Use of buprenorphine in primary care Lambeth Shared Care GP

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Use of buprenorphine in primary care Lambeth
Shared Care GP

• Dr Nicholas Lintzeris, MBBS, PhD, FAChAM
• Senior Lecturer Honorary Consultant,
• National Addiction Centre, Institute of
  Psychiatry The Maudsley

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Overview of presentation
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Buprenorphine clinical pharmacology
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Buprenorphine

• A synthetic opioid
• Partial agonist at the ? opiate receptor
• - Low intrinsic activity only partially activates
  opiate receptors
• High affinity for the ? receptor
• - Binds more tightly to opiate receptors than
  other opiates

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Classification of Opioids
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Safety Aspects

• Less risk of overdose c/w full opiate agonists
• Less respiratory depression sedation than
  methadone
• BPN tolerated by individuals with low levels of
  opiate dependence
• Potential concerns re safety
• BPN related deaths reported in combination with
  other sedatives (EtOH, BZDs)
• Severe respiratory depression seen in opiate
  naïve individuals

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BPN effects in ex-opiate addicts(Walsh et al
1994)

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Australian mortality data (2002-3)(Gibson et al
2005)
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Pharmacological clinical properties
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Pharmacokinetics

• Bioavailability IVgt SC gt SL gt oral
• Sublingual tablets
• 0.4, 2 8 mg tablets available
• tablets take 3 to 10 minutes to dissolve
• Quick onset of action 3060 min
• Peak effects 1 4 hours
• Duration of action is dose related
• low dose (2 4 mg) 4 12 hrs
• med dose (8 16 mg) 24 hrs
• high dose (16 32 mg) 2 3 days

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Withdrawal from buprenorphine

• Opiate withdrawal syndrome on stopping long-term
  BPN treatment
• Milder withdrawal than typically seen with heroin
  / morphine / methadone
• Peak withdrawal experienced within first 2 to 5
  days after stopping chronic BPN treatment, with
  mild symptoms persisting for weeks
• Minimal withdrawal if used for short courses
• e.g. for heroin detox

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Common side-effects

• Headache
• Constipation
• Nausea
• Drowsiness, sedation
• Tiredness, lethargy
• Sleep disturbances
• Sweating
• Precipitated withdrawal on commencing BPN

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Drug interactions

• Sedatives
• Mixing sedatives (e.g. EtOH, BZDs) can produce
  respiratory depression, heavy sedation, coma,
  death
• No worse than methadone (subjective respiratory
  effects, less impairment cognitive-performance
  measures)
• Opioid agonists
• BPN blocks effects of other opiate analgesics
• Hepatic enzyme (CYP450) inhibitors / inducers
• appears to be less impact that with methadone
• important for clients with poor adherence to
  medications

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BPN Livers

• BPN metabolised mainly (conjugation) in liver
• At normal doses BPN appears to have no adverse
  effects in healthy livers
• Concerns with
• some patients with liver disease (e.g. HCV, EtOH)
  have had elevation in LFTs after commencing BPN
• high dose BPN can be toxic (e.g. 100mg at a time,
  injecting BPN)
• Recommend LFTs at start of treatment reviewed 1
  - 6 months later if abnormal

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BPN Pregnancy

• So far so good ...
• hundreds babies born on BPN with no short term
  adverse effects with ?milder Neonatal Abstinence
  Syndrome
• But, small numbers no long-term follow-up to be
  certain of safety hence methadone still
  considered the devil we know
• Clinical recommendations
• get informed consent if going to use in pregnancy
• do not transfer pregnant methadone patient to BPN
  (risk of precipitated withdrawal)

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BPN in DetoxThe evidence
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Objectives of detoxification

• Detox is not a cure for heroin dependence
• Most heroin users relapse after withdrawal
• Need long-term treatment to achieve long-term
  changes
• Short-term intervention that aims to
• Interrupt a pattern of heavy regular drug use
• Alleviate withdrawal discomfort
• Prevent complications of withdrawal
• Facilitate post-withdrawal treatment linkages

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Components of detox program

• Assessment client-treatment matching
• Supportive care
• safe environment
• provision of information
• supportive counselling
• regular monitoring
• Medication
• Post-withdrawal linkages

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Cochrane Review on BPN Detoxification (Gowing et
al. 2004 in press)

• Compared to symptomatic medication (clonidine /-
  BZDs)
• BPN less withdrawal severity
• BPN greater treatment retention in detox
• No sig diff re adverse events
• Compared to methadone
• BPN more withdrawal early in detox
• BPN less severe withdrawal later in detox less
  prolonged withdrawal

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BPN Vs Clonidine Withdrawal symptoms
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RCT Meth vs BPN for heroin detox Petitjean et al
2002

• N 37 (19 BPN, 18 Meth)
• Inpatient unit, Basel
• Completed detox
• 88 BPN, 89 Meth
• Conclusion
• more early withdrawal in BPN group but less
  withdrawal when medication ceased

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Selecting detox medications

• Symptomatic medications
• in settings where BPN / methadone cannot be used
• for clients not wanting opioids
• Methadone
• gradual reduction regimes, but rebound withdrawal
• Buprenorphine
• ?becoming gold standard d.t. flexibility
• rapid / gradual reduction regimes
• increased post-detox options (NTX, maintenance)
• Naltrexone
• for those considering NTX for post-detox treatment

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BPN for detoxification

• Short term regimes (3 to 14 days)
• inpatient / outpatient
• use BPN to ameliorate main features of heroin
  withdrawal
• minimal rebound withdrawal on stopping BPN
• no / minimal other medication required
• Gradual outpatient reduction regimes (1 6
  months)
• allows more time for stability to be achieved
• greater withdrawal discomfort on stopping BPN

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• but beware of limitations of detox

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RCT BPN Maintenance vs Detox Kakko et al Lancet
2003

• 40 subjects randomised to
• 1 week detox / 1 year maintenance
• all provided counselling for 1 year
• Heroin use
• Detox all relapsed
• Maintenance 75 Opiate (-)ve UDS
• Mortality (p0.015)
• Detox 4/20 (20)
• Maintenance 0/20

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RCT Methadone maintenance vs gradual detoxSees
et al JAMA 2000

• N154 randomised to
• 1 year methadone maintenance, or
• 6 months gradual reduction intensive
  psychosocial
• Results MMT had significantly
• better treatment retention
• less heroin use
• fewer HIV risk practices
• fewer legal problems

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Subutex as a gateway to treatment
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Key points about detox

• Do not expect cures from detox programs
• Short term treatment usually short term changes
• Medication only one aspect to good detox
• BPN increases post-detox options

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Maintenance
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Principles of effective maintenance treatment

• Duration of treatment
• Dose
• Quality of therapeutic relationship
• Regular review, supervision monitoring
• Participating in psychosocial services
• Bio-psycho-social model for chronic condition

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Efficacy of BPN maintenance treatmentFor heroin
use treatment retention in RCTs

• High dose MMT (gt 80 mg)
• better than
• Medium dose MMT(40-80mg) Medium dose
  BMT(8-12mg)
• better than
• Low dose MMT (lt 40 mg) Low dose BMT (lt 8 mg)
• Note No RCTs of high dose BMT (?16mg) to Meth

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Clinical recommendations What maintenance doses
should we use?

• Methadone
• Recommend daily doses 60 120 mg if lower doses
  not achieving treatment goals
• Buprenorphine
• Recommend daily doses of 12 32 mg if lower
  doses not achieving treatment goals

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Do certain types of clients respond better to BPN
or methadone?

• Substance use issues
• severity of dependence / duration of heroin use
• injectors / non-injectors
• co-use of stimulants, BZDs, alcohol (efficacy /
  safety)
• Co-morbidity
• Psychiatric (depression, anxiety)
• Pregnancy, HIV
• Cardiac problems (QT prolongation)
• Concomitant medications
• hepatic enzyme-inducers (epilepsy, TB, SSRIs,
  HIV)
• Chronic pain

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Advantages disadvantages of buprenorphine c/w
methadone
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Clinical aspects to delivering BPN treatment
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Goals of induction

• To initiate patient into appropriate treatment
• To minimise adverse events
• Opioid side effects
• Precipitate toxicity with methadone
• Precipitate withdrawal with BPN
• Stabilise patient in treatment so that not in
  withdrawal / intoxicated
• To retain patient in treatment

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Understanding precipitated withdrawal

• BPN competes with and displaces full opioid
  agonists (heroin, methadone) from receptors
• BPN has lower intrinsic opioid activity than full
  agonists
• Reduction in opioid activity experienced as
  opiate withdrawal
• Only likely to occur if first dose of BPN is
  given whilst patient experiencing effects of
  other opiates

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Precipitated withdrawal profile

• More common features include
• Autonomic withdrawal features
• Sweating, anxiety
• GI symptoms (abdo cramps, diarrhoea, nausea)
• If patient unaware confusion, disillusionment
• Symptoms related to peak BPN effects
• Start 3060 min after 1st BPN dose
• Peak within 90 min to 3 hrs after 1st dose, then
  subside

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Factors impacting upon precipitated withdrawal

• Amount of opioid full agonist in system
• Duration of action of opioid
• Dose last used
• Is the patient in opiate withdrawal at time of
  the 1st BPN dose?
• Size first BPN dose
• Greater precipitated withdrawal with higher first
  dose
• Expectancy information

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Ive been in withdrawal
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Preventing precipitated withdrawal

• Delay first BPN dose until patient in early
  withdrawal
• gt6 hrs after last use of heroin
• gt24 hrs after low methadone dose (lt40 mg)
• gt3648 hrs after medium methadone dose
  (4060mg)
• Size of first BPN dose
• Less risk with low dose (eg ?4 mg)
• Role of dispensing pharmacist / nurse
• Assess patient prior to dose
• Communication with patient and doctor
• Provide information to patient (and carers)

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Recommendations

• Recommendations re clinical practice reflect the
  context in which treatment is delivered
• Specialist clinic with onsite dispensing
• Primary care GP and community pharmacy dispensing
  
• Supervised / unsupervised dispensing
• Availability of take-aways

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Induction into BPN treatment

• dependent heroin use
• low dose (lt40mg) methadone
• ? / ? medium dose (40-60) methadone
• high dose (gt 60 mg) methadone

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Examples of induction doses (heroin users)
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Difficulties encountered in transferring from
methadone to BPN

• Precipitated withdrawal on commencing
  buprenorphine
• Prolonged dysphoria
• Destabilisation of stable patients
• Treatment drop-out
• Inconvenience (and resources) of transfer
  procedures

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Factors implicated in ppted withdrawal in M to B
transfers

• Methadone dose
• Time interval between last methadone and first
  buprenorphine dose
• Buprenorphine dose
• Patient expectancy and supports
• Concomitant use of heroin / medications

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Precipitated withdrawal following methadone
(Strain et al 1992, 1994)

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Low dose methadone transfers (lt40 mg)
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When should we stop treatment?

• Chronic condition needs long term treatment
• Premature cessation of treatment usually results
  in relapse to dependent heroin use
• Consider ending treatment when
• no illicit drug use for months / years
• stable social environment
• stable medical / psychiatric conditions
• patient has a life that does not revolve around
  drugs

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When should we consider alternatives?

• Treatment goals not being achieved
• Medication-related adverse events
• Review of treatment
• Options
• Rearrange aspects of treatment
• Transfer to alternative oral opioids
• Role of other routes of administration?
• Stopping substitution treatment

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Supervised BPN dispensing

• Recommended at beginning of treatment, and then
  relaxed as patient achieves stability
• Can be difficult to co-ordinate in pharmacies, as
  tablets slow to dissolve
• Poor supervision associated with
• poor adherence with medication
• diversion to others
• injecting tablets

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Conclusion

• Safe effective
• Advantages disadvantages to its use
• Increased treatment options
• by better tailoring treatment
• .. better outcomes