Neuropsychopharmacology (2011) 36, 2659–2673 & 2011 American College of Neuropsychopharmacology. All rights reserved 0893-133X/11 www.neuropsychopharmacology.org Imaging Drugs with and without Clinical Analgesic Efficacy 1,2 1,2 1,3 1,4 1,4 Jaymin Upadhyay , Julie Anderson , Adam J Schwarz , Alexandre Coimbra , Richard Baumgartner , 1,2 1,2 1,2 1,2 1,2 1,5 G Pendse , Edward George , Lauren Nutile , Diana Wallin , James Bishop , Saujanya Neni , 1,5 1,3 1,4 1,3 1,4 Gary Maier , Smriti Iyengar , Jeffery L Evelhoch , David Bleakman , Richard Hargreaves , 1,2,6 ,1,2,6 Lino Becerra and David Borsook* 1 2 3 Imaging Consortium for Drug Development; P.A.I.N. Group, Brain Imaging Center, McLean Hospital, Belmont, MA, USA; Lilly Research 4 5 Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; Merck Research Laboratories, West Point, PA, USA; Sunovion Inc., Marlborough, MA, 6 USA; Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with m-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK1 receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts. Neuropsychopharmacology (2011) 36, 2659–2673; doi:10.1038/npp.2011.156; published online 17 August 2011 Keywords: phMRI; evoked fMRI; analgesia; buprenorphine; fosaprepitant INTRODUCTION when a suitable radioactive ligand is available), and possibly an exploration of pharmacodynamic effects in experimental The identification of effective drugs for pain treatment has pain models. In early experimental pain models and larger proven to be extremely difficult (Hewitt et al, 2009; Katz scale clinical pain investigations, subjective pain ratings et al, 2008). It is often the case that pharmacological have been typically used as primary behavioral endpoints. candidate compounds are efficacious in preclinical pain Although measurements such as pain rating are critical in studies and are progressed to large-scale clinical trials, yet evaluating potential analgesics, pain ratings are intrinsically do not show clinical efficacy for pain treatment. Prior to highly variable measures (Lin et al, 2011; Nicholson, 1978; clinical trials involving patients, early clinical evaluation of Steingrimsdottir et al, 2004; Victor et al, 2008) and do not potential analgesic drugs includes safety and tolerability facilitate a comprehension of how or whether the CNS pain studies, and pharmacokinetic evaluation in healthy subjects, circuitry (ie, limbic, mesolimbic, or sensorimotor circuits) ideally an assessment of target engagement (eg, receptor are pharmacologically modulated. From pain ratings alone, occupancy through positron emission tomography (PET) it is not possible to determine whether the mechanisms of action or targets that were linked to producing analgesia in preclinical studies were successfully engaged in the target *Correspondence: Dr D Borsook, P.A.I.N. Group, Brain Imaging Center, McLean Hospital, Harvard Medical School, 115 Mill St Belmont, clinical population. Knowledge of the pharmacological MA 02478, USA, Tel: + 1 6 17 855 3772, Fax: + 1 6 17 855 2691, impact on CNS pain systems may facilitate a better E-mail: [email protected] understanding between clinically efficacious and non- Received 26 February 2011; revised 14 June 2011; accepted 15 June efficacious drug mechanisms, and doses for pain treatment. 2011 Thus, methodology and pharmacodynamic biomarkers that phMRI and evoked pain fMRI J Upadhyay et al 2660 would enable an objective evaluation of drug action on CNS whether and how the central effects of BUP and APREP pain systems may be highly valuable. could be differentiated from neurological and behavioral Previous pharmacological magnetic resonance imaging perspective. (4) To define whether and how phMRI/fMRI- (phMRI) studies have assessed the feasibility of this based measures relate to other endpoints such as drug technique as a means to define regions of increased activity concentrations in plasma and subjective pain ratings. in the human brain solely owing to drug administration (Becerra et al, 2006; Borras et al, 2004; Leppa et al, 2006). Moreover, blood oxygenation level-dependent (BOLD) MATERIALS AND METHODS functional MRI (fMRI) is a method that can be used to Twenty-four healthy, male, right-handed subjects were probe the CNS circuitry during a painful stimulus and also included in this study (age: 28.0±2.5 years old (mean± in the presence of a pharmacological compound (Iannetti SEM)). Intravenous administration of 0.2 mg/70 kg BUP et al, 2005; Wise et al, 2002). Whereas phMRI is in reference (Reckitt Benckiser Pharmaceuticals) and 96 mg/70 kg APREP to measuring the effects of pharmacological compounds on (Merck) was investigated. The present study included a the resting BOLD signal, fMRI refers to measuring the distinct 12-subject cohort for each drug investigated. In BOLD signal in response to an evoked stimulation each study cohort, subjects underwent two scanning subsequent to drug or placebo administration. Both MR- sessions on a Siemens 3T Trio machine that were B2 based methods can be implemented to objectively weeks apart, where either placebo (saline solution) or BUP/ characterize the neuroanatomical localization of an analge- APREP (drug plus saline solution) was administered sic effect for a specific pharmacological compound, and intravenously in each scanning session. A randomized, used in conjunction with standard clinical methods (ie, double-blinded, crossover design was implemented. The subjective pain ratings). This approach may be used for subjects in the BUP cohort were previously used to develop identifying clinically ineffective and effective pharmacology the general linear model (GLM) analysis for phMRI infusion for pain treatment. data (Pendse et al, 2010b). One subject in the BUP Here, drug action on the human CNS pain circuitry was cohort consumed anti-histamines on an as needed basis; evaluated by using the phMRI and fMRI methodology for however, all other subjects were on no medications. two drugs previously appraised as analgesics: a partial Subjects reported no history of pain or drug abuse. Each m-opioid agonist and k-opioid antagonist, buprenorphine subject gave informed consent prior to entering the study. (BUP) (Lutfy and Cowan, 2004), and a neurokinin-1 (NK1) The McLean Hospital Institutional Review Board approved antagonist, fosaprepitant (Once fosaprepitant (phospho- this investigation. prodrug) is intravenously administered, it is metabolized into aprepitant (APREP) (also orally active). Following this Subject Preparation metabolism, APREP binds to NK1 receptors.) (Patel and Lindley, 2003). BUP has FDA approval as an analgesic Specific study protocols were implemented for subject (Budd, 1981; Christoph et al, 2005; Cowan et al, 1977; preparation; intravenous administration of BUP, APREP, Jasinski et al, 1978; Kogel et al, 2005), however, multiple or saline; drug concentration measurements; Quantitative clinical trials of NK1 antagonists as analgesics have failed Sensory Testing (QST); imaging data acquisition; and image (Goldstein et al, 1997, 2001; Hill, 2000). Specifically, APREP preprocessing. Details on these procedures have been given failed to demonstrate significant analgesic effects in phase- under Supplementary Materials and Methods. II clinical trials. BUP and APREP are also ideal comparators given the substantial overlap in the anatomical distribution Evoked Pain (Heat) Stimulation of their primary target receptors in the brain, whereas their target receptor type and associated cellular mechan- Heat fMRI data were collected B35 and B25 min after isms of action differ. We sought to differentiate the central completion of BUP and APREP administration, respectively. neurobiological effects of these two compounds with a view During the fMRI scan, noxious heat stimuli were applied to to understanding their differential efficacy in pain treatment. the