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Review
. 2014 Nov 1:144:1-11.
doi: 10.1016/j.drugalcdep.2014.07.035. Epub 2014 Aug 19.

Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: implications for clinical use and policy

Mark K Greenwald  1 , Sandra D Comer  2 , David A Fiellin  3
Affiliations
Review

Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: implications for clinical use and policy

Mark K Greenwald et al. Drug Alcohol Depend. .

Abstract

Background: Sublingual formulations of buprenorphine (BUP) and BUP/naloxone have well-established pharmacokinetic and pharmacodynamic profiles, and are safe and effective for treating opioid use disorder. Since approvals of these formulations, their clinical use has increased. Yet, questions have arisen as to how BUP binding to mu-opioid receptors (μORs), the neurobiological target for this medication, relate to its clinical application. BUP produces dose- and time-related alterations of μOR availability but some clinicians express concern about whether doses higher than those needed to prevent opioid withdrawal symptoms are warranted, and policymakers consider limiting reimbursement for certain BUP dosing regimens.

Methods: We review scientific data concerning BUP-induced changes in μOR availability and their relationship to clinical efficacy.

Results: Withdrawal suppression appears to require ≤50% μOR availability, associated with BUP trough plasma concentrations ≥1 ng/mL; for most patients, this may require single daily BUP doses of 4 mg to defend against trough levels, or lower divided doses. Blockade of the reinforcing and subjective effects of typical doses of abused opioids require <20% μOR availability, associated with BUP trough plasma concentrations ≥3 ng/mL; for most individuals, this may require single daily BUP doses >16 mg, or lower divided doses. For individuals attempting to surmount this blockade with higher-than-usual doses of abused opioids, even larger BUP doses and <10% μOR availability would be required.

Conclusion: For these reasons, and given the complexities of studies on this issue and comorbid problems, we conclude that fixed, arbitrary limits on BUP doses in clinical care or limits on reimbursement for this care are unwarranted.

Keywords: Buprenorphine; Opioid dependence; Opioid receptors; Policy; Positron emission tomography; Treatment.

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Conflict of interest statement

Conflict of Interest

M.K.G. has received compensation as a scientific consultant to Reckitt-Benckiser Pharmaceuticals, Inc., which manufactures and markets buprenorphine products, and Titan Pharmaceuticals, Inc., which manufactures a buprenorphine product.

S.D.C. has received compensation (in the form of partial salary support) from investigator-initiated studies supported by Reckitt-Benckiser Pharmaceuticals, Inc. and Schering-Plough Corporation, companies that currently or previously market buprenorphine products. In addition, she received consulting income from Grunenthal GmbH and BioDelivery Sciences International, two companies that market buprenorphine products.

D.A.F. has received honoraria from Pinney Associates for serving on an external advisory board monitoring the abuse and diversion of buprenorphine.

Figures

Figure 1
Figure 1
Left panel: Non-linear regression curves on μOR availability (non-displaceable binding potential, BPND) fitted to brain region-of-interest (ROI) [11C]-carfentanil PET data from Greenwald et al. (2003) for different buprenorphine (BUP) maintenance doses (log2 – linear plot) at 4-hr post-dose. The seven ROIs illustrated are: Brodmann area (BA) 10 in prefrontal cortex (PFC); BA 25 in subgenual anterior cingulate cortex (ACC); BA 32 in rostral ACC; caudate nucleus; nucleus accumbens; thalamus; and amygdala. Dashed lines indicate estimated range of μOR availability across ROIs for an 8-mg/day BUP dose (12 – 33%). See Table 1 for estimates of μOR availability (based on these curve fits) for BUP doses that were not experimentally studied. Right panel: Non-linear regression curves on regional μOR availability (BPND) fitted to [11C]-carfentanil PET data from Greenwald et al. (2007) following discontinuation of BUP 16-mg/day maintenance. The Y-intercept values at the 4-hr time point for each ROI were adjusted to data for the identical condition (4 hr after BUP 16-mg) in the Greenwald et al. dose-response study (2003).
Figure 2
Figure 2
Non-linear exponential correlations between BUP plasma concentrations and μOR availability (absolute BPND values) in thalamus (upper row) and nucleus accumbens (N.Acc., lower row) across experimental conditions for all subjects in the BUP dose-response study ([Greenwald et al., 2003], left column) and the BUP discontinuation time-course study ([Greenwald et al., 2007], right column). In these plots, the maximum plasma concentration was constrained to ≤15 ng/mL for each subject.
Figure 3
Figure 3
Upper left: Non-linear hyperbolic regression curves fitted to mean μOR availability in thalamus (representative region of interest) and mean self-reported opioid withdrawal and agonist symptoms, and heroin craving (percent maximum effect on each scale) from Greenwald et al. (2003). Data points from left to right (low to high μOR availability) reflect responses at 4 hr after daily 32-mg, 16-mg, 2-mg, and 0-mg BUP maintenance doses. Upper right: Hyperbolic regression curves fitted to estimates of receptor availability (at 15 hr after BUP/NAL doses of 32-mg/8-mg, 8- mg/2-mg, and 2-mg/0.5-mg) for self-administration of various intranasal heroin doses from Comer et al. (2005). Data points to the right of the disconnected lines represent heroin self-administration (12.5 and 50 mg only) in a separate control group of opioid-detoxified volunteers, who are presumed to have nearly 100% μOR availability. Lower left: Hyperbolic regression curves fitted to mean μOR availability in thalamus (representative ROI) and self-reported opioid withdrawal and agonist symptoms, and heroin craving (percent maximum effect on each scale) during BUP maintenance, and response to cumulative hydromorphone 24-mg IM challenge, from Greenwald et al. (2007). Data points from left to right (low to high μOR availability) reflect responses at 4 hr, 28 hr, 52 hr, and 76 hr after discontinuation of the BUP 16-mg maintenance dose.
Figure 4
Figure 4
Correlations between mean μOR availability in the subgenual anterior cingulate cortex (Brodmann area [BA] 25) and mean pharmacodynamic responses among heavier cigarette smokers (≥20 per day, n=5) and lighter cigarette smokers (≤15 per day, n=5) in the BUP time-course study (Greenwald et al., 2007). Upper left: Total opioid withdrawal symptom score. Upper right: Total heroin-craving score. Lower left: Change in total opioid agonist symptom score in response to cumulative 24-mg versus 0-mg hydromorphone injection.
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