Long acting injectable buprenorphine (Buvidal®) protocol

Buprenorphine is licensed in the UK for treatment of opioid dependence¹. Like Methadone, it is a medication taken daily and certainly during the initiation period, under supervision at the pharmacy.

Buvidal® contains the active agent, buprenorphine, which comes as prolonged-release solution for injection. It is available in weekly and monthly depot injections with flexible dosing that can be increased or decreased which facilitates individualised patients care. Buvidal® ensures that therapeutic plasma buprenorphine levels are maintained over an extended period i.e. a week or a month thus improving compliance and effectiveness of the medication by preventing the onset of opioid withdrawal symptoms and reducing cravings for opioids. In addition, Buvidal® has shown to block the effects of hydromorphone¹ and this feature may help to reduce the temptation for those patients wanting to take additional opioids. Haight and colleagues maintain that the availability of an extended-release buprenorphine, delivered by health-care providers, represents an advance in treatment for opioid use disorder that enhances the benefits of buprenorphine by delivering sustained, optimal exposure, while reducing risks of current buprenorphine products.²

Buvidal® administration is restricted to healthcare professionals only. This is because prescribing, dispensing, and patient follow-up visits with clinical monitoring is tailored to the patient needs. Consequently, take-home use or self-administration of this medicine is contraindicated.

Buvidal® is licensed for the treatment of opioid dependence within a framework of medical, social and psychological treatment. Treatment is intended for use in adults and adolescents aged 16 years or over.

Buvidal® will only be administered by Borders Addiction Service staff; patients would need to commit to attending for injections at the required intervals.

Within NHS Borders specific factors to consider for patients being considered for Buvidal include:

1. On sublingual Buprenorphine / Espranor and will prefer the convenience of a weekly / monthly drug regimen OR coming into treatment with clear patient preference for long acting injection.
2. With work or study commitments that taking daily Buprenorphine is challenging.
3. Finding it difficult fulfilling taking a daily dose of methadone/buprenorphine.
4. Unable to attend the local pharmacy regularly for scripts pickups.
5. Experiencing withdrawals before their next daily dose.
6. Ongoing illicit opiate use and not managing to achieve stability despite current treatment.

Indications c) to e) can often diminish the accessibility and/or effectiveness of treatment and consequently may increase the risk of drug related deaths.

• Patients without corroborated opiate dependence.
• Patients for whom daily or frequent contact with a pharmacy is seen. as an important part of their treatment plan.
• Allergy or intolerance to OST medications.
• Take-home use or self-administration.
• Severe respiratory insufficiency.
• Severe hepatic impairment.
• Acute alcoholism or delirium tremens.
• Hypersensitivity to Buprenorphine or to any of the inactive substance that serves as the vehicle or medium for the drug - soybean phosphatidylcholine, glycerol dioleate, ethanol anhydrous (weekly preparation only), N-Methylpyrrolidone (monthly preparation only).

Use with caution in

• Those with concomitant use of benzodiazepines, alcohol and/or other CNS depressants (gabapentinoids, psychotropics etc).
• Those taking other opiates where there is a risk of precipitated withdrawals.
• Elderly patients > 65 years.
• Pregnancy / Breastfeeding.
• Patients with severe or moderate hepatic impairment.
• Patients with severe renal impairment (creatinine clearance < 30 ml/min).
• Children and adolescents <16 years of age (such use is off label and should be discussed and agreed with a Consultant).

Consideration should be given to medical review for patients already established on Buvidal® who then move into one of the above groups as dose adjustment may be needed.

Use with Disulfiram

Buvidal® injections at the weekly, 8mg, 16mg, 24mg and 32mg strengths contain small amounts of ethanol (alcohol) less than 100mg per dose. This is a small amount, for context a unit is 8g. For patients on Disulfiram usually a mild reaction would not be expected until 7-15ml/5-15g of alcohol is ingested orally. However given that the data is limited and Buvidal® delivers ethanol in an injected form it seems prudent that these strengths of Buvidal are not used when patients are on Disulfiram.

The higher strengths for monthly use, 64mg, 96mg and 128mg do not contain ethanol and could be considered.

There have been no interaction studies performed with Buvidal®. Notwithstanding, caution should be noted with the following drugs:

• Benzodiazepines.
• Gabapentinoids.
• Alcoholic drinks or medicinal products containing alcohol.
• Other central nervous system depressants like opioid derivatives (e.g. methadone, analgesics and antitussives); certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, antipsychotics, clonidine and related substances.
• Naltrexone and nalmefene.
• CYP3A4 inhibitors may inhibit the metabolism of buprenorphine resulting in increased Cmax and AUC of buprenorphine and norbuprenorphine. CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, nelfinavir or indinavir, or azole antifungals such as ketoconazole or itraconazole, or macrolide antibiotics).
• CYP3A4 inducers may induce the metabolism of buprenorphine resulting in decreased buprenorphine levels. CYP3A4 inducers (e.g. phenobarbital, carbamazepine, phenytoin or rifampicin).

As with other Buprenorphine preparations patients should be made aware that adequate analgesia may be difficult to achieve when administering a full opioid agonist. The long acting nature of Buvidal® will likely prolong this effect.

The adverse reactions most frequently reported for Buvidal® are headache, nausea, hyperhidrosis (sweating), insomnia, drug withdrawal syndrome and pain around the administration site.

A table of associated side effects and classification as to how common they are is available with the SPC for Buvidal®, the BNF also contains information regarding adverse effects associated with Buprenorphine.

PATIENTS MAY PRESENT TO PRIMARY CARE OR ACUTE MEDICAL SERVICES. IF A SIGNIFICANT ADVERSE REACTION IS SUSPECTED TO HAVE OCCURRED RELATED TO BUVIDAL®, THE BORDERS ADDICTION SERVICE SHOULD BE CONTACTED IMMEDIATELY.

Patients being considered for treatment with Buvidal® should be assessed as per existing guidelines and best practice within the Borders Addiction Service for those being considered for Opiate Substitution Therapy (OST).

Buvidal® is less likely to be suitable for “same day” prescribing and patients would usually require a full assessment and consideration of the suitability of Buvidal® before it is commenced. Any “same day” use should be only on approval of a doctor or experienced NMP in the Borders Addiction Service after consideration of risks and potential benefits for that individual patient.

It must also however be recognised that for patients who are chaotic or unstable a “low threshold” approach with individualised assessment and consideration of the balance of risks should be used. Patients should not be excluded from treatment with Buvidal® due to being chaotic and struggling to engage in more formal assessment processes, where specialists within the service judge that potential benefits of Buvidal® treatment may outweigh the risks, and the patient wishes to engage in treatment. The importance of “low threshold” prescribing and removing barriers and delays in access to treatment is widely recognised as significant within goals to reduce harm and deaths relating to drug misuse and dependence.

Information and discussion with patients

It is expected that Borders Addiction Service staff will have discussed Buvidal® fully with patients as part of the assessment process, this will include:

• Discussion of the mode of action of Buvidal®, including potential risks and benefits.
• Discussion of the administration of the Buvidal® injection and the practicalities of attending for this.
• Explanation of how they will be switched from an oral Buprenorphine or Methadone if they are already in treatment.
• Offering written information regarding Buvidal®.

1. Route = Subcutaneous only. Injected slowly and completely into the subcutaneous tissue of different areas (buttock, thigh, abdomen, or upper arm), provided there is enough subcutaneous tissue in the patient. A minimum of 8 weeks should be left before reinjecting a
previously used injection site with the weekly dose. It must not be administered intravascularly (intravenously), intramuscularly or intradermally.

2. Recommended starting dose.

Initiation of treatment in patients who are buprenorphine naive

Patients not previously exposed to buprenorphine must receive a sublingual buprenorphine 4 mg or Espranor 4mg dose and be observed for an hour before the first administration of weekly Buvidal®. This is to confirm tolerability to buprenorphine.

• Start dose of Buvidal® is 16 mg, with one or two additional 8 mg doses at least 1 day apart, allowing doses of 24 mg or 32 mg during the first treatment week if required.
• The dose for the second week should therefore be the sum of the total dose in the first week and should be administered 7 days after the first Buvidal dose of 16mg.
• Monthly Buvidal® can be started after treatment initiation with weekly Buvidal.

Switching from Espranor or sublingual buprenorphine products to Buvidal®

Espranor or sublingual buprenorphine may be switched directly to weekly or monthly on clinical discretion. Buvidal® can be started on the day after the last daily Espranor or sublingual buprenorphine treatment.

^a 25-30% higher bioavailability for Espranor than for SL Subutex tablet (MHRA Public Assessment Report Decentralised Procedure Espranor 2 mg and 8 mg lyophilisate).

Closer monitoring of patients is recommended during this period of change from oral buprenorphine to Buvidal®

3. Patients may be maintained on a weekly or monthly dose depending on what is judged to be most clinically appropriate.

Maintenance treatment and dose adjustments

Doses may be increased or decreased and patients may be switched between weekly and monthly doses according to individual patient’s needs and Doctor’s clinical judgement.

Dose conversion when switching from weekly to monthly dosing or from monthly to weekly dosing

Closer monitoring of patients is recommended around switch from monthly to weekly dosing or vice versa.

4. It is important to note Supplemental dosing may be required: A maximum of one supplemental Buvidal® 8 mg dose may be administered at an unscheduled visit between regular weekly and monthly doses, based on individual patient’s temporary needs and the prescribers judgement.

1. In rare situations where supplemental Buvidal® 8 mg is not possible (e.g. being out of area) then supplementation with a low dose of Espranor (2-6mg) or Sublingual Buprenorphine (2-8mg) might be considered. This should not exceed 14 days.

5. In the situation of Missed doses: weekly dose may be administered up to 2 days before or after the usual weekly time point, and the monthly dose may be administered up to 1 week before or after the usual monthly time point. If a dose is missed, the next dose should be administered as soon as practically possible.

6. Buvidal® Treatment termination: This should be done gradually and in a structured manner, generally it would be recommended that the Buvidal® depot dose be reduced before stopping. If the patient is to be switched to treatment with sublingual buprenorphine or Espranor, this should be done one week after the last weekly dose or one month after the last monthly dose. See also section on detoxification – page 9.

All dose adjustments or initiation of Buvidal® will be agreed by a doctor or experienced NMP in the Borders Addiction Service.

Patients presenting intoxicated at the time of Buvidal® Injection

Patients presenting intoxicated at the time of dose administration should be assessed to identify any safety concerns regarding dosing. Peak plasma and clinical effects occur 24 hours after weekly Buvidal®, and at 6-10 hours for monthly Buvidal® and hence there is usually little clinical indication to withhold a depot injection due to a patient presenting intoxicated, in contrast to intoxicated presentations for Espranor / Sublingual Buprenorphine or Methadone dosing, where peak medication effects are likely to occur whilst the patient is still intoxicated. However, patients should be assessed as having capacity to provide informed consent to their usual dose, and to understand warnings regarding risks of sedation and overdose from polysubstance use. If there are concerns that the patient is very intoxicated and unable to understand or follow instructions, the administration of the dose may be deferred and rescheduled. Acute alcohol withdrawal states or delirium tremens are contraindications to the dose being given.

The choice between maintenance and detoxification may take place at any stage of treatment, and should be patient led. Maintenance treatment has a strong evidence base and it is often an important step towards longer term detoxification and abstinence. Some patients may wish to
remain on longer term maintenance treatment.

If patients do seek a gradual reduction in Opiate Substitution Therapy (OST) doses, it is important that the motivation to reduce comes from the patient and that the prescriber does not try to impose a reduction on someone who is not ready. There is clear evidence that coerced detoxification against the patient’s will is likely to lead to relapse and increased risks of harm such as overdose and blood borne viruses.

Reduction is generally carried out over a prolonged timescale with discrete, separately negotiated steps. It is also important to recognise that periods of treatment with inadequate doses of Opiates may place patients at a higher risk of overdose than those maintained on treatment doses.

Those patients requesting to reduce OST doses who are not stable and still using illicit substances, should have the risks around reduction clearly discussed with them by their key-worker. In the same way that services will not impose a reduction on someone who is not ready, services will not
attempt to force patients to remain on OST doses that they are unwilling to accept as part of treatment.

The process varies in duration from person to person, usually up to 12 weeks in the community. Ultra rapid detoxification is contraindicated and patients who do not successfully detoxify should be offered seamless access back onto OST.

The following factors can guide the clinicians and patients opinions about whether the patient is suitable for detoxification:

• Patient is fully committed to and informed about the process,
• The patient is fully aware of the high risk of relapse,
• The patient is either in a stable or supportive social situation, or able to go into one following detoxification.
• Plans for continuing support and treatment are in place.

Patients must be advised of the potential loss of tolerance to opioids after reduction or detoxification, and the increased risk of overdose if they relapse.

There is now experience both locally and in other areas in Scotland of using Buvidal® for opioid detox, though this remains off label and patients should be consented accordingly. Clinical experience has been that the long taper time from the injection gives a generally well tolerated detox with limited withdrawals. Patients who have previously detoxed from both Methadone and oral Buprenorphine have fed back that they found detox with Buvidal® more comfortable.

It is recommend in BAS that if a patient wishes to detox they allow themselves to reach a steady state over 3 months, or longer, on each monthly dosing step before reducing.

e.g. Buvidal® 128mg for 3 months, 96mg for 3 months, 64mg for 3 months, then stop.

It has not been the experience in BAS that patients have needed to transfer from the 64mg dose to weekly Buvidal®, or oral buprenorphine. Most have found it comfortable to detox directly from the 64mg dose. Some have reported minimal withdrawals for a few days around 4 – 6 weeks from their last injection. However all patients should be assessed individually to consider if further buprenorphine or other medication for symptomatic relief is needed during detox. Support from a senior prescriber should be sought if needed.

Following detox from Buvidal® all patients should be followed up for 3 months minimum, to support relapse prevention and allow rapid access back to OST if needed.

Patient information leaflet:
https://www.choiceandmedication.org/nhs24/generate/pillbuprenorphinelai.pdf
https://www.medicines.org.uk/emc/files/pil.9705.pdf