CoChat
Sign Up
Cited by 174Opioid Use Disorder TreatmentSubstance Abuse Treatment and OutcomesPain Management and Opioid Use

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

Open access
Greenwald, Mark K., Comer, Sandra D., Fiellin, David A.·2014·Drug and Alcohol Dependence
DOI 10.1016/j.drugalcdep.2014.07.035PMC PMC4252738
Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.drugalcdep.2014.07.035

Cites

105 of 105 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The pivotal importance of the MOR in the effect of opioids is borne out by studies that find that opioid agonist effects are linearly related to occupancy of this receptor.

    “The pivotal importance of the MOR in the effect of opioids is borne out by studies that find that opioid agonist effects are linearly related to occupancy of this receptor. 18”

    From Tapering and withdrawing opioids: guidance informed by fundamental principles to minimise withdrawal symptoms (2025) · cites this paper as [18]

    The Results (section 3; page not provided) relate μ-opioid receptor availability to pharmacodynamic responses using non-linear regression curves, contrary to the claimed linear relationship. The Methods (section 2.1; page not provided) also caution that receptor availability is an indirect measure and that calling it occupancy can be misleading. (LLM, conf=0.86)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • A linear relationship is evident between occupancy of MORs and subjectively measured withdrawal symptoms, with greater withdrawal symptoms correlated with lower MOR occupancy in subjects with opioid use disorder.

    “A linear relationship is also evident between occupancy of MORs and subjectively measured withdrawal symptoms, with greater withdrawal symptoms correlated with lower MOR occupancy in subjects with opioid use disorder. 18”

    From Tapering and withdrawing opioids: guidance informed by fundamental principles to minimise withdrawal symptoms (2025) · cites this paper as [18]

    The Results (Section 3) report that greater μ-opioid receptor availability is associated with more withdrawal symptoms, which supports the claimed direction because lower availability reflects greater occupancy. But the paper plots non-linear curves for the availability–withdrawal relationship; its reported linear relationship is between withdrawal symptoms and buprenorphine dose, not receptor occupancy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • We derived a curve of best fit for buprenorphine from dose-occupancy data in Greenwald et al. 17 (as reported in Greenwald et al. 18) where occupancy was measured 4 h after 12 days of maintenance treatment with doses ranging from 1 to 32 mg.

    “We derived a curve of best fit for buprenorphine from dose-occupancy data in Greenwald et al. 17 (as reported in Greenwald et al. 18 ) where occupancy was measured 4 h after 12 days of maintenance treatment with doses ranging from 1 to 32 mg (Figure 2 and Table 3).”

    From Tapering and withdrawing opioids: guidance informed by fundamental principles to minimise withdrawal symptoms (2025) · cites this paper as [18]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • There was a single study by Greenwald et al. 17 (as reported in Greenwald et al. 18) that reported occupancy data for mu-opioid occupancy for buprenorphine.

    “There was a single study by Greenwald et al. 17 (as reported in Greenwald et al. 18 ) that reported occupancy data for mu-opioid occupancy for buprenorphine.”

    From Tapering and withdrawing opioids: guidance informed by fundamental principles to minimise withdrawal symptoms (2025) · cites this paper as [18]

    The Results discuss buprenorphine-related μ-opioid receptor availability data from Greenwald et al. (2003) and (2007), so the cited review does report relevant data. It does not establish that there was only one such study. The Methods (section 2.1.1; page unavailable) also caution that receptor availability is an indirect measure and should not be called directly measured “occupancy.” (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • High-dose TMB may be needed to block ultra-high potency and high affinity opioids by reducing mu-opioid receptor availability.

    “High-dose TMB may be needed to block the effects of ultra-high potency and high affinity opioids by reducing mu-opioid receptor availability.10”

    From Oral Health Risks of Transmucosal Buprenorphine: Commentary on Tuan et al. and Zheng et al. (2025) · cites this paper as [10]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Greenwald MK Steinmiller CL Dean R Negus SS Bilsky E Imaging opioid receptors: applications to substance use disorders Opioid Receptors and Antagonists: From Bench to Clinic 2009 New York Humana Press 45 65

Cited by

Sorted by citations

Related

Authors
Greenwald, M. K., Comer, S. D., & Fiellin, D. A.
Affiliations
  • Eugene Applebaum College of Pharmacy and Health Sciences (US)
  • New York State Psychiatric Institute (US)
  • Yale University (US)
Corresponding author
Greenwald, Mark K.
ORCID
Venue
Drug and Alcohol Dependence
Publisher
Elsevier BV
Published
2014-11
Volume
144
Pages
1-11
ISSN
0376-8716 (ISSN-L)
DOI
10.1016/j.drugalcdep.2014.07.035
PMC
PMC4252738
OpenAlex
W2056888894
Cited by
174
References
105
Citations by year
2026: 16 · 2025: 15 · 2024: 20 · 2023: 19 · 2022: 19 · 2021: 21 · 2020: 21 · 2019: 15 · 2018: 13 · 2017: 9 · 2016: 1 · 2015: 4 · 2014: 1
FWCI
0.79
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Drug and Alcohol Dependence (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (P30MH062294)
  • National Institute on Drug Abuse (R01DA015462, R01DA035616, P50 DA-09236, R01DA016759, P50DA009236, R01DA025991, R01DA16759)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
Keywords
buprenorphine, opioid use disorder, maintenance therapy, buprenorphine/naloxone, sublingual formulation, trough concentration, dosing regimen, reimbursement policy, opioid use disorder treatment
MeSH terms
Administration, Sublingual, Analgesics, Opioid, Buprenorphine, Health Policy, Humans, Naloxone, Opioid-Related Disorders, Protein Binding, Receptors, Opioid, mu, Opiate Substitution Treatment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review