ethenoguanosine 3',5'-cyclic monophosphorothioate, ((Rp)-and (Sp)-8-bromo-PET-cyclic GMPS) was investigated by use of purified protein kinases. In addition, the effects of (Rp)-8-bromo-PET-cyclic GMPS on protein phosphorylation in intact human platelets and on [3H]-noradrenaline release and neurogenic vasoconstriction in electrical field stimulated rat tail arteries were also studied. 6 The NO donor, 3-morpholinosydnonimine (SIN-1) relaxed rat tail arteries precontracted with phenylephrine (1 gM). The SIN-1 concentration-relaxation curve was shifted in a parallel manner to the right by (Rp)-8-bromo-PET-cyclic GMPS, suggesting that the relaxation was mediated by a cyclic GMP/ PKG-dependent mechanism. 7 The [3H]-noradrenaline release-enhancing effect and stimulation-induced decrease in vasoconstriction of forskolin were unaffected by (Rp)-8-bromo-PET-cyclic GMPS. Moreover, the forskolin concentrationrelaxation curve was not changed in the presence of the PKG inhibitor, suggesting a high selectivity in intact cells for PKG-over PKA-mediated effects.8 The results obtained indicate that (Rp)-8-bromo-PET-cyclic GMPS presently is the most potent and selective inhibitor of PKG and is helpful in distinguishing between cyclic GMP and cyclic AMP messenger pathways activation. Therefore, this phosphorothioate stereomer may be a useful tool for studying the role of cyclic GMP in vitro.

Objective. Increasing evidence suggests a central nervous system (CNS) component underpinning persistent pain disease states. This study was undertaken to determine regional cerebral blood flow (rCBF) changes representing ongoing pain experienced by patients with painful osteoarthritis (OA) of the carpometacarpal (CMC) joint and to examine rCBF variability across sessions. We used pulsed continuous arterial spin labeling (pCASL), a perfusion magnetic resonance imaging (MRI) technique.Methods. The study included 16 patients with CMC OA and 17 matched controls. Two pCASL scans and numerical rating scale (NRS) estimates of ongoing pain were acquired in each of two identical sessions. Voxelwise general linear model analyses were performed to determine rCBF differences between OA and control groups, rCBF differences between sessions within each group, and whether sessionwise rCBF differences were related to variability in perceived ongoing pain.Results. In the OA group, rCBF increases representing ongoing pain were identified in the primary and secondary somatosensory, insula, and cingulate cortices; thalamus; amygdala; hippocampus; and dorsal midbrain/pontine tegmentum, including the periaqueductal gray/nucleus cuneiformis. Sessionwise rCBF differences in the OA group in the postcentral, rostral/ subgenual cingulate, mid/anterior insula, prefrontal, and premotor cortices were related to changes in perceived ongoing pain. No significant sessionwise rCBF differences were observed in controls.Conclusion. This is the first quantitative endogenous perfusion MRI study of the cerebral representation of ongoing, persistent pain due to OA. Observed rCBF changes potentially indicate dysregulated CNS appraisal and modulation of pain, most likely the maladaptive neuroplastic sequelae of living with painful OA. Understanding the neural basis of ongoing pain is likely to be important in developing novel treatment strategies.Persistent pain is a major health care problem. As many as 100 million people in Europe alone experience an intractable, ongoing malaise that affects quality of life, places an increasing burden on health care resources, and costs the economy in excess of €50 billion every year (1). While multidisciplinary pain management strategies help patients cope (2), there is a recognized, unmet need for the development of novel, more

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Development of treatments for acute and chronic pain conditions remains a challenge, with an unmet need for improved sensitivity and reproducibility in measuring pain in patients. Here we used pulsed-continuous arterial spin-labelling [pCASL], a relatively novel perfusion magnetic-resonance imaging technique, in conjunction with a commonly-used post-surgical model, to measure changes in regional cerebral blood flow [rCBF] associated with the experience of being in ongoing pain. We demonstrate repeatable, reproducible assessment of ongoing pain that is independent of patient self-report. In a cross-over trial design, 16 participants requiring bilateral removal of lower-jaw third molars underwent pain-free pre-surgical pCASL scans. Following extraction of either left or right tooth, repeat scans were acquired during post-operative ongoing pain. When pain-free following surgical recovery, the pre/post-surgical scanning procedure was repeated for the remaining tooth. Voxelwise statistical comparison of pre and post-surgical scans was performed to reveal rCBF changes representing ongoing pain. In addition, rCBF values in predefined pain and control brain regions were obtained. rCBF increases (5–10%) representing post-surgical ongoing pain were identified bilaterally in a network including primary and secondary somatosensory, insula and cingulate cortices, thalamus, amygdala, hippocampus, midbrain and brainstem (including trigeminal ganglion and principal-sensory nucleus), but not in a control region in visual cortex. rCBF changes were reproducible, with no rCBF differences identified across scans within-session or between post-surgical pain sessions. This is the first report of the cerebral representation of ongoing post-surgical pain without the need for exogenous tracers. Regions of rCBF increases are plausibly associated with pain and the technique is reproducible, providing an attractive proposition for testing interventions for on-going pain that do not rely solely on patient self-report. Our findings have the potential to improve our understanding of the cerebral representation of persistent painful conditions, leading to improved identification of specific patient sub-types and implementation of mechanism-based treatments.