Buprenorphine/Naloxone (Suboxone)

Primer

Buprenorphine/Naloxone (Trade name: Suboxone) is a combination medication used in opioid replacement therapy in opioid use disorder, and chronic pain management. Buprenorphine is a partial opioid agonist, while naloxone is a competitive opioid antagonist added to prevent misuse.

Why Naloxone?

Suboxone contains both buprenorphine and naloxone in a 4:1 ratio (the lowest possible prescribed ratio is 2 mg/0.5 mg).
Buprenorphine is the active opioid partial agonist, while naloxone is an opioid antagonist added to reduce abuse potential.
Naloxone has poor oral bioavailability and will precipitate withdrawal in opioid-dependent patients if injected intravenously.

Mechanism of Action

Buprenorphine is a partial µ-receptor agonist with a low intrinsic activity at the receptor site.
Clinically, this gives it a “ceiling effect”: the opioid agonist effects plateau at higher doses.
As a result, there is a much lower risk of overdose (including respiratory depression) compared to methadone and other opioids.
Buprenorphine also attaches tightly to opioid receptors and dissociates slowly, giving it up to 72 hours duration of action.

Pharmacokinetics

Rapid absorption by buccal mucosa, then slowly released into bloodstream, 45 to 90 minutes
Peak plasma concentration in 1 to 4 hours
Very low oral bioavailability due to first pass metabolism, hence it is delivered either sublingual or intradermal (via a patch)

Dosing

See also main article: Opioid Withdrawal

Induction Principles

Ensure the patient has waited the appropriate amount of time prior to induction (see Table).
Buprenorphine/naloxone is a safe medication, but will displace any opioids attached to the opioid receptors.
Suboxone must be taken sublingually, since it has poor oral bioavailability.
Always remind the patient to keep the sublingual tablet in their mouth until the tablet is dissolved, which can take several minutes.

Waiting Period Prior to Induction

	Short-Acting Opioid	Intermediate-Acting Opioid	Long-Acting Opioid
Example	Heroin, morphine, hydrocodone, immediate-release oxycodone	Slow-release oral morphine, controlled-release hydromorphone, sustained-release oxycodone	Methadone
Tapering Schedule	Stop at midnight	Stop at midnight	Reduce methadone by up to 30mg per day over a period of 1 week
Onset of Moderate Withdrawal Symptoms (i.e. - COWS > 12)	12–16 hours after last dose	17–24 hours after last dose	30–48 hours (or more) after last dose
When to Start Induction	As soon as COWS > 12	As soon as COWS > 12	Wait at least 24 hours, but preferably 48–72 hours after last methadone dose if patient can tolerate withdrawal symptoms, before beginning induction

Ambulatory Clinic Induction

Patient waits in ambulatory care office until the report withdrawal symptoms and have a COWS score of 12+
First dose: 4 mg SL
Reassess in 2 hours. If patient improved but still in withdrawal, give another 4 mg to take in office or at home
Maximum dose is 12 mg in 24 hours

Home Induction

Prescribe 2 mg SL q4H PRN, up to 6 tabs over 24 hours, x 1–3 days (e.g. - 18 tabs all as take-home or 6 tabs daily dispensed for 3 days)
Patient must wait at least 12 hours after last opioid, or longer if using a long-acting.
First dose: 4 mg SL
If still in withdrawal after 2 hours, take another 4 mg SL
Maximum dose is 12 mg in 24 hours

Titration and Maintenance

If there are no withdrawal symptoms present since last dose, continue with a once daily dose equal to the total amount administered on Day 1. It is appropriate to increase the dose by 2–4 mg per day if the patient continues to report withdrawal symptoms or cravings. Each dose increase should increase duration of relief from withdrawal and cravings. The typical maintenance dose is usually 8 to 16 mg daily, with a maximum dose of 24 mg daily. Higher doses have been noted in case reports. An optimal dose will relieve withdrawal symptoms and cravings for 24 hours. During the titration phase, clinicians should ask for common side effects such as sedation.

Missed Doses

Suggestions for Managing Missed Doses

Buprenorphine Dose	Number of Consecutive Days Missed	Missed New Starting Dose
> 8 mg	> 7 days	4 mg
> 8 mg	6-7 days	8 mg
6-8 mg	6 or more days	4 mg
2-4 mg	6 or more days	2-4 mg

Burnese Method

The Burnese Method is an induction method of using microdoses of buprenorphine in patients with concomitant full opioid agonist use.^[1]
The theory behind this method is that repetitive administration of very small doses of buprenorphine in regular intervals will not precipitate opioid withdrawal.
Since there is a long receptor binding time, buprenorphine will continue to accumulate at the opioid receptor and an increasing amount of a full μ-agonist will be replaced by buprenorphine at the opioid receptor. It is important to note, however, that this is not yet considered an evidence-based method of opioid induction.
This method may be helpful for patients fearful of precipitated withdrawal, or if they experience severe withdrawal symptoms during conventional induction.

A common starting dose for the Burnese induction method is buprenorphine 0.5 mg, which involves splitting the Suboxone 2 mg/0.5 mg tablet into quarters. Here are is a sample micro-induction schedule for individuals on short-acting opioids:

Burnese Method: Short-Acting Opioid

Day	Buprenorphine / Naloxone	Opioid
1	0.5 mg daily	Maintain dose
2	1.0 mg daily	Maintain dose
3	1.5 mg daily	Maintain dose
4	2.0 mg daily	Maintain dose
5	2.5 mg daily	Maintain dose
6	3.0 mg daily	Maintain dose
7	4.0 mg daily	Stop short-acting opioid

See the patient on Day 7, after 4 mg of buprenorphine/naloxone, and give another 2 mg every 1 hour until comfortable, to a max of 12 mg that day. You may instead choose to give an additional 2 mg as needed on Day 7, with daily follow-ups thereafter, and increases of 2 mg to 4mg/day as needed, until comfortable. Final maximum dose is typically 16 mg/day.

Sublingual, Patch, or Injection?

Patch

To transition from sublingual Suboxone to intradermal (patch):
- Stop all opioid medications at midnight (no opioids x 8-12 hours)
- To prevent the patient from going into precipitated withdrawal, the COWS must be > 12. Allow patient to enter into withdrawal for at least 8 hours if they are on a short-acting opioid
- Start buprenorphine patch 20mcg/hr patch x 7 days

Injection

See main article: Buprenorphine Extended-Release Injection (Sublocade)

Buprenorphine Extended-Release Injection (Trade name: Sublocade) is a long acting monthly subcutaneous injectable opioid for use in patients with moderate to severe opioid use disorder.
It is the long-acting form of sublingual Suboxone.

Clinical Pearls

Remind your patients: do not swallow the foam, the sublingual tablet must sit under the tongue and be absorbed by the buccal mucosa. If the foam is swallowed, the medication will not have any effect due to its poor oral bioavailability!
Avoid prescribing benzodiazepines with Suboxone! The combined use of opioids with benzodiazepines can result in serious side effects, including respiratory depression and death. If prescribed together, limit the dosages and duration of each drug to a minimum. Warn patients and caregivers about the risks of slowed or difficult breathing and/or sedation. The vast majority of deaths involving buprenorphine also had the presence of other sedating drugs, especially benzodiazepines.^[2]

Concomitant Alcohol Withdrawal

In patients with concomitant alcohol and opioid withdrawal, the alcohol withdrawal should always be treated first. While opioid withdrawal can be extremely uncomfortable, it is not fatal! On the other hand, untreated alcohol withdrawal can result in death.
When treating concomitant withdrawal symptoms, consider using lorazepam instead of diazepam, to reduce the length of respiratory depression.
Once the alcohol withdrawal has resolved, then the patient can start on a suboxone induction. While the patient is on alcohol withdrawal treatment, they can be treated symptomatically for opioid withdrawal with clonidine 0.05mg PO q1h.

Pregnancy

Naloxone poses a theoretical risk of elevating maternofetal cortisol levels, thus pregnancy was previously a contraindication to starting Suboxone. However, recent studies have not validated these concerns, and as a result pregnancy is no longer considered a contraindication to Suboxone.^[3]

Side Effects

Buprenorphine has side effects similar to other opioids, including sedation, constipation, and nausea.

Contraindications

Liver dysfunction 3-5x the upper limit of normal, due to the naloxone's effect on the liver

Guidelines

See also: Psychiatry Clinical Practice Guidelines (CPGs)

Opioid Use Disorder Guidelines

Guideline	Location	Year	PDF	Website
Canadian Medical Association Journal (CMAJ)	Canada	2018	-	Link
BC Centre on Substance Use (BCCSU)	Canada	2023	Link	Link
META:PHI	Canada	2019	Link	Link
Canadian Guidelines on Opioid Use Disorder Among Older Adults	Canada	2020	PDF	Link
National Institute for Health and Care Excellence (NICE)	UK	2007	-	Link
American Psychiatric Association	USA	2006, 2007	-	• Guideline (2006) • Guideline Watch (2007) • Quick Reference

Resources

For Providers

META:PHI Prescriber Tools

¹⁾ Hämmig, R., Kemter, A., Strasser, J., von Bardeleben, U., Gugger, B., Walter, M., ... & Vogel, M. (2016). Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method. Substance abuse and rehabilitation, 7, 99.

²⁾ Kleber, H. D. (2007). Pharmacologic treatments for opioid dependence: detoxification and maintenance options. Dialogues in clinical neuroscience, 9(4), 455.

³⁾ Zedler, B. K., Mann, A. L., Kim, M. M., Amick, H. R., Joyce, A. R., Murrelle, E. L., & Jones, H. E. (2016). Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta‐analysis of safety in the mother, fetus and child. Addiction, 111(12), 2115-2128.

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