Background: Buprenorphine is a high affinity, partial mu-opioid agonist with increasing use as an analgesic in patients with serious illness (See Fast Facts #441) including those with comorbid opioid use disorder (OUD) or misuse (See Fast Facts #221) (1,2). An X-waiver is no longer required to prescribe buprenorphine for OUD (3). However, one significant barrier to initiating the sublingual (SL) formulation of buprenorphine via traditional methods is the requirement of an opioid free period (i.e., discontinuation of all full agonists for about 12-36 hours) to reduce the risk of an uncomfortable precipitated withdrawal (see Fast Fact #441). For someone facing a short prognosis, this can be a significant sacrifice. This Fast Fact describes the low dose initiation method in which there is a period of concomitant buprenorphine and full agonist opioid administration.

Low dose buprenorphine initiation: what does that mean?  Low dose initiation of buprenorphine is the preferred phrasing for “microdosing” or “micro-induction.” (4). It is distinct from the more traditional method of rotating to buprenorphine (see Fast Fact #441) because it circumvents the need for stopping full agonist opioids to clear them from the system prior to starting buprenorphine. Instead, small, and gradually increasing doses of buprenorphine (typically 0.25 to 1mg SL buprenorphine) are administered. This essentially negates the risk of precipitated opioid withdrawal seen in the traditional method (occurs due to a sudden shift in replacing full agonist opioid effect with partial agonist effect in key brain regions) (5). Full agonist opioids are continued while buprenorphine is started and titrated to a therapeutic dose (usually 16-24 mg SL for OUD, often less for pain, see Fast Fact #221) via the low dose method, at which time the full agonist opioids may be stopped or tapered off (4–7).

Clinical setting: Low dose initiation protocols typically occur over 3 to 14 days and have been adapted to inpatient and outpatient settings. To work well, patients should be able to follow multi-step medication instructions, be open to caregiver support, and respond to near daily telemedicine check-ins by clinic staff to assess symptoms and adverse effects.  Clinicians should utilize a non-stigmatizing approach to OUD and buprenorphine (see Fast Fact #429) and develop a strong alliance with pharmacists, nurses, and other interdisciplinary team members to maximize successful initiations. It can be helpful to have patients pick up buprenorphine initiation packs and comfort medication prescriptions to bring to clinic visits (live or via telehealth).  Preparing a timeline and reviewing each step of the plan with the patient is essential.

Patient selection: Low dose initiations are appropriate in patients who are maintained on full opioid agonists for concurrent pain; patients transitioning from very long-acting opioids (e.g., methadone, fentanyl patches); and patients who may have experienced precipitated withdrawal in the past or have significant fear of doing so. A traditional method is appropriate if the patient is already presenting in a degree of opioid withdrawal (e.g., ran out of opioid medications early) or in patients with experience or preference for this method. Ultimately, initiation method should be a patient-centered decision balancing various factors like speed of transition, preference to avoid withdrawal, clinical setting, baseline full agonist dose, and ability to follow the more complicated instructions of the low dose method.

Methods: While there are no controlled trials to inform off-label use of buprenorphine in low dose initiation, there is a body of case reports, case series, and clinical experience that support the safety and tolerability of this approach. Reaching out to mentors (e.g. local specialists, the National Clinician Consultation Center Warmline) can help clinicians formulate patient-specific protocols ((8,9). Published protocols vary by timelines (e.g., longer in outpatient settings or patients on moderate-high dose methadone) and the buprenorphine formulation used (6,7). Importantly, initiation protocols can be modified or paused if a patient experiences intolerable worry, withdrawal symptoms, or pain flares (10).

What about the full agonist? With a low-dose initiation, full agonist opioids should be continued until buprenorphine titration reaches a threshold of opioid receptor activity to minimize risk of opioid withdrawal symptoms. Tapering or stopping full agonists generally begins at buprenorphine doses of 6 to 12 mg daily. Buprenorphine can continue to be up titrated by 2 to 4 mg SL daily until an effective dose is reached for analgesia indications, or when the goal OUD treatment dose of 16-24 mg/day SL is reached. Long-acting full agonist opioids are usually tapered or discontinued first; short-acting full agonists should be continued as needed to treat intolerable pain or withdrawal symptoms during initiation before buprenorphine reaches an effective dose. Alternatively, short-acting opioids can be continued after the low-dose buprenorphine initiation is completed to treat breakthrough pain. Two sample initiation protocols are presented below for transdermal and SL formulations (derived from references 10-17). See references for protocol variations using buccal film (12) or intravenous (17) formulations.

	Transdermal (TD) A,(10)	SL tab/filmB,(13,14)	Full agonist
Day 1	20mcg/hr TD	0.5 mg SL once	Continue baseline dose in most cases
Day 2	—	0.5 mg SL q12 hrs
Day 3	1 mgc SL once	1 mg SL q12 hrs
Day 4	1 mg SL q12 hrs	2 mg SL q12 hrs
Day 5	2 mg SL q12 hrs	3 mg SL q12 hrs
Day 6	3 mg SL q12 hrs	4 mg SL q12 hrs	Discontinue or start tapering off full agonist
Day 7	4 mg SL q12 hrs **	6 mg SL q12 hrs **

** Continue to adjust buprenorphine dose to symptoms by 2-4 mg SL daily.
^A – Maintain the TD patch until it expires in 7 days, then remove and do not replace.
^B – A 0.5 mg SL buprenorphine or buprenorphine-naloxone dose can be achieved by cutting a 2 mg film into quarters. Films may be preferred given they are easier to split.
^c– A 1mg SL dose can be achieved by cutting a 2 mg film or tablet in half.

Potential Barriers: The TD patches are only FDA approved for indications of ‘pain’ in the outpatient setting; however, it can be used to treat opioid withdrawal or OUD inpatient. TD buprenorphine can be more expensive than SL formulations, and clinicians may encounter insurer limitations. Buprenorphine/ naloxone is required to be covered by insurers for OUD by the Affordable Care Act, but a prior authorization may be required. An ‘opioid dependence’ ICD-10 diagnosis can sometimes help obtain insurance coverage for buprenorphine/naloxone products used off-label for chronic pain without OUD. Some pharmacies may not yet be familiar with concurrent use of full agonist and buprenorphine, so clinicians should ensure patients have sufficient supply of prescribed full agonist before initiation. Clinicians may also need to advocate with a pharmacy and insurers on the rationale of co-prescribing since widely held misconceptions about buprenorphine remain prevalent (18).

References:

1. Hansen E, Nadagoundla C, Wang C, Miller A, Case AA. Buprenorphine for Cancer Pain in Patients With Nonmedical Opioid Use: A Retrospective Study at a Comprehensive Cancer Center. Am J Hosp Palliat Care. 2020 May;37(5):350–3.
2. Davis MP. Twelve Reasons for Considering Buprenorphine as a Frontline Analgesic in the Management of Pain. The Journal of Supportive Oncology. 2012 Nov;10(6):209–19.
3. https://www.deadiversion.usdoj.gov/pubs/docs/A-23-0020-Dear-Registrant-Letter-Signed.pdf.  Last accessed January 20, 2023
4. Weimer MB, Fiellin DA. Low- and very low-dose buprenorphine induction: new(ish) uses for an old(ish) medication? Addiction [Internet]. [cited 2022 Mar 21];n/a(n/a). Available from: http://onlinelibrary.wiley.com/doi/abs/10.1111/add.15799
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6. Quirk K, Stevenson M. Buprenorphine Microdosing for the Pain and Palliative Care Clinician. Journal of Palliative Medicine [Internet]. 2021 Dec 20 [cited 2022 Jan 5]; Available from: https://www.liebertpub.com/doi/abs/10.1089/jpm.2021.0378
7. Ghosh SM, Klaire S, Tanguay R, Manek M, Azar P. A Review of Novel Methods To Support The Transition From Methadone and Other Full Agonist Opioids To Buprenorphine/Naloxone Sublingual In Both Community and Acute Care Settings: The Canadian Journal of Addiction. 2019 Dec;10(4):41–50.
8. National Clinician Consultation Center. Available at https://nccc.ucsf.edu Last accessed January 9, 2023.
9. Provider Clinical Support System Medication for Opioid Use Disorder. Available at  http://pcssnow.org Last accessed January 9, 2023.
10. Cohen SM, Weimer MB, Levander XA, Peckham AM, Tetrault JM, Morford KL. Low Dose Initiation of Buprenorphine: A Narrative Review and Practical Approach. J Addict Med. 2021 Dec 23. doi: 10.1097/ADM.0000000000000945. Epub ahead of print. PMID: 34954746
11. Button D, Hartley J, Robbins J, Levander XA, Smith NJ, Englander H. Low-dose Buprenorphine Initiation in Hospitalized Adults With Opioid Use Disorder: A Retrospective Cohort Analysis. Journal of Addiction Medicine. 2022 Apr;16(2):e105.
12. Weimer MB, Guerra M, Morrow G, Adams K. Hospital-based Buprenorphine Micro-dose Initiation. Journal of Addiction Medicine. 2021 Jun;15(3):255–7.
13. Randhawa PA, Brar R, Nolan S. Buprenorphine–naloxone “microdosing”: an alternative induction approach for the treatment of opioid use disorder in the wake of North America’s increasingly potent illicit drug market. CMAJ. 2020 Jan 20;192(3):E73.
14. Becker WC, Frank JW, Edens EL. Switching From High-Dose, Long-Term Opioids to Buprenorphine: A Case Series. Ann Intern Med. 2020 Jul 7;173(1):70–1.
15. Weimer MB, Guerra M, Morrow G, Adams K. Hospital-based Buprenorphine Micro-dose Initiation. Journal of Addiction Medicine. 2021 Jun;15(3):255–7
16. Cohen SM, Weimer MB, Levander XA, Peckham AM, Tetrault JM, Morford KL. Low Dose Initiation of Buprenorphine: A Narrative Review and Practical Approach. J Addict Med. 2021 Dec 23. doi: 10.1097/ADM.0000000000000945. Epub ahead of print. PMID: 34954746
17. Thakrar AP, Jablonski L, Ratner J, Rastegar DA. Micro-dosing Intravenous Buprenorphine to Rapidly Transition From Full Opioid Agonists. Journal of Addiction Medicine. 2022 Feb;16(1):122–4
18. Neale KJ, Weimer MB, Davis MP, et al. Top Ten Tips Palliative Care Clinicians Should Know About Buprenorphine. Journal of Palliative Medicine. 2022;doi:10.1089/jpm.2022.0399

Authors’ Affiliations: University of California San Francisco, San Francisco, CA (JJH); VA Boston Healthcare System, Boston, MA (KFJ); Dana Farber Cancer Institute, Boston, MA (ZS); University of Pittsburgh, Pittsburgh, PA (JM, JC).
Conflicts of Interest:  The authors have declared no conflicts of interest.
Version History: first electronically published in January 2023; originally edited by Sean Marks MD