Cracking Addiction

On Cracking Addiction this week

Methadone is a synthetic long acting mu receptor agonist suitable for the treatment of opioid use disorder. Methadone has a longer plasma half life than morphine (average 22 hours (15-32 hours) vs 2 hours for morphine) which permits once daily supervised dosing. Methadone is well absorbed after oral administration with a peak effect after four hours and does cross the blood-brain barrier. It is thought that 20 to 50 mg daily of Methadone usually prevents opiate withdrawal phenomena and doses of > 60 mg prevents the euphoria from additional use of unsanctioned opioids.

Regardless of previous opiate or opioid usage the same low starting dose of methadone is prescribed. Starting doses of Methadone are usually between 20-30mg daily with higher risks patients starting at 20mg daily and doses can be up-titrated every 3-5 days based on clinical need. It is important to remember that it takes 5 half lives for Methadone to reach steady state in plasma. Methadone has a half life of approximately one day and thus half of each day’s dose remains in the body and is added to the next day’s new dose. Serum methadone levels will continue to rise (which can reach dangerous levels if doses are excessive) until steady state is achieved. It can take 5 days for Methadone to reach a steady state in plasma and can take 10 days for Methadone to equilibrate between plasma and body tissues.

Causes of Methadone overdose include:
• Single overdose
• Starting dose too high
• Accidental ingestion
• Accumulated toxicity
• Rapid induction
• Polypharmacy
• Hypnosedative combinations -benzodiazepines etc
• Reduced opioid tolerance
• Low neuroadaptation
• Comorbidity

Safety principles to consider when prescribing Methadone include:
• Risk of overdose highest in the first two weeks of treatment
• Safety principle: Start low and go slow
• No cross tolerance with other opioids
• Same low starting dose irrespective of previous opioid burden
• Never increase dose without a face-to-face review
• Usual practice to review patient weekly and increase the dose weekly
• Can take 6-8 weeks to achieve stability
• Cease other illicit and prescribed opioids / hypno-sedatives

On Cracking Addiction this week

Methadone is a drug with a wide variability in its absorption with oral bio-availability ranges from 35% to 100%. This is a significant amount of variability and explains why the same dose of Methadone can impact different patients differently. Methadone is also highly protein bound and there is a four fold variability in Methadone’s distribution within the body-further explaining the differing effects that can occur when taking Methadone.

Methadone is metabolised within the liver by the cytochrome P450 enzymes but mainly 3A4. There is a 17-fold inter-individual variation of methadone blood concentration for a given dosage and variations in metabolism account for a large part of this variation. Kinetic interactions influenced by the CYP 450 enzyme can affect plasma methadone levels.

• Inducers of CYP450 can
• Accelerate the metabolism of methadone
• lower methadone plasma levels
• Precipitate opioid withdrawal
• Inhibitors of CYP450 can
• Slow the metabolism of methadone
• Increase plasma levels
• Produce opioid toxicity (sedation, overdose)

Methadone is excreted renally with approximately 10% of drug renally eliminated unchanged. Renal excretion of methadone urinary pH dependent with increased Methadone excretion noted at pH less than 6 and decreased Methadone excretion at higher pH levels.

On Cracking Addiction this week

Long acting injectable buprenorphine (LAIB) are long acting buprenorphine depot preparations that are injected subcutaneously and provide patients with a sustained release of buprenorphine for the duration of the depot preparation. Currently, two LAIB products are available for the Australian market. They differ in their formulations, administration and pharmacology. The two products available are Buvidal and Sublocade. Buvidal formulations allow for weekly or monthly dosing frequency. Sublocade formulations allow for monthly dosing only.

Buvidal Weekly strengths: 8 mg, 16 mg, 24 mg, 32 mg
Buvidal Monthly strengths: 64 mg, 96 mg, 128 mg
Sublocade strengths: 300mg, 100mg

Buvidal dose should be determined according to patient’s Suboxone dose and subsequent doses can be titrated post clinical review. Buvidal may be initiated directly if required and usually a 24 mg Buvidal Weekly dose is started and the dose is titrated from this starting point until clinical effect is achieved.

Sublocade dosage is usually commenced post initiating treatment with Suboxone and a dose of Suboxone greater than 8mg daily. The recommended induction is: 300 mg monthly injections x 2 doses (8 weeks) and then 100 mg monthly doses (if the patient is stable on initial 2 x 300 mg doses) or 300 mg monthly doses if require additional buprenorphine effects.

If there are any issues, concerns or uncertainty about dosing it is always worthwhile to contact a more experienced prescriber or seek specialist assistance to ensure the right dosage of medication is being prescribed and given in an appropriate manner.

Weekly or monthly administration of LAIB takes away the need for daily dosing and takeaways, and reduces the frequency of supervised dosing to weekly or monthly intervals. This serves to reduce travel, stigma and out of pocket expenses for patients. Eliminating takeaway doses also reduces the scope for medication diversion. It is a medication with great potential but it is not for every patient and appropriate patient selection and follow up is important to ensure patients do not get destabilised on a new treatment.

On Cracking Addiction this week

This episode of Cracking Addiction is the second of a two-part series on Suboxone.

Buprenorphine acts as a partial agonist on the mu opioid receptor and an antagonist on the kappa opioid receptor.

The effects of buprenorphine on the mu receptor are best described by Dr Ferghal Armstrong’s pneumonic SPEAR:
• Sweating sedation
• Pinpoint pupils
• Physiological dependence
• Emesis
• Euphoria
• Analgesia
• Retention or urine and faeces
• Respiratory depression

Buprenorphine is also an antagonist of the kappa receptor and opposes the effects of the kappa receptor which can cause dysphoria so buprenorphine can assist with some improvement in mood.

Agonists bind to and activate a receptor to cause a biological response. Inverse agonist binds to the same receptor as an agonist but induces a biological response opposite to that induced by the agonist. Neutral antagonists bind to a receptor and causes no biological response in the absence of an agonist or inverse agonist but can block the activity of either. A partial agonist binds to but only partially activates a given receptor.

Buprenorphine is a partial agonist of the mu receptor which results in a plateauing of effect on the dose-response curve upon which a further dose increase results in no further effect. Buprenorphine’s dose plateaus at 32mg.

Buprenorphine is effective as a form of opioid substation therapy as it:
• Has a long half life
• Suppresses cravings and withdrawal
• Freedom from the shackles of dependence

With Suboxone it is important to administer the first dose when the patient is in opioid withdrawal or there is a risk of precipitated withdrawal. Buprenorphine has a high avidity for the mu opioid receptor but is a partial agonist but will still displace full agonists from the mu receptor if they are still bound to the receptor resulting in an acute withdrawal syndrome.

Overall Suboxone is a safe and effective form of opioid substation therapy and is a useful tool to assist patients with opioid use disorder achieve stability and possibly remission of their substance use disorder.

On Cracking Addiction this week

The kinetics of first dose differ from that of steady state for all doses of both LAIB products. Troublesome symptoms of relative overdosing tend to abate within the first few days after weekly LAIB, and after the first two weeks of monthly LAIB as the plasma buprenorphine concentration rapidly falls to trough levels. Symptoms of withdrawal or craving associated with relative underdosing may emerge in the second half of a treatment window for both LAIB products early on in the journey to steady state. As steady state is achieved one can expect a reduction in the intensity of symptoms associated either with underdosing or overdosing.

It is important to warn patients that their experience of sublingual buprenorphine will be different to that of LAIB. Patients may interpret any symptom, including those of relative overdosing, or symptoms associated with any comorbid medical or psychiatric condition as opioid withdrawal. It is important to educate the patient regarding the symptoms of relative overdosing, and opioid withdrawal and to emphasise the need for adequate clinical assessment prior to diagnosing opioid withdrawal.

Dr Ferghal Armstrong has developed a useful mnemonic to conceptualise the symptoms of opioid withdrawal is “Army Finds” which demotes the following.

• Aches and pains
• Rhinorrhoea
• Mood disturbance
• Yawning
• Fever
• Insomnia
• Nausea and vomiting
• Diarrhoea
• Sweating

Buprenorphine demonstrates high avidity for the mu receptor. Therefore, it displaces other opioids from that receptor. It is a partial agonist of the mu receptor. So therefore, having displaced other full mu-agonists from the opioid receptor, it only partially agonises that mu receptor thereby causing an opioid withdrawal effect known as precipitated withdrawal.
When starting buprenorphine, it is important for patients to be already in withdrawal to avoid a worse precipitated withdrawal. Withdrawal can occur six to 12 hours after short acting opioids, such as heroin, codeine or oxycodone. But it may take 24 to 48 hours or even longer to manifest after exposure to long-acting opioids, including methadone. If we are to avoid precipitated withdrawal during induction of buprenorphine, we must administer buprenorphine only after withdrawal from other opioids has occurred. Therefore, we must recognize the signs and symptoms of opiate withdrawal.

The following are listed as contra-indications for both Buvidal and Sublocade.

Child-Pugh C liver disease
Respiratory insufficiency
Hypersensitivity to either buprenorphine or excipients

Contra-indications that are unique to Buvidal include.

Children less than 16 years of age
Acute alcoholism or delirium tremens
Pregnancy and lactation

Contra-indications unique to Sublocade include.
Subjects less than 18 years of age Acute intoxication with alcohol or other CNS depressants Pregnancy and lactation

Regarding review of the patient on LAIB this will depend on the formulation of LAIB chosen and expected treatment effect. It is a useful idea to review the patient regularly post commencing LAIB treatment and until patient has achieved a steady state of buprenorphine within their system. It is useful to review the patient 1-2 weeks prior to their second LAIB injection to ensure that the patient is progressing well and to trouble shoot any potential problems before they become significant issues.

On Cracking Addiction this week

This episode of Cracking Addiction is the first of a two-part series on Suboxone.

Suboxone is a combination of buprenorphine and naloxone which is administered sublingually as a form of opioid substitution therapy. Suboxone comes in two strength a 2mg buprenorphine/0.5mg naloxone and 8mg buprenorphine/2mg naloxone strength. The naloxone is not absorbed buccally or orally and if taken as intended the patient is only administered a dose of buprenorphine. Hepatic first pass metabolism prevents access of the naloxone into the systemic circulation though this can be impaired in severe liver disease such as Child Pugh C liver cirrhosis. In general, however naloxone does not become systemically active if Suboxone is taken as intended sublingually but if it is injected naloxone would antagonise the effect of any opioids within a patient’s system which could lead to an acute withdrawal syndrome.

Suboxone is an effective form of opioid substitution therapy taking between 30 minutes to four hours to reach peak plasma concentration from time of administration. Suboxone has a peak plasma concentration of 8.45ng/mL and average plasma concentrations of 2.91 ng/mL and trough plasma levels of 1.61ng/mL. It takes on average around 5-6 days to get to a steady state of buprenorphine with Suboxone. Suboxone has a half life of between 13-46 hours.

Thus one can see some of the benefits that are available in using Suboxone for opioid substitution therapy.