Buprenorphine

• only partially activates opioid receptors producing less euphoric or sedating effects than full opioid agonists such as heroin, morphine and methadone
• has enough opioid activity to reduce cravings and prevent or alleviate opioid withdrawal in opioid dependent people despite only being a partial agonist
• has a higher affinity (attraction) for opioid receptors than heroin, methadone and many other opioid This means that:
  • buprenorphine can cause precipitated withdrawal (see below)
  • at higher doses buprenorphine can block or reduce the effects of other opioid drugs
  • patients may be less likely to use additional opioids on top of their buprenorphine prescription as they will experience less effect
  • if opioid pain relief is required the analgesic effect achieved can be less than
• has a ceiling effect. Continued dose increases will not result in a proportionate increase in opioid effect
• has very little effect if swallowed. Oral buprenorphine products are therefore administered UNDER or ON the tongue or inside either cheek. Always check the administration guidance for the product prescribed in the Summary of Product Characteristics (SmPC) (see resoources).
• Has a lower risk of overdose than full opioid agonists if taken as prescribed. Overdose can still occur particularly with poly drug use. The impact of prescribing other CNS depressant drugs alongside buprenorphine should be considered. Adverse  effects such as sedation and respiratory depression should be monitored for and  information on opioid overdose and a supply of naloxone given. Refer to NHS Highland Naloxone Policy (see resources).

The high affinity of buprenorphine for opioid receptors means it can displace (knock) other opioids off of opioid receptors.  This leads to a drop in opioid effect which can cause symptoms of withdrawal in opioid-dependent patients starting on buprenorphine. 

To avoid precipitating withdrawal, the first dose of buprenorphine should be taken when the patient is experiencing early signs of opioid withdrawal (see initiation of therapy, Table 1). Use of a clinical opioid withdrawal scale can help assess for withdrawal (see resources).

Methadone and buprenorphine are both effective medicines for managing opioid dependence, particularly when prescribed at optimal doses¹. There is insufficient evidence to recommend one drug as more effective or safer than the other. The prescriber should provide the patient with a balanced view of each medicine to support informed decision making on treatment selection as outlined in the Medication Assisted Treatment (MAT) Standards for Scotland (Standard 2) (see resources).

A number of factors can help the patient and prescriber decide which medicine (methadone or buprenorphine) is most appropriate. These include:

• a patient’s pre-existing preference for a particular
• previous patient experience or outcomes from treatment with OST
• patient age and duration and extent of drug use
• risk of overdose. In patients with lower levels of dependence and older patients more sensitive to sedative effects of opioids, buprenorphine may be safer
• specific safety concerns, e.g. diversion, poly drug and alcohol use, previous overdose etc
• the potential value of rapid induction onto effective maintenance which is more achievable with buprenorphine
• likely need for strong opioids other than buprenorphine for acute pain management may make methadone more appropriate
• relevant drug interactions or co-morbidities such as respiratory disease, history of cardiac abnormalities, advanced heart disease, ischaemic heart disease, cardiac conduction problems, Long QTc syndrome or those prescribed/taking drugs which prolong QTc, etc. Buprenorphine produces less respiratory depression and has less impact on QTc than methadone
• current treatment is no longer effective eg at lower doses of methadone might not provide cover for the full 24 The longer half-life of buprenorphine may make dose reductions easier to tolerate
• opioid analgesic dependence (prescribed or over the counter). Buprenorphine may be an option however patients need to be assessed on a case by case basis to take into account ongoing requirements for  pain management. Resources are available from the “Opioids Aware | Faculty of Pain Medicine” website (see resources)
• time to dissolve. Faster dissolving products require less time to supervise. This can improve the patient experience in the pharmacy and reduce opportunity for diversion where this is a concern
• combination products. The addition of naloxone might reduce the risk of injection or snorting where there is evidence or concerns of this.
• cost-effectiveness of equivalent formulations and dosages.

Treatment is more likely to be successful when combined with psychological and/or social interventions tailored to the individual. Patients should be supported to access appropriate interventions however treatment should not be withdrawn if patients are not currently engaging with these.

Buprenorphine oral lyophilisate (wafer) (Espranor®) (currently non-formulary)

Espranor^® is a freeze-dried wafer formulation of buprenorphine available as 2mg and 8mg oral lyophilisate (wafers).  Wafers should be dissolved on top of the tongue. This differs from buprenorphine sublingual tablets and buprenorphine plus naloxone sublingual film and tablets. These are administered under the tongue (all) or inside the cheek (film only). Espranor^® can dissolve in as little as 15 seconds however factors such as how dry or moist the mouth is and the number wafers administered at the same time will affect this.

Espranor^® has a high bioavailability. The amount of drug reaching the blood stream may be higher than sublingual buprenorphine products (see section on Initiation of therapy).  Patients should be monitored for signs of withdrawal or adverse effects when switching between different buprenorphine products and dose adjustments may be required.

Specific advice on administration of Espranor® oral lyophilisate can be found in the patient information leaflet (see resources).

Combined buprenorphine and naloxone Products 

• Generic buprenorphine and naloxone is available as 2mg/0.5mg and 8mg/2mg sublingual tablets
• Suboxone^® is available as
  • Sublingual TABLETS: 2mg/0.5mg, 8mg/2mg and 16mg/4mg strengths
  • Sublingual FILM (Suboxone^®): 2mg/0.5mg and 8mg/2mg strengths

These formulations contain the opioid antagonist naloxone. If taken as prescribed under the tongue or inside cheek (film only) the naloxone will have no effect as very little is absorbed from the mouth. If injected or snorted, naloxone can produce symptoms of opioid withdrawal in opioid dependent patients.  This might deter some people IF this is a specific concern. 

Suboxone sublingual film^® may have higher bioavailability than sublingual tablets. Patients should be monitored for signs of withdrawal or adverse effects when switching between different buprenorphine products.  Dose adjustment may be required.  Administration advice for Suboxone film^® can be found in Appendix 3.

Buprenorphine sublingual tablets 

• Generic buprenorphine is available as 4mg, 2mg and 8mg sublingual tablets.
• Temgesic^® (buprenorphine) 200 micrograms sublingual tablets do not have a licensed indication for treatment of opioid dependence therefore any prescribing for this indication is classed “off-label”.
• Generic buprenorphine is available in lower doses which may be helpful at the end of treatment or during detoxification.

Tips to improve absorption 

For sublingual tablets: the active ingredient will generally be absorbed after 3 to 5 minutes. A pulp may be present for 10 to 15 minutes after administration but will contain little buprenorphine. For oral lyophilisate and film products this time is significantly reduced.

For all products: time to dissolve can vary depending on how moist or dry the mouth is and the number of tablets, waters or films administered at the same time. Prescribing the lowest number needed to achieve the dose can help. Community pharmacies should offer water for the patient to moisten the mouth before administration of buprenorphine products if dry mouth is an issue.

For Suboxone Film^®: Precipitated withdrawal appears to be more common where the initial dose is given in the cheek (buccally) therefore it is recommended that the first dose given to patients new to buprenorphine is given under the tongue.  This is not necessary when switching between different buprenorphine products. See patient information leaflet (see resources). 

Buprenorphine is inactive if swallowed therefore patients should be counselled against moving products around the mouth and minimising swallowing as much as possible during the administration process.

Opioid dependence must be diagnosed prior to starting treatment. A comprehensive assessment should be undertaken and include drug screening which is positive for opioid drugs. Drug screens should be interpreted alongside clinical information and should not be treated as definitive themselves.

Patients must be assessed on an individual basis by a health care professional with sufficient knowledge in the use of buprenorphine products to determine suitability of treatment. The patient’s medical history and other prescribed medicines should be considered for contraindications, cautions and interactions when determining if treatment is suitable (see sections: 'Precautions for buprenorphine containing products' and 'Adverse effects').

Baseline liver function testing (LFTs) and documentation of viral hepatitis status is recommended in the Summary of Medicines Product Characteristics (see resources) of all buprenorphine products before starting treatment, however there is little evidence of buprenorphine being likely to cause deranged liver function or liver damage (excepting patients with viral Hepatitis). Baseline LFTs should be taken if clinically indicated. Even when LFTs are indicated, the absence of baseline LFTs should not prevent same day prescribing. Providing there are no immediate and significant clinical concerns regarding liver function, LFTs can be arranged for a later date. (Opioid Drugs in Patients With Liver Disease: A Systematic Review - PMC nih.gov) (see resources). 

Patients who have active viral hepatitis infection may be prescribed medicines which interact with buprenorphine, or have existing liver impairment and are at risk of accelerated liver injury.  Regular monitoring of liver function is recommended in these patients.

Lower initial doses and careful dose titration in patients with mild to moderate hepatic impairment are recommended. Buprenorphine products are contraindicated in patients with severe hepatic impairment.

Both methadone and buprenorphine can accumulate in patients with hepatic impairment. Clinicians should weigh up the risk of continued illicit drug use versus  the risks associated with the prescribed drug and monitor accordingly.

Precipitated withdrawal may occur when buprenorphine is first administered (see section 'Precipitated withdrawal'). If it happens, it typically begins within 1 to 3 hours after the first buprenorphine dose and peaks within 3 to 6 hours before improving. This should be discussed with all patients prior to commencing treatment with buprenorphine products and they should be reassured that, should they experience precipitated withdrawal, symptoms will improve.

Initial Dosing Schedules

To minimise the risk of precipitated withdrawal, and get the maximum benefit from buprenorphine, the patient should be displaying mild signs of opioid withdrawal before administering the first dose of buprenorphine (see Table 1). Use of a clinical opioid withdrawal scale can provide objective and subjective measures for assessing symptoms of withdrawal (see resources).

During titration, daily supervision is recommended (see section 'Supervised self administration of medication') to ensure proper placement of the product in the mouth and to observe patient response to treatment.

Clinicians should contact the community pharmacy to confirm they have stock or allow time to order it in. They should discuss initial dosing instructions and ask them to check that the patient is displaying mild symptoms of opioid withdrawal before they give the first self-administered dose.

If the clinician is not able to assess the patient in person prior to giving the first dose on day 1:

• There should be a clear plan agreed between the clinician and community pharmacist as to how the assessment of opioid withdrawal symptoms will take. The clinical opioid withdrawal scale can be used to measure this (see resources).
• This could be a phone consultation between clinician and patient. Pharmacy staff would then confirm this with the patient in person.
• Another option is to prescribe day 1 doses as a take away dose for the patient to take when they are in withdrawal. This may support same day prescribing where it is clinically appropriate. Supervised administration can then begin on day 2.  This is possible due to the relative safety of buprenorphine.  Patient understanding of this plan, and how to take the product, must be confirmed.

To reduce the severity and duration of precipitated withdrawal (should it occur) it is recommended that the dose for day 1 is split. Following treatment induction on day 1, the patient should be stabilised to a maintenance dose during the next few days by adjusting the dose according to the clinical effect of the individual patient (Table 2).

Table 1: Induction from full opioid agonists

Table 2: Dosing during induction

Table 3: Maximum daily doses

Note: Higher doses of buprenorphine are associated with improved retention in treatment

Less than daily dosing 

Less than daily dosing is not commonly used in practice but may be of benefit to some patients, particularly in the later stages of dose reductions. If prescribing in this way, the dose given   on any one day should not exceed the product’s licensed maximum daily dose.

Transferring patients between sublingual buprenorphine products and Espranor^®

The bioavailability of Espranor^® oral lyophilisate (wafer) is higher than sublingual tablets. It has potential to result in an increase in adverse effects (transfer TO Espranor) or symptoms of withdrawal (transfer TO a sublingual product) at the same dose. The following table can be used as a guide to equivalence. Dose can be adjusted according to response which may vary between patients.

Table 4: Suggested Espranor® conversions

Patients should be reviewed more frequently (at least fortnightly) initially and when stable, less frequently, such as once a month. Depending on local service arrangements, patient risk assessment and other support available, prescribers may feel prescriptions can be reviewed as little as every three months.

Co-existing physical, emotional social and legal problems as well as drug and alcohol misuse should be addressed. Third sector agencies may be able to provide this additional support and patients should be signposted or referred access to treatment should not be dependent on engagement with wider support.

Drug testing can be used to monitor patient concordance with prescribed medication and detect ongoing drug use. Urine or oral fluid tests should be undertaken according to each individual patient’s Presence of substances should be used to guide treatment and risk assess.  It should not be used to exclude patients from treatment.  Regular drug testing when a patient in treatment openly discusses substance use is of less value. Where available, point of care testing may identify buprenorphine.

The decision to begin dose reduction should be made jointly with the patient and clinician. Readiness will vary between patients, there is no set duration for the maintenance period. Patient response and ability to continue with dose reduction is key. If they struggle with the rate of reduction, stabilise the patient on a comfortable Review treatment plan and support offered.

Buprenorphine doses can be reduced initially by 2mg every two weeks or so, with final reductions in 400 microgram increments. Reducing frequency of administration to alternate days is another option that might work for some patients.

Patients can experience withdrawal symptoms at the end of treatment irrespective of the speed of reduction and should be advised/supported accordingly.

For detoxification regimens, more rapid reductions are possible with buprenorphine however the patient’s motivation, ability to cope and support structure should be carefully assessed. The risk of relapse and overdose due to loss of tolerance are increased. Rapid reductions are only recommended for use by specialist clinicians in substance misuse and are not generally recommended in community settings.

As with other opioid drugs, buprenorphine can be misused (eg snorted or injected) for its effects or diverted (eg in exchange for other substances). Risk to the patient through bullying or theft of medication is also possible.

Prescribing sub-optimal doses of buprenorphine may result in use of medicines/other substances by the patient.  They may self-medicate with substances eg opioids, alcohol or other sedative medication such as benzodiazepines.

To minimise the risk, prescribers should take appropriate precautions when prescribing and dispensing buprenorphine, such as use of supervised administration, avoiding prescribing large quantities of medication on a “take home” basis and ensuring that review assesses that the dose is appropriate and avoids symptoms of withdrawal or craving.

Intravenous or intranasal use of combined buprenorphine/naloxone products are theoretically less likely than buprenorphine alone as naloxone can precipitate withdrawal in individuals dependent on heroin, methadone, or other opioid agonists.  At this stage, wider review is needed to consider whether buprenorphine remains the most appropriate treatment option.

Supervised self-administration provides the best guarantee that a medicine is being taken as directed. It is recommended during initial stages of treatment and should continue for a length of time appropriate to each person’s needs and risks. It provides patients with support and monitoring from the community pharmacy team and ensures that the product is being administered correctly.  A period of supervision is also recommended for patients who have been switched from methadone to buprenorphine product for the same reasons.

It can enhance compliance, reduce the sharing or selling of medication, increase prescriber confidence in prescribing higher doses give regular contact with a healthcare professional and introduce routine with daily attendance.

Disadvantages include difficulties for people in employment, education or with child care needs, stigmatisation and reduced personal responsibility.

Changes to supervised consumption should be considered on an individual patient basis following assessment of risk. The community pharmacist should be contacted to discuss patient presentation and gain their view on making changes to the level of supervision prior.

Table 5: Supervised self-administration versus take home doses

For most patients, “take home” instalments of no more than one week’s supply of buprenorphine will minimise risks associated with holding large amounts of controlled drugs. This might include coercion/bullying to divert medication. Twice or three times a week dispensing should be considered as a first step. 

The risk of overdose when restarting buprenorphine following missed doses is lower than with methadone. If the patient has been using full opioid agonists such as heroin or methadone in the period of missed buprenorphine doses, there may be a risk of precipitated withdrawal if buprenorphine is re-introduced. The patient’s use of other opioids in the days since last buprenorphine dose should be considered by the pharmacist and prescriber alike when deciding which action to take. If the patient does not return to the pharmacy and there are concerns for patient safety, the pharmacist should contact the prescriber to alert them.

Table 6: Advice for missed doses of buprenorphine

The high affinity of buprenorphine for opioid receptors may impact on the management of acute pain during hospital admissions. For planned admissions this can be minimised by:

• ensuring that the patient is aware of this effect when starting buprenorphine
• contacting the hospital ward ahead of admission to alert them and where possible agree a plan

There are a number of strategies which can be used to manage pain which include but are not limited to:

• Prescribing non-opioid analgesia and/or use of anaesthesia
• Using higher doses of full opioid agonists
• Splitting the dose of buprenorphine across the day

Involving the specialist pain management team (where available) can help optimize pain control. Contact via Raigmore switchboard.

On admission ward staff should contact the community pharmacist and community prescriber to make them aware of the admission and ask them to put a hold on dispensing instalment prescriptions until otherwise informed.

The community prescriber should be contacted at an early stage for discharge planning. If the buprenorphine product has been temporarily reduced or stopped in hospital where clinically appropriate this should be re-titrated before discharge.

Where ongoing treatment with an opioid analgesic is required following discharge a plan should be agreed including information on when and how to reduce and stop the opioid analgesic and re-titrate/reintroduce the agreed opioid substitute.

It is the responsibility of the patient to inform the DVLA of their current medical status. Doctors and other healthcare professionals should:

• advise the individual on the impact of their medical condition for safe driving ability
• advise the individual on their legal requirement to notify the DVLA of any relevant condition
• treat, manage and monitor the individual’s condition with ongoing consideration of their fitness to drive
• notify the DVLA when fitness to drive requires notification but an individual cannot or will not notify the DVLA
• For buprenorphine (oral) DVLA guidance (see resources) for health care professionals states that application for a Group 1 license (car and motorcycle) “may be considered when all of the following conditions can be met” See DVLA guidance for information on Group 2 licences:
  • stable on the programme for a minimum of 1 year
  • the treatment programme is supervised by a consultant or specialist GP
  • the treatment is for management of opiate dependence
  • oral/sublingual treatment only (not parenteral) but subcutaneous long-acting buprenorphine or naltrexone implants may be considered
  • there has been compliance with the programme (adherence to prescription and appointments, and toxicology testing with sustained stability)
  • no non-prescribed psychoactive drug use during the programme or extra use of prescribed drugs such as methadone, buprenorphine, benzodiazepines
  • there is no toxicological evidence of drug misuse
  • there is no adverse effect from treatment likely to affect safe driving
  • there is no alcohol misuse or dependence.

A full list of contraindications, cautions and adverse effects can be found in the relevant Summary of Product Characteristics or the British National Formulary (see resources).

Contra-indications

• Severe respiratory insufficiency
• Severe hepatic insufficiency
• Acute alcoholism or delirium tremens
• Hypersensitivity to buprenorphine, naloxone or to any of the
• Patients suffering chronic pain for which additional opioid analgesia is frequently.

Cautions

Pregnancy 

Specialist support should be sought when treating pregnant patients. UK clinical guidance states: “Research evidence demonstrates no difference in adverse effects between methadone and buprenorphine with both having no adverse effects on the pregnancy or neonatal outcomes, with incidence of Neonatal Abstinence Syndrome (NAS) similar to methadone exposure (Blandthorn, Forster & Love 2011, Jones et al 2010). However, there is some evidence that buprenorphine use results in NAS of lower severity.”

Therefore, in a pregnant woman who is informed of the risks it is reasonable to allow her to remain on methadone or buprenorphine. It is necessary for women and their clinicians to weigh up the risks and benefits to both mother and baby of not taking a specific treatment against those of initiating or continuing the treatment. This will vary from person to person and depend on the severity of the mother’s condition and the complications that could arise if her treatment is altered. Transfer from Methadone to buprenorphine during pregnancy is not generally recommended due to the potential risk of precipitated withdrawal during initiation of treatment and the risk of inducing withdrawal in the foetus. Women not yet on OST can be titrated on to buprenorphine during the first and second trimester, if assessed as otherwise low risk of developing precipitated withdrawals. Current advice and information leaflets to support discussion can be found on the BUMPs (Best Use of Medicines in Pregnancy) website (see resources). 

The impact of buprenorphine on pain management plans during labour should be considered.

Breastfeeding 

For mums stabilised on a buprenorphine product who wish to breastfeed, an individual risk-benefit analysis to inform decision making should be undertaken. Due to the lack of evidence of the effects of these drugs on breastfed infants, manufacturers’ advice is to avoid, although expert consensus opinion states that the effects of these medications on the breastfed infants is likely to be minimal and that breastfeeding is not contraindicated. See also BUMPs (Best Use of Medicines in Pregnancy) website. 

UK Guidance states “Breastfeeding should be encouraged, even if the mother continues to use drugs, except where she uses cocaine or crack cocaine, or a very high dose of benzodiazepines. Specialist advice should be sought if she is HIV positive. Hepatitis C is not a contraindication to breast feeding (HIS 2013).

Methadone or buprenorphine treatment is not a contraindication to breastfeeding and breastfeeding may reduce the intensity and length of neonatal abstinence syndrome and has been shown to improve outcomes (Mayet et al 2008)”

Liver function

See section 'Initiation of therapy' above.

Overdose 

Buprenorphine is reported to be safer in overdose than full agonists, such as methadone, causing less respiratory depression. This being said, drug related deaths involving buprenorphine have been reported particularly when taken in combination with other sedative drugs such as alcohol or benzodiazepines.

In the event of overdose, medical advice should be sought. Standard procedures for reversing opioid-induced respiratory depression should be followed. It may be necessary to use more than the normal amount of naloxone.

Adverse effects

The most common side effects of buprenorphine products include: constipation, headaches, sleepiness, insomnia, sickness and sweating. It should be noted that patients often report a “clear head” with buprenorphine containing products as opposed to the “clouding” effect often experienced with methadone or heroin.

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2. Scottish Government (2021). Medication Assisted Treatment (MAT) standards: access, choice, support [online]. Available from: www.gov.scot [Accessed 28/07/2022]
3. National Institute of Clinical Excellence. Methadone and buprenorphine for the management of opioid dependence. London: NICE technology appraisal guidance 114. January 2007. Available at: https://www.nice.org.uk/guidance/ta114 [Accessed 27/07/2022]
4. Ford, C. Halliday, K. Lawson, E. Browne, E. et al. Guidance for the use of substitute prescribing in the treatment of opioid dependence in primary care. London: January Available at: https://www.rcgp.org.uk/-/media/Files/SMAH/RCGP-Guidance-for-the-use-of-substitute-prescribing-in-the- treatment-of-opioid-dependence-in-primary-care-2011.ashx?la=en . [Accessed 27/07/2022]
5. Medicines.org.uk. (2019). Home - electronic Medicines Compendium (eMC). [online]. Available at: http://www.medicines.org.uk/emc/ [Accessed 27/07/2022].
6. Whittaker, A. The Essential Guide to Problem Substance Use during A Resource Book for Professionals. London: DrugScope. Updated edition 2011.
7. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. Available at: medicinescomplete.com [Accessed on 12/07/2019]
8. DE, Woods JH, Kilbourn MR, Koeppe RA, et al. Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology. 2003; 28:2000–2009