Background

General Drug Issues

1. Increasing the Methadone or Buprenorphine/Naloxone Dose
   • This may be indicated when the patient is reporting that the dose is not sufficiently suppressing opioid withdrawal symptoms for the full 24 hours. The symptoms typically have their onset during the evening and overnight, are most marked in the hours before their usual dosing time and are markedly relieved within an hour or two of dose consumption. (See #2 below, Signs and Symptoms of Opioid Withdrawal and Intoxication/Overdose).
   • This may occur as the result of:
     • Ongoing development of tolerance to methadone or buprenorphine/naloxone.
     • Interaction with other medications or alcohol (see methadone or buprenorphine/naloxone interactions).
     • Decreased patient ability to manage previously tolerated mild withdrawal symptoms because of increased stress.
     • Cessation of illicit opioid use.
   • Where continued, or relapse to illicit opioid use is reported:
     • Check for signs of injecting.
     • Check for signs of opioid intoxication.
     • Get a urinalysis done (full drug screen).
     • Enquire about triggers/stressors.
   • Notes:
     • Once a stable, comfortable dose has been achieved, it is not usual that the dose needs to be repeatedly adjusted upwards because of increasing tolerance.
     • Patients may report craving without significant physical withdrawal. If in doubt, prescribers can defer a decision and advise patients to discuss with the Addiction Liaison Clinician.
     • Measurement of serum levels may sometimes help inform a decision regarding dose adequacy. See serum levels page.
     • In the situation of risky alcohol use (or other CNS depressants), methadone or buprenorphine/naloxone dose increase may actually increase clinical risk. Seek advice if necessary.
   • Where, after careful clinical assessment, the decision is to trial an increase in dose, the G.P should contact the Addiction Liaison Clinician. Dose increases should be titrated up at no more than 5 to 10mgs at intervals of 5 to 7 days.  It is advised to consider a temporary return to daily dispensing whilst re-stabilising, so that the pharmacist can also provide support and observe for any signs of sedation.
   • If there is evidence of injecting, provide harm reduction information related to safer injecting practices and access to needle exchange. Notify Addiction Liaison Clinician.
   • There are occasions when patients request an increase in dose to manage acute or chronic pain. We advise consultation with the Addiction Liaison Clinician before increasing the dose for pain relief. It is generally advised to add short-term additional medication for pain relief rather than altering OST medication.
2. Signs and Symptoms of Opioid Withdrawal and Intoxication/Overdose
   • Signs and symptoms of opioid withdrawal:
     • lacrimation
     • perspiration
     • fatigue
     • yawning
     • dilated pupils
     • weakness
     • restlessness
     • gooseflesh
     • abdominal cramps
     • hot and cold flushes
     • joint pain, backache
     • drug seeking behaviour
     • anorexia/nausea diarrhoea
     • muscle aches/leg cramps
     • insomnia
     • rhinorrhoea
   • The onset of methadone or buprenorphine/naloxone withdrawal starts at 24 to 48 hours after the last dose. The duration of methadone or buprenorphine/naloxone withdrawal is up to 21 days. Psychological and neurological (including pain receptors) adjustments can last up to six months. Research indicates withdrawal symptoms from buprenorphine/naloxone are less than from methadone.
   • Signs and symptoms of opioid intoxication/overdose:
     • sedation
     • hypotension
     • coma
     • pulmonary oedema
     • seizures
     • scratching of skin
     • respiratory depression
     • pinpoint pupils
     • bradycardia
   • In cases of overdose ensure that the airway is clear and perform emergency cardiopulmonary resuscitation as necessary.
   • Transfer to hospital as soon as possible where treatment with an infusion of naloxone can be commenced.
3. Urine Toxicology Guidelines
   • International evaluation of urinalysis shows that it is not in itself instrumental in reducing harm related to illicit drug use. Urinalysis provides information only about a patient's recent drug use and not about quantity, frequency or route of drug use and is a supplement to patient self-report. With these limitations in mind, urinalysis results are integrated into the clinical assessment.
   • Research has consistently indicated that where patients do not have to be concerned that they will be punished for disclosure of illicit drug use the reliability of self-reported drug use increases.
   • However, urinalysis may be indicated or useful in the following situations:
     • Where the patient or GP wishes to verify self-report of drug use.
     • Where there is doubt regarding the accuracy of reported drug use or methadone or buprenorphine/naloxone consumption.
     • Where the GP or pharmacist is concerned that a patient is intoxicated. Here a full drug screen is indicated.
     • As supportive information for monitoring by other services e.g. Community Corrections, Child Youth and Family Service.
     • For use in overall programme evaluation.
   • Essential factors to promote reliability include:
     • Random sampling.
     • Observed by Medical Officer/nurse.
     • Requests must be on an appropriate laboratory request form.
   • Note: If a patient does not complete a requested urinalysis further investigation is required.
   • *See Appendix 6 Approximate Detection Time for Selected Drugs in Urine page 105 of "New Zealand Practice Guidelines for Opioid Substitution Treatment 2014"
4. Serum Levels
   • Methadone serum levels are indicated when the clinical picture does not agree with expected/typical responses to a given dose of methadone and when this additional clinical information would be of use in making decisions regarding changes in the methadone dose.
   • The serum methadone level for a given dose will vary between individuals because of individual tolerance and the influence of other factors (e.g. other medications, pregnancy, individual variations in hepatic metabolism and renal clearance).
   • Research to date on the clinical application of serum methadone levels is inconsistent, generally indicating that the overall clinical picture must be the foundation for any decisions regarding adequacy of methadone dose. Serum levels may not provide conclusive information.
   • Consult with BOPAS OST prior to any serum level testing.
     • Clinical situations where serum levels may be useful are:
     • a client's responses to methadone OST does not align with the expected response.
     • a client is suspected of poor compliance with the programme, or of diverting their does (comparison of serum level measurements taken on the same individual within the last 6-12 months, with careful observation of dosing and retention of doses, may assist in determining compliance). 
     • when dose increase beyond 120mg/day is being considered (only to be done in conjunction with BOPAS).
     • when there is doubt about the clinical indications for a dose increase.
     • if there is a suspected drug interaction.
     • when determining the need for split dosing (only to be done in conjunction with BOPAS).
     • when there is doubt regarding the accuracy of reported methadone consumption-comparison of serum levels taken on the same individual within the last 6-12 months, may assist in determining compliance).
     • in pregnancy.
     • when a client has a serious liver or other physical disease and there may be methadone accumulation.
   • Serum level testing: This procedure should be undertaken in liaison with the dispensing pharmacist and the BOPAS OST service.
     • The patient must consume their methadone at the pharmacy at approximately the same time for 4 days (usually Mon-Thurs) prior to the blood test/s (on Fri). This is to ensure they reach a steady state for a known dose consumed daily under observation.
     • On the day of the blood test the patient presents to the laboratory for their trough blood level to be taken before they consume their dose and at the same time, they have been consuming for previous four days.
     • If clinically indicated (see split dosing) a peak blood level is taken 3 ½ to 4 hours after the patient has consumed their dose, and before any takeaway doses are dispensed.
     • Serum methadone levels can be measured using capillary blood samples when venous access is difficult. A 1ml SST tube is sufficient.
   • Serum level interpretation and guidelines:
     • Serum methadone trough level: Level to provide 24-hour relief of withdrawal symptoms is usually 650-1000 ng/ml, though this should be approached on a case-by-case basis.  Where a client presents with a higher trough level than 1000, this must be discussed with the OST specialist service.
   • Serum methadone or buprenorphine/naloxone trough and peak levels:
     • Where the peak: trough ratio is 2 or 2.5:1 or greater then split dosing may be indicated in a stable patient. Consult with the BOPAS OST Service, prior to instituting split dosing.See Split methadone or buprenorphine/naloxone dosing.
   • *See Section 5.5 Measuring Methadone Serum Levels page 39 of "New Zealand Practice Guidelines for Opioid Substitution Treatment 2014"
5. Treatment Completion
   • "Entering and staying in treatment, coming off opioid substitution treatment and exiting structured treatment are all important indicators of an individual's recovery progress, but they do not in themselves constitute recovery. Coming off OST or exiting treatment prematurely can harm individuals, especially if it leads to relapse, which is also harmful to society. Recovery is broader and more complex journey that incorporates overcoming dependence, reducing risk-taking behaviour and offending, improving health, functioning as a productive member of society and becoming personally fulfilled. These recovery outcomes are often mutually reinforcing."The National Treatment Agency for Substance Misuse (2012) in the NZ Practice Guidelines for Opioid Substitution Treatment (2014) p26"
   • Where a patient expresses an intention or desire to withdraw from methadone or buprenorphine/naloxone please contact the Addiction Liaison Clinician for support with this.
   • Consider:
     • Motivation for withdrawal.
     • Giving information to the patient e.g. the orange Coming off Methadone booklet.
     • Discuss withdrawal options and develop a plan with the patient. BOPAS OST prefers clients are offered the opportunity to reduce "at request", so as to ensure they feel in control of their reduction regime at all times.  For example, the script can be annotated to "reduce 1mg per week at request".
     • Patients may also stop reduction for a period or have small dose increases before recommencing reductions. As with the opening quote; Recovery is broader and more complex journey.
     • Review the withdrawal process each time the patient is seen or at the patient's request.
     • Offer and negotiate a 'window period' of between 0 and 12 weeks with the patient during and prior to the completion of the withdrawal from methadone or buprenorphine/naloxone. The window period is the time after the last methadone or buprenorphine/naloxone dose is consumed within which the patient can choose to immediately restabilise on methadone or buprenorphine/naloxone. (Note: The restabilisation on methadone or buprenorphine/naloxone will be carried out by BOPAS OST, and the patient transferred back to the GP programme as appropriate).
     • Notify the Addiction Liaison Clinician of the date on which the patient last consumed methadone or buprenorphine/naloxone and of the negotiated window period.
     • If the patient makes contact wishing to re-stabilize on methadone or buprenorphine/naloxone within the window period contact the Addiction Liaison Clinician about making an appointment at BOPAS OST for assessment regards restabilisation.
     • If the patient makes contact wishing to recommence on methadone or buprenorphine/naloxone after the window period is completed then refer them to BOPAS for reassessment.
   • If you believe that positive treatment outcomes will be compromised by withdrawal, contact the Addiction Liaison Clinician to arrange a joint appointment with the patient to discuss and decide on an appropriate course of action, or contact the BOPAS OST, medical officer for advice/support.
6. Method of Withdrawal
   • There is no ideal method of withdrawal from methadone or buprenorphine/naloxone. It is important that any reduction plan is done in consultation with the client, GP and Addiction Liaison Clinician.  Possible approaches to withdrawal are:

   1. 1. Fixed: The rate of reduction of methadone or buprenorphine/naloxone is set by the GP in consultation with the patient and can only be altered by the GP. Recommended methadone reduction rate is 2.5mgs per script cycle. Some patients tolerate larger and faster initial reductions. Statistically the faster the reductions, the higher the rate of relapse as smaller reductions are better tolerated and momentum maintained.
      2. Flexible: The rate of reduction of methadone or buprenorphine/naloxone is entirely within the control of the client.  The client and GP agree on a rate that is then added to the prescription, for example 1mg per week or 2mg per fortnight AT REQUEST.  It then allows the client to access a reduction from the pharmacy whenever they feel ready. These patient-initiated dose changes may only be   reductions, any increase in dose must be renegotiated with the GP and a new prescription written.  The script must then be annotated with "adjust dose for reduction" to allow pharmacist to adjust the dose accordingly.
      3. Blind: The patient has the option of requesting a blind reduction, to be arranged by the GP in consultation with the Addiction Liaison Clinician and Pharmacist and the script to be appropriately annotated by the GP. The details of the dose reductions and administration are arranged by the GP with the pharmacist.

   • Decisions must be made after assessment of the patient's needs and preferences, and in consultation with the patient.
   • Rate of withdrawal recommended guidelines

   Current methadone or buprenorphine/naloxone dose/day	Weekly or fortnightly or monthly reduction
   Above 50mg	5mg or less
   30-50mg	2.5mg or less
   Less than 30mg	1-2mg or less

   • The rate of withdrawal should be reviewed each time a patient is seen. If there is evidence that a patient's treatment outcomes are compromised by the rate of withdrawal, a slowing or cessation of the dose reduction, or even a temporary increase in the dose is recommended, rather than introducing ancillary medication.
   • Note:  Once down to 20mg per day or less, consider changing to the Biodone 2mg/ml substance to enable small reductions to be made more easily. The pharmacy will need to be notified in advance so that they can order this in.
   • If clients struggle with the reduction off lower doses of methadone, they could be offered a transfer to Buprenorphine/naloxone, as this might be better tolerated.
   • *See Section 3.9.1 Planned Withdrawal page 29 of "New Zealand Practice Guidelines for Opioid Substitution Treatment 2014"

Methadone Specific Issues

1. Absorption, distribution, and half-life
   • Methadone is rapidly absorbed after oral administration with detectable plasma levels after 30 minutes.
   • It undergoes considerable tissue distribution and crosses the blood brain barrier.
   • Peak level is 3 to 4 hours after consumption.
   • With regular doses the half-life is 6 to 96 hours with a mean of 25 hours.
   • Steady state plasma levels are reached after approximately 4 hours.
   • Methadone accumulates on repeated administration therefore doses should not be increased more often than every 4 days.
   • *See Appendix 3 Pharmacology and Pharmacokinetics of Methadone and Buprenorphine page 97 of "New Zealand Practice Guidelines for Opioid Substitution Treatment 2014"
2. Methadone Toxicity
   • Methadone causes respiratory depression and coma in overdose. There can be a narrow margin between a safe and a fatal dose especially in the presence of other CNS depressants (prescribed or illicit) or if there is no opioid tolerance established.
     • For non-tolerant adults oral or parenteral doses of 50 mg or less have been fatal. Potentially fatal dose for children under 14 years is 10 mg.
     • Potentially lethal overdoses can occur within 0.5 to 6 hours after ingestion by non-tolerant or partially tolerant individuals.
     • A child consuming any quantity of methadone or buprenorphine/naloxone must be taken to an accident and emergency department immediately.
   • This is one of the major underlying reasons behind the emphasis on safety and the limitations on takeaway doses in OST patients.
   • *See Section 4.1 Overdose; 4.1.1 Consumption of takeaway doses by a child, page 30 of “New Zealand Practice Guidelines for Opioid Substitution Treatment 2014"
3. Metabolism and Excretion
   • Methadone is primarily metabolized in the liver and is excreted in urine and bile.
   • A small amount is excreted unchanged by the kidneys and this amount increases with increased urinary acidity.
4. Methadone Side Effects
   • Some of these side effects may be confused with withdrawal symptoms and may be experienced even when the dose is appropriate.

   Side effects	Notes	Interventions/advice
   Aching muscles and joints	Some individuals report rheumatic type pains and 'bone pain' - uncommon	Medical examination for any underlying pathology. Hot Epsom salts bath may ease symptom
   Analgesia and hypo-analgesia	Systemic analgesia, long term can lead to opiate receptor saturation and hypo-analgesia or increased pain sensation	Advise patient to discuss chronic pain with GP/pain specialist
   Constipation	A common side effect	Increase intake of water and fiber and increase exercise. If necessary, take regular Lactulose or Movicol
   Galactorrhoea	Due to mildly/moderately increased prolactin levels	Check prolactin level and rule out pathology. Seek specialist endocrinologist advice if uncertain
   Irregular menstrual cycle/amenorrhoea	Common in women who take opioids	Educate women about the risk of pregnancy despite menstrual irregularity/amenorrhoea
   Lowered sex drive and impotence	Common with all opioid use	Reduce dose but needs to be weighed against compromising outcomes on MMT
   Oedema	Fluid retention, puffiness, swelling, particularly of feet & ankles - uncommon	Usually resolves within a few weeks of starting treatment
   Other G.I effects	Include: Nausea and vomiting Reduced gastric emptying Elevated pyloric sphincter tone Biliary tract outflow effects (can result in biliary spasm) Loss or increased appetite	To reduce nausea and vomiting, suggest patient eat before consuming dose and drink dose slowly Other symptoms may be reduced by reducing the dose
   Increased Perspiration	Common especially at peak serum levels
   Q-T prolonging effect	Potential for QTc prolongation, especially if combined with other drugs with similar effect	Annual ECG tests recommended. See medications also with QT prolonging effects
   Sedation	Drowsiness may be experience at peak serum level (3 to 4 hours after dose) especially during initial stabilisation	Check serum levels Reduced dose or split dose may be necessary - see relevant sections
   Shallow breathing	From the respiratory depressive action of opioids	Reduce dose
   Skin rash/itching		Appropriate skin lotion, e.g. BK lotion or similar emollient, antihistamine
   Tooth decay/dry mouth	Opioids reduce the production of saliva	Increase fluid intake Chew sugar free gum Regular flossing and tooth brushing Regular dental checks
   Weight gain	Occurs in small number of patients	Assistance with weight management strategies
   Weight loss	Lack of appetite, may be associated with mood	Assistance with weight management strategies

   • *See Section 6.2 Managing Side Effects page 44 and Appendix 4 Side Effects page 101 of "New Zealand Practice Guidelines for Opioid Substitution Treatment 2014"
5. Interactions
   • NZ Formulary
   • *See Section 4.4 Drug Interactions page 34 and Appendix 5 Drug Interaction page 103 of" New Zealand Practice Guidelines for Opioid Substitution Treatment 2014"
6. How to write a prescription

   Writing a methadone H572 controlled drug prescription

   The use of H572M controlled drug prescription forms is restricted to prescribing methadone for patients under the authority conferred by Section 24(2) (d) Misuse of Drugs Act 1975 (i.e. where BOPAS has authorised a prescriber for a specific patient). The form is not used for prescribing of methadone to other patients in other circumstances (e.g. pain relief for a non-BOPAS client); in these cases the general H572 controlled drug prescription is used.

   H572 Prescription example

   

   Instructions:  

   1. Date prescription written to be no more than 7 days from prescription starting date (point 5).
   2. Name and current residential address of patient. It is not acceptable to use the pharmacy address as the patient address.
   3. Patient's NHI number.
   4. Written dose, in numeric and word form e.g. 80 (eighty) mg.  Note, if a patient is undertaking any type of withdrawal from methadone, then the new prescription should state the current dose as the starting dose.  The script should then be annotated "adjust for reduction" to allow pharmacist to adjust the starting dose. Annotate with formulation of methadone to be used - BOPAS authorises 5mg/ml (consider isomg a stamp to pre-populate scripts). (2mg/ml can be used in doses under 20mg). 
   5. Start date (actual date pharmacist is to begin dispensing).  Check that the commencement date is a consumption day.
   6. Total period of supply up to a maximum of 30 days, however a 28-day cycle is routine to ensure ease of keeping to a regular cycle.
   7. Maximum rate of any withdrawal regimen (if any) is specified. eg. Reduce 1mg/week at request.
   8. Days for which takeaways are authorised.  For example, 'Tuesday, Wednesday, Friday, Saturday and Sunday' for a patient on twice weekly dispensing who collects and consumes doses on Mondays and Thursdays.
   9. Name of pharmacy.
   10. Prescriber's signature.
   11. Prescriber's stamp or print NZMC Reg. No., doctor name and address.  Each copy must be stamped.
   12. Top three copies to pharmacy (via patient or post). Note: Bottom copy (blue) to be kept on patient file; please do not send to the pharmacy.
       
       

   • Ordering
     • These CD pads are requested 3-6 monthly by GPs based on their current number of authorised patients.
     • Orders are faxed to the Ministry of Health using the approved order form (refer to Forms section).  On receipt of the pads, sign the enclosed verification of delivery form and fax to the Ministry of Health as soon as possible.

   • Ministry of Health contacts
     • MedSafe Office - ph. 09 441-3670
   • Storage
     • These CD pads must be stored in a secure place as for other CD prescription pads.  You are advised to keep the receipt for the pads as a record of the prescription pad numbers.
   • Theft of prescription forms
     • If the prescription numbers are known, inform the Ministry of Health MedSafe office.  If the prescription numbers are unknown, inform the Ministry of Health and request the prescription numbers of the pads recently sent to the practice.  Inform the MOH MedSafe office of the numbers.
   • Ceasing to prescribe
     • Notify the Ministry of Health that you no longer require these pads.
   • Receipt of excess pads
     • Notify the Ministry of Health that you no longer require these pads. Destroy or return any unused pads to the Ministry of Health

Suboxone Specific Issues

1. Buprenorphine/Naloxone - Absorption, Distribution and Half-life
   • Buprenorphine/naloxone is a combination of buprenorphine (a semi-synthetic partial opiate agonist) and naloxone (a full opiate antagonist). It is used in opioid substitution treatment as an alternative to methadone.
   • Both buprenorphine and naloxone are rapidly metabolized in the small intestine and liver and both have very poor bioavailability when taken this way. For this reason, buprenorphine/naloxone is taken sublingually: buprenorphine has rapid absorption and good bioavailability via this route, whereas bioavailability for sublingual naloxone remains poor. Once absorbed, buprenorphine undergoes rapid distribution and readily crosses the blood-brain barrier. Although the serum half-life of buprenorphine is only around 3 hours, it has a very high affinity for the mu-opioid receptor, and once across the blood-brain barrier it will exert a clinical effect for 24-36 hours.
   • The naloxone is to discourage intravenous use. If taken intravenously, naloxone has good bioavailability and exerts a strong antagonist effect at the opioid receptors. This is likely to cause unwanted symptoms of opiate withdrawal in those who are opiate tolerant.
   • As a partial opiate agonist, buprenorphine exhibits a plateau effect with increasing dose, and this makes it far safer in overdose than a full agonist such as methadone.  As the risk of accumulating a toxic dose is reduced, doses can be increased more frequently during the induction/ titration phase of treatment, and with specialist drug service supervision, daily increases in dose are possible until stability is achieved.
   • *See Appendix 3 Pharmacology and Pharmacokinetics of Methadone and Buprenorphine page 97 of "New Zealand Practice Guidelines for Opioid Substitution Treatment 2014"
2. Buprenorphine/Naloxone Toxicity
   • Buprenorphine is a partial opiate agonist and unlike full agonists (morphine, methadone), the pharmacological effects of buprenorphine exhibit a "ceiling effect" with increasing doses. This makes buprenorphine/naloxone safer in overdose than, say, methadone, as the negative opiate effects (eg respiratory depression) are also constrained by this ceiling effect. Nevertheless, certain groups may be particularly vulnerable to respiratory depression, eg children, those who are opiate-naïve or individuals with chronic obstructive pulmonary disease, and care should be taken to consider these factors when prescribing.
   • Although buprenorphine is far safer than full opiate agonists in overdose, there have been some reports of fatalities in adult users, and in particular where there have been contributing factors including:
     • Opiate-naïve users.
     • Co-use of other substances (alcohol, benzodiazepines).
     • Use by crushing and snorting (although this risk is reduced with buprenorphine/naloxone due to the presence of naloxone).
   • Children who accidentally ingest buprenorphine/naloxone are particularly at risk of toxic effects:
     • Toxic effects are more pronounced in children under 2 years of age.
     • In retrospective studies, effects below 2mg dose were unlikely to be severe but at least some effects (lethargy, nausea, vomiting) occurred in all children who ingested 4mg or more.
     • Respiratory depression occurred in 7% of paediatric overdoses, and coma in 3%.
   • Immediate hospital treatment must be sought in every case where a child or a non-tolerant adult has ingested buprenorphine/naloxone. Similarly, those who are prescribed buprenorphine/naloxonemust be medically assessed if overdose or co-use of other respiratory depressants (alcohol, benzodiazepines) is suspected.
3. Metabolism and Excretion
   • Buprenorphine is primarily metabolized via the cytochrome P450 pathway in the liver. Care should be taken when co-prescribing medications which induce this pathway (carbamazepine, phenytoin, phenobarbital, rifampin, reverse-transcriptase inhibitors) or inhibit it (azole antifungals, macrolide antibiotics, protease inhibitors). Buprenorphine metabolites are primarily (70%) eliminated in the faeces by biliary excretion, with the remainder excreted in the urine. Naloxone is eliminated via the urine.
4. Side Effects of buprenorphine/naloxone
   • Very common (reported in at least 10% of patients)
     • Headache, withdrawal syndrome (usually during induction phase of treatment)
     • Constipation
     • Insomnia
     • Increased perspiration.
   • Common (reported in at least 1% of patients)
     
     

   § Chills/ 'flu'-type symptoms	§ Peripheral oedema
   § Tiredness/ malaise	§ Parasthesia
   § Reduced appetite/ weight loss	§ Somnolence
   § Nausea and vomiting	§ Abnormal liver function
   § Abdominal cramps	§ Depression/ increased anxiety
   § Diarrhoea	§ Cough/ pharyngitis/ rhinitis
   § Hypertension	§ Rash/ pruritus/ urticaria
   § Vasodilation	§ Lacrimation disorder
   § Reduced libido	§ Amblyopia
   § Impotence	§ Irregular menstrual cycles
   § Leg cramps/ myalgia/ back pain/ chest pain/ general pain
   § Dental caries

   • Many of these symptoms will resolve within a few days of commencing treatment. Other, more long term concerns may be managed by changes in behaviour and lifestyle, eg the increased incidence of dental caries can be managed by improved oral hygiene, dental visits and dietary changes.
   • *See Section 6.2 Managing Side Effects page 44 and Appendix 4 Side Effects page 101 of "New Zealand Practice Guidelines for Opioid Substitution Treatment 2014"
5. Buprenorphine/Naloxone Interactions
   • Consideration should be given to the potential interactions with Buprenorphine/Naloxone before the following medications are prescribed:
     • CNS depressants, narcotics.
     • General anaesthetics.
     • Mitochondrial toxins (aspirin, isoniazid, valproate, amiodarone, antiviral nucleoside analogues).
     • CYP3A4 inhibitors (protease inhibitors, azole antifungals, calcium channel blockers, macrolides).
     • CYP3A4 inducers (phenobarbitone, carbamazepine, phenytoin, rifampicin).
     • *See Section 4.4 Drug Interactions page 34 and Appendix 5 Drug Interaction page 103 of "New Zealand Practice Guidelines for Opioid Substitution Treatment 2014"
6. The 'precipitated withdrawal' and 'opiate-blocking' effects of Buprenorphine/Naloxone
   • The 'precipitated withdrawal' and 'opiate-blocking' effects of buprenorphine/naloxone. Buprenorphine has an extremely high affinity at the mu-opioid receptor but exerts only a moderate effect at the receptor. Consequently, if the initial buprenorphine/naloxone dose is taken too soon after the last use of another opiate, buprenorphine will both displace that opiate and cause a marked reduction in overall opiate effect. This is the so-called 'precipitated withdrawal' effect, which can be both unpleasant and frightening for opiate-dependent patients. Precipitated withdrawal is not reversible once triggered, although the effects will pass within a few hours and symptomatic relief during this time may be useful.
   • To avoid precipitated withdrawal, care must be taken to ensure that sufficient time has elapsed since the last opiate dose, usually at least 12-24 hours for a short-acting opioid such as dihydrocodeine. Checking that a patient is in at least mild opiate withdrawal before starting buprenorphine/naloxone, eg by using the Clinical Opioid Withdrawal Scale, can be useful. Transition to buprenorphine/naloxone from longer-acting opioids, eg methadone, requires a much longer abstinence period, and this is best carried out under the supervision of specialist alcohol and drug services. In these situations, a mico-dosing regime could be utilised.
   • Once successfully inducted onto buprenorphine/naloxone, the strong affinity of buprenorphine for the mu-receptor means that the consequences of the patient subsequently using unprescribed opiates are unpredictable. Usually, the buprenorphine will prevent the opiate from accessing the receptors and the user will feel that the opiate has had no effect at all - this is the so-called 'blocking effect'. In some cases however, using another opiate may trigger a precipitated withdrawal event. Some patients have been known to try to override the blockade effect of buprenorphine by taking very large doses of opiates; such behaviour is extremely risky in terms of accidental overdose and if such behaviour is suspected treatment should be reviewed, including the suitability of buprenorphine/naloxone as a treatment choice.
7. Dosing and Maintenance Treatment
   • Initial dose is usually 2-4mg buprenorphine/naloxone on the first day with subsequent doses titrated upwards against withdrawal symptoms in 2-4mg increments, to a maximum daily dose of 32mg. For most patients, good compliance can be achieved in the range 8-16mg daily. Unlike methadone there are no buprenorphine/naloxone 'fast metabolizers' and once-daily dosing is appropriate for the vast majority of patients.
   • For some patients who have had a suitable period of stabilisation at a regular daily dose, the frequency of dosing may be reduced to alternate-days at twice the titrated daily dose, with no reduction in clinical effect. For example, a patient stable at 8mg buprenorphine/naloxone daily may be prescribed 16mg on alternate days. However, the maximum dose given on any one day should never exceed 32mg and alternate-day dosing should only be done with the full informed consent of the patient.

Information

• For Providers
  • GP Shared Care Manual
  • GP Shared Care 3 monthly OST Patient review checklist
  • GP Shared Care Agreement
  • Authority for GP to prescribe controlled drugs for the treatment of addiction
  • NZ Practice Guidelines for Opioid Substitution Treatment
  • National Opioid Substitution Treatment Training Programme
  • Best Practice Article on Opioid Addiction October 2014
  • BOPDHB Community Pharmacy Feedback form
  • Auckland Opioid Treatment Service Website and Resources
  • Regional Maori Health Services Cultural Practice Manual
• For Patients
  • OST and you - A guide to Opioid Substitution Treatment
• Acknowledgements

  This pathway was developed in collaboration with:

  Service	Name
  Mental Health SMO Tauranga	Sue Mackersey*
  WBOPPHO GP	Jocelyn Heard*
  GP Liaison Nurse - OST	Andy Walford
  WBOPPHO GP	Tony Farrell
  Clinical Team Leader, BOP Addiction Service	Paula Abbey
  Clinical Lead BOPAS	Sally Whitelaw
  Mental Health SMO	David Chaplow
  Community Pharmacist	Rebecca Lukey
  P&F	Lesley Watkins
  Pain Service	Vicky Beveridge
  Program Manager Bay Navigator	Caroline Davy

  *Pathway Lead

Disclaimer: These pathways, for the care and management of patients within Bay of Plenty, have been developed jointly by primary and secondary care clinicians. They provide guidance for General Practice teams to diagnose and manage patients suffering from a number of different conditions, and contain patient information resources. The pathways are maps of publicly-funded services accessed by referral from the community, and are strongly evidence based, but are not full clinical guidelines. As the pathways are suggested guidance only, while using them you must exercise your own clinical judgement and pertinent clinical data when treating your patient. This site is intended to be flexible and frequently updated. While every effort has been made to ensure accuracy, all information should be verified.