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Codeine dependence with buprenorphine: A presentation on

two local studiesDr Sarah Reilly with thanks to co-researchers & supervisors:

- Dr Mark Daglish & Dr Jeremy Hayllar

Definitions u ADS: Alcohol and Drug Services (usually refers to public)

u CACC: Combination analgesics containing codeine

u OTP: Opioid treatment program –

u including treatment with buprenorphine and methadone

u MATOD: Medication Assisted Treatment of Opioid Dependence

u OTP + holistic psychosocial support

Talk outline 1. Background on codeine dependence 2. Review outcomes of a retrospective study on treatment of codeine dependence with buprenorphine 3. Discuss second trial, recruitment underway. No results yet!

The opioid crisis: >70 000 deaths in the US last year from overdose (predominantly opioid)

Codeine use in Queensland MATOD clinics

Codeine dependence pre 2018

u Codeine – the ‘weak’, ‘socially acceptable’ opioid

u Limited evidence of analgesic superiority

u In 2016 3.6% of Australians had recently used pharmaceutical analgesics for non medical purposes (1)

u 75% had used CACC (Likely to be >500 000 Australians).

u Morbidity and mortality associated with codeine over-use is significant

u “For every two S8 opioid deaths in 2009, there was one codeine-related death”. 3

u Ibuprofen:

u Renal tubular acidosis

u Hypokalaemia

u GI bleeding: ulcers/perforation/anaemia

u Paracetamol:

u hepatotoxicity 1) National Drug Strategy Household Survey (2016/2019)2) The extent and correlates of community-based pharmaceutical

opioid utilisation in Australia3) Roxburgh et al: Trends and characteristics of accidental and

intentional codeine overdose deaths in Australia. 2015

Codeine… an unpredictable drug

u Morphine is converted to codeine by the P450 2D6 isoenzyme systemu 2D6 efficiency varies leading to

unpredictable morphine levels

u Poor metabolisrs (PM) = no analgesia

u Ultra-rapid (UM) metabolisers produce greater morphine than expected

u Risks include unintentional overdose by respiratory depression – especially in breast-fed babies, children and polysubstance users.

u Insidious tolerance and dependence in ultra-rapid metabolisers.

“Prepare for the Influx”u Between 2007 and 2016, the

number of treatment episodes for codeine dependence rose from 5.9% to 14.1% (1)

u In 2016, 17.1% of people on OTP listed codeine as their primary drug of concern (2)

u ADS prepared for an increase in codeine related presentations post rescheduling

1) Non-Medical use of pharmaceuticals: Trends, harms and treatments (2006-2007 to 2015-2016)

2) NOPSAD – 2019 data

Research Opportunities

u 1. How did presentations change

u 2. Literature review of treatment of codeine dependence

u 3. Retrospective chart review of two metro north ADS

u Patients initiated on OTP for codeine dependence

u What led to their dependence

u How were they treated

u Recently completed for a scholarly project

u 4. Cross sectional genetic study looking at the frequency of ultra-rapid metabolisers in patients on OTP for codeine dependence

u Pharmacogenomics study – ongoing

Changes in type and number of ADS presentations at Biala

2. Literature review: Identifying and managing codeine dependence

Literature review Nielsen (up to 2016) Repeated literature review (2018-2020)

* Nielsen S et al. Opioid agonist treatment for pharmaceutical opioid dependent people. Cochrane Database of Systematic Reviews 2016

Describing people with codeine dependence

Compared to illicit substance users: u More women (50/50 v 30/70)

u Higher rates of

u Employment/positive social supports

u Chronic pain

u Psychiatric comorbidity

u Lower rates of

u criminal activity/substance diversion

u Homelessness

u IVDU

Two main reasons for codeine use: u Pain – “legitimate”, “chronic pain issue not an addiction issue”,

u Other – “secret solace”, “mood elevator”, “Social confidence”, “stress relief”, “use associated with shame”,

u Both groups had insidious escalation. Group 1 overlaps with group 2

Most users were hesitant to access ADS treatment. u Most had never sought help due to:

u “Stigma”, “lack of knowledge about pain”, “OTP being restrictive and demeaning”

Applying general guidelines to the codeine using population

u Stepped care approach

u Withdrawal verse maintenance treatment

u Maintenance has better outcomes

u Queensland OTP retention goal of 40% at 12 months

u Maintenance OTP: Bup v Methadone

u Based off patient preference, previous treatment, pattern of opioid use, comorbid conditions and other medications

u Cochrane review on pharmaceutical opioid dependence

u Equal efficacy, buprenorphine slightly better tolerated (small number of studies).

u Buprenorphine Dose range of 12-24mg

u Receptors saturated at 16mg

u Methadone: >60mg

Treatment of codeine dependence at two Metro North ADS (study 1)Retrospective chart review• Convenience sample of patients initiated on OTP for codeine dependence

• Jan 2016 and July 2018• Codeine must have been the PRIMARY drug of concern• OTP dose must have been available• Must have been initiated on buprenorphine

Aims: 1. Describe demographics and comorbid conditions of codeine dependent patients2. Describe buprenorphine prescribing patterns 3. Assess the association between codeine and buprenorphine doses

Flow of included patients

u 112 OTP episodes for codeine codeinedependence (11% of OTP registrations. Higher numbers at melaleuca)

u 3 were initiated on methadone = excluded

u 100 initiated on buprenorphine

u 71 initiated on maintenance

u 29 underwent supported withdrawal

Demographics and comorbid health conditions

Comorbid psychiatric conditions

Features of codeine use

Treatment with buprenorphine

0%

5%

10%

15%

20%

25%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32BUPRENORPHINE DOSE (MG)

Figure 1 - Maximum Buprenorphine Doses

Withdrawal Maintenance

Association between codeine and buprenorphine doses

Limitations

u Accuracy of data

u Recall bias

u Researcher’s were not blind

u Comorbid diagnosis was based off self disclosure rather than formal assessment

u Likely to under-report personality disorder and trauma history

u Potentially will under-report other substance use due to fear of stigma

u Limited to treatment of severe codeine dependence

u Ideally results would be replicated in a larger, prospective study

Conclusions of study 1

u Small statistically significant association between maximum codeine and buprenorphine dose – PROBABLY not clinically significant

u Codeine using patients required a median buprenorphine dose of 18mg

u Within the 12-24mg recommended in OTP guidelines

u Buprenorphine favoured over methadone ++

u The service achieved 40% retention in this group!

2nd study : Phrmacogenomics: Are UM at greater risk of opioid use disorder?

u Currently underway across our two clinics - 43 patients recruited at present – hoping to at least double that

u Aim: determine whether patients who are codeine “normal” metabolisers (NM) and “ultra-rapid” metabolsiers (UM) are overrepresented among those who have commenced opioid treatment for a codeine use disorder.

Hypothesis

u 1. Higher prevalence of efficient metabolisers in patients with codeine use disorder, compared to the general population

u 2. UM will require higher doses of buprenorphine proportionate to their stated codeine intake

Methods

u A specific CYP2D6 assay previously validated in an Australian population (Moustafa et al) is being used – samples sent to Melbourne

u Clinicians are encouraged to continue to recruit patients who are receiving OTP. Simple buccal swab. Patients are able to find out their results

u $30 coles voucher available

Thoughts for the future

u Possibly CYP2D6 genotyping prior to prescription of codeine (and maybe anti-depressants)

u Need to be aware of the overdose risk associated with Codeine

u Consider Naloxone scripts

u Focus on multi-disciplinary, non pharmacological measures for chronic pain:

u Chronic disease model approach

u Allied health: Physio, psychology and OT

u Psychiatrist and or addiction specialist

u Pain specialist

u General practitioner

Thanks for joining us today!

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