Elsevier

NeuroImage

Volume 59, Issue 4, 15 February 2012, Pages 3762-3773
NeuroImage

Modulation of CNS pain circuitry by intravenous and sublingual doses of buprenorphine

https://doi.org/10.1016/j.neuroimage.2011.11.034Get rights and content

Abstract

Buprenorphine (BUP) is a partial agonist at μ-, δ- and ORL1 (opioid receptor-like)/nociceptin receptors and antagonist at the κ-opioid receptor site. BUP is known to have both analgesic as well as antihyperalgesic effects via its central activity, and is used in the treatment of moderate to severe chronic pain conditions. Recently, it was shown that intravenous (IV) administration of 0.2 mg/70 kg BUP modulates the blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) response to acute noxious stimuli in healthy human subjects. The present study extends these observations by investigating the effects of BUP dose and route of administration on central nervous system (CNS) pain circuitry. Specifically, the modulation of evoked pain BOLD responses and resting state functional connectivity was measured following IV (0.1 and 0.2 mg/70 kg) and sublingual (SL) (2 mg) BUP administration in healthy human subjects. While 0.1 mg/70 kg IV BUP is sub-analgesic, both 0.2 mg/70 kg IV BUP and 2.0 mg SL BUP are analgesic doses of the drug. Evoked BOLD responses were clearly modulated in a dose-dependent manner. The analgesic doses of BUP by both routes of administration yielded a potentiation in limbic/mesolimbic circuitry and attenuation in sensorimotor/sensory-discriminative circuitry. In addition, robust decreases in functional connectivity between the putamen and the sensorimotor/sensory-discriminative structures were observed at the two analgesic doses subsequent to measuring the maximum plasma BUP concentrations (Cmax). The decreases in functional connectivity within the sensorimotor/sensory-discriminative circuitry were also observed to be dose-dependent in the IV administration cohorts. These reproducible and consistent functional CNS measures at clinically effective doses of BUP demonstrate the potential of evoked pain fMRI and resting-state functional connectivity as objective tools that can inform the process of dose selection. Such methods may be useful during early clinical phase evaluation of potential analgesics in drug development.

Highlights

► Dose response measurement of evoked pain BOLD signal for 0.1 and 0.2 mg/70 kg IV BUP. ► Comparison of evoked pain BOLD responses due to 0.2 mg/70 kg IV and 2.0 mg SL BUP. ► Characterization of dose response using functional connectivity for 2 IV BUP doses. ► Characterization of functional connectivity along PK curve for 2.0 mg SL BUP.

Introduction

Opioids are a class of analgesics that act on the human central nervous system (CNS) and are a common therapeutic choice for pain treatment (Olsen et al., 2006). A number of pharmacological magnetic resonance imaging (phMRI) and functional MRI (fMRI) studies of opioids have been previously performed (Becerra et al., 2006, Leppa et al., 2006, Oertel et al., 2008, Wise et al., 2002, Upadhyay et al., 2011). Such investigations have importantly demonstrated the coupling between subjective pain intensity ratings and objective blood oxygenated level-dependent (BOLD) responses measured in CNS structures. For example, using a thermal pain and remifentanil infusion paradigm, Wise and colleagues demonstrated simultaneuous reductions in both pain intensity ratings and the BOLD response amplitude within the insular cortex (Wise et al., 2004). Our group previously reported that intravenous (IV) administration of buprenorphine (BUP) reduces pain intensity ratings while also modulating activity in CNS circuitry that mediates affective and sensory components of pain (Upadhyay et al., 2011). Moreover, within the chronic pain state, Baliki et al. have demonstrated a relationship between perceived pain, evoked pain BOLD responses in nucleus accumbens, and changes in nucleus accumbens-based functional connectivity (Baliki et al., 2010). These and other investigations demonstrate the utility of fMRI methodology in defining the underlying neurobiology of pharmacologically-induced analgesia and the functional modulation of the CNS in the chronic pain state. In vivo evaluation of analgesics with functional imaging methodology enables a direct and objective measure of drug effect on CNS function. By investigating the effects of analgesics on the CNS during evoked pain and the resting-state, common circuitry that may be pharmacologically-modulated during these two CNS states could also be determined. In the context of analgesic drug development, such objective neurobiological information could be used in conjunction with behavioral pain rating data to determine whether a specific mechanism of action is engaged in healthy subjects or chronic pain patients.

One hurdle in analgesic drug development is choosing the proper dose(s) to investigate in Phase II trials, in which a signal of clinical efficacy is sought. Often, this choice is based on doses projected from preclinical studies or the maximum tolerated dose in humans. If specific doses of a novel drug are evaluated in small (i.e., N = 12) subject cohorts using traditional pharmacokinetic (PK) approaches and show robust and significant pharmacodynamic (PD) changes (i.e., modulation of CNS pain circuitry and behavioral pain ratings), it is possible to obtain more confidence in the choice of dose(s) investigated in costly large-scale clinical trials. Herein, the utility of fMRI as a PD tool to objectively define a dose response relationship for BUP was assessed. BUP is an opioid that binds to multiple opioid receptor types (μ-, δ-, κ- and ORL1/nociceptin) (Sadee et al., 1982, Rothman et al., 1995, Hawkinson et al., 2000, Huang et al., 2001). However, the partial agonist action and high affinity of BUP at the μ-opioid receptor site are believed to drive the supraspinal analgesic effect (Lutfy et al., 2003, Ide et al., 2004).

As with many medications, opioids such as BUP can be administrated via different routes, including intravenously or sublingually. Due to differences in metabolism and bioavailability, oral routes typically have different PK profiles, and may yield distinct PD effects compared with parenteral (e.g., intramuscular, IV, intrathecal) or transdermal administration. Such PK/PD information can in turn be utilized to estimate factors that include analgesic onset and the duration of sustained analgesia. What remains unknown is the degree to which the modulation of CNS pain circuitry, which underlies the analgesic effect, depends on the route of opioid administration or opioid exposure levels. Thus, a second objective of this study was to compare the PD effects on CNS pain circuitry for efficacious doses of BUP that varied by route of administration (i.e., IV versus sublingual (SL)).

As a test case, two doses of intravenously administered BUP (0.1 and 0.2 mg/70 kg) were investigated in this work. These two IV doses of BUP were specifically chosen based on their established non-analgesic (0.1 mg/70 kg) versus analgesic (0.2 mg/70 kg) qualities (Yassen et al., 2006). We hypothesized that only the 0.2 mg/70 kg IV dose of BUP would significantly and robustly modulate both the evoked BOLD response to painful stimuli and resting-state connectivity in CNS circuitry mediating affective and sensory aspects of pain. Moreover, PK properties of BUP differ between IV and SL routes of administration (Johnson et al., 2005). For example, the bioavailability of IV BUP is approximately 50% greater than the sublingual (SL) formulation. The differences in PK properties between IV and SL BUP make these two routes of administration interesting to compare using fMRI methodology. We hypothesized that efficacious doses of BUP (0.2 mg/70 kg IV and 2.0 mg SL) should yield similar PD effects measured in the CNS once the mechanism of action – μ-opioid partial agonist activity – was sufficiently engaged. However, PK properties such as bioavailability and clearance rate specific to IV or SL routes may underlie differences observed in the CNS during the evoked pain and resting-state.

Here, we extend the findings of previous functional imaging work involving opioid-mediated analgesia by addressing the effect of dosing regimen (delivered dose and route of administration) for BUP on modulation of both evoked pain and resting-state fMRI signals. Two IV doses (0.1 and 0.2 mg/70 kg) and one SL dose (2 mg) of BUP were compared to placebo using BOLD fMRI in healthy human subjects. The aims of this study were (1) to compare the evoked pain fMRI signals due to non-analgesic (0.1 mg/70 kg) and analgesic (0.2 mg/70 kg) IV doses of BUP, (2) to compare the evoked pain fMRI signals resulting from efficacious doses of BUP delivered by IV and SL routes of administration, (3) to compare the effects of the two IV BUP doses on functional connectivity in pain circuitry and (4) to measure functional connectivity changes subsequent to 2 mg SL BUP administration during the ascending and plateau phase of the PK curve.

Section snippets

Materials and methods

36 healthy, right-handed males were included in this study (Age: 28.0 ± 2.5 years old (mean ± S.E.M.)) and segregated into 3 cohorts of 12 subjects. All subjects were scanned under the same conditions (e.g., same scanner, same protocol for pain measures and same experimental team). We investigated 2 IV doses of BUP (0.1 mg/70 kg (N = 12) and 0.2 mg/70 kg (N = 12)) and a single SL BUP dose (2.0 mg (N = 12)) (Reckitt Benckiser Pharmaceuticals, Inc.). The subjects and corresponding data in the 0.2 mg/70 kg IV BUP

Buprenorphine concentration in plasma

For 0.1 mg/70 kg IV, 0.2 mg/70 kg IV and 2.0 mg SL BUP, Cmax (mean ± S.E.M.) was 0.96 ± 0.14 ng/mL, 2.01 ± 0.46 ng/mL and 1.22 ± 0.23 ng/mL, respectively (Fig. 2). Tmax for 0.1 and 0.2 mg/70 kg IV BUP occurred at 5 minutes post drug administration, while for 2.0 mg SL BUP Tmax occurred at 60 min. The minimum detection threshold for BUP was 0.5 ng/mL. While the heat fMRI scans for 0.1 and 0.2 mg/70 kg IV BUP were performed below or at the minimum detection thresholds, for 2.0 mg SL the BUP levels in plasma ranged

Summary of results

In the current study, the PD effects of IV (0.1 and 0.2 mg/70 kg) and SL doses (2 mg) of BUP on CNS pain circuitry were measured in three separate cohorts of healthy, opioid-naïve males. This is the first time PK, functional imaging and subjective pain rating methodologies have been jointly used to compare the effects of multiple doses and routes of administration of BUP. Each dose and mode of BUP administration yielded distinct PK properties. The PK profiles and exposure levels measured in the

Conclusions

By utilizing evoked pain fMRI, the current study demonstrated a dose-dependent modulation of affective and sensory CNS pain circuitry between 0.1 and 0.2 mg/70 kg IV BUP. For the two clinically efficacious doses of BUP that differed in route of administration, 0.2 mg/70 kg IV BUP and 2 mg SL BUP, consistent evoked pain fMRI patterns as well as consistent decreases in resting-state functional connectivity between the putamen and sensorimotor/sensory-discriminative regions were observed. The evoked

Disclosures

Adam J. Schwarz, Smriti Iyengar and David Bleakman are employed by Eli Lilly and Company. Alexandre Coimbra, Richard Baumgartner, Jeffery L. Evelhoch and Richard Hargreaves are employed by Merck and Company. Soujanya Neni and Gary Maier are employed by Sunovion Incorporated. In the last 3 years, David Borsook and Lino Becerra received research grants from Eli Lilly and Company, Merck and Company, Sunovion Inc, and GlaxoSmithKline. David Borsook serves as a consultant for Theravance Inc and

Acknowledgments

The authors would like to thank Margaret Grant for assistance in preparing this manuscript. The authors would also like to thank Dr. Brigitte Robertson for her contributions. This study was funded by the Imaging Consortium for Drug Development.

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