Author name: Tony Laughton

Drugs of concern
Cracking Addiction, Global Awareness, Healthcare

Understanding Drugs of concern

On Cracking Addiction this week

There are a whole range of drugs of concern that one can become dependent upon or become addicted to and this list can seem daunting. The list of drugs that a ‘use disorder’ can be appended to under the DSM 5 criteria is similarly long. Dr Ferghal Armstrong though provides us with a useful mnemonic to remember these drugs ‘COCA SHITS’.

• Cocaine
• Opioids
• Cannabis
• Alcohol
• Stimulants
• Hallucinogens
• Inhalants
• Tobacco
• Sedatives

Similarly an alternative classification system of drugs of dependence making it easier to remember these drugs is as follows:

The Legals
Alcohol tobacco
The prescribed
Opiates benzodiazepines quetiapine pregabalin stimulants
The uppers
Cocaine amphetamine methamphetamine
Downers
Heroin cannabis
Party drugs
MDMA LSD magic mushrooms GHB

Identifying those patients who may be ta risk of prescription drug aberrancy can be difficult and is an area that can leave a doctor feeling quite fraught. A useful set or patterns of behaviours to be aware of can be remembered through Dr Armstrong’s mnemonic ‘USE TALK’

Urgency
Unscheduled medical appointments
Splitting
“You are the only one who can help”
Efficacy
“Nothing else works for me”
Timing
Saturday afternoon and I have run out of my medication – no option for cross checking with other agencies
Allergies
“I am intolerant of all other pharmacological options”
Lost
Lost prescriptions that trigger requests for further replacement prescriptions
Knowledge
High degree of knowledgeability surrounding the drug in question

Managing Opioid Use Disorder in Pregnancy
Cracking Addiction, Global Awareness, Healthcare

Managing Opioid Use Disorder in Pregnancy

On Cracking Addiction this week

Most women presenting with opioid dependence are of child-bearing age with chaotic drug use predisposes to amenorrhoea. The initiation of opioid substitution therapy (OST) facilitates stability and reinstatement of regular menstrual cycles and thus OST is a risk factor for unplanned pregnancy. Contraception needs to be discussed with all female patients of child bearing age who present to OST treatment services.

Substance use disorder in pregnancy mandates referral to a specialist services with best practice including involvement in a multidisciplinary drug and alcohol antenatal clinic. This multidisciplinary team should include: midwives, Obstetricians, Paediatricians, social workers and Addiction Medicine specialists.

Counselling needs to be provided regarding the risks and benefits of OST during pregnancy and lactation. There is a significant risk of miscarriage if doses of OST missed/opioid withdrawal occurs. Pregnant patients may be reluctant to engage with antenatal services or OST treatment programs because of chaotic lifestyles, stigma or concerns about child protective services and removal of their child from them post birth. By focussing on the health of the baby this may promote engagement with treatment services.

Suboxone, Subutex and Methadone are all Category C drugs in pregnancy. However inadequately treated opioid use disorder is a significant risk to the viability of the pregnancy. Opioid withdrawal in the first trimester can cause uterine contractions and does increase the risk of miscarriage in the first trimester and opioid withdrawal in the third trimester increases the risk of intrauterine growth restriction as well as risk of premature labour.

Another concern about OST in pregnancy is adequately dosing the pregnant woman. The half life of Methadone is reduced in pregnancy from 22-24 hours in non-pregnant women to 8.1 hours in pregnant women. Methadone metabolism is accelerated due to increased CYP3A4 expression by liver, intestine, and placenta and methadone clearance increases with advancing gestational age. As a result of this higher doses and split dosing of Methadone may be required.

An optimal dose of methadone remains controversial with doses of 80-120mg per day not inappropriate. Twice or thrice daily dosing can result in more sustained plasma levels, fewer withdrawal symptoms, and less illicit drug use and less suppression of foetal movement and breathing.

Thus in summary it is important to adequately treat women who are pregnant with opioid use disorder to prevent harms to both the woman and foetus.

Managing Methadone and Buprenorphine Use in Pregnancy
Cracking Addiction, Global Awareness, Healthcare

Managing Methadone and Buprenorphine Use in Pregnancy

On Cracking Addiction this week

Post birth the patient’s usual oral methadone dose can be continued in the peripartum and post partum period. There is a theoretical concern in the postpartum period of over-sedation as methadone levels may increase as plasma volume and hepatic clearance normalise post the delivery of the child. Women should be closely monitored during this time period to guard against complications.

There are three approaches to manage this potential problem including: stay on the same dose of Methadone with close monitoring, decrease the Methadone dose by 10-20% or reduce the methadone dose by 20 to 40 percent immediately postpartum and closely monitor and follow up the woman to ensure the patient is not in significant withdrawal.

Most women who undergo buprenorphine maintenance therapy will not experience large dose adjustments during their pregnancies and may continue the same doses after delivery

Breast feeding should be promoted with confidence unless active substance use is occurring or otherwise contraindicated. Breastfeeding may reduce the severity of neonatal withdrawal syndrome in the neonate. With Methadone about 1-3% of maternal dosage will be transferred into the breast milk and with buprenorphine the amount of buprenorphine in breast milk is <1 percent of maternal dose. There is a low oral bioavailability with significant absorption unlikely.

Neonatal abstinence syndrome (NAS) is a phenomena when the infant withdraws from drugs that they have been exposed to in utero. NAS is not unique to opioids and can occur with benzodiazepines, nicotine and also SSRI and SNRIs. Methadone causes a withdrawal syndrome in 60–80% of cases with symptoms occurring usually between 48 to 72 hours after birth but also up to five days. In rare circumstances symptoms can be delayed by up to a month. The severity of NAS is not related to the maternal dose of Methadone.

There are lower rate of NAS with buprenorphine compared to methadone which is thought to be secondary to: lower bioavailability, lower transplacental passage and partial agonism. The risk of NAS with buprenorphine is also not dose dependent. However overall the risks of opioid withdrawal during pregnancy are greater to the foetus than those of NAS to the infant so it is important to adequately treat the pregnant woman with opioid use disorder rather than be concerned about the risks of NAS.

Understanding Methadone Treatment
Cracking Addiction, Global Awareness, Healthcare

Understanding Methadone Treatment

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

Understanding Methadone Treatment
Cracking Addiction, Global Awareness, Healthcare

Methadone Absorption and Metabolism Variability

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.

Understanding Stress
Global Awareness, Healthcare, Lifestyle Matters, MedHeads

Understanding Stress

In this episode of Lifestyle Matters.

This week Dr Ferghal and I discuss stress. Some regard it as the modern-day trash which needs to be regularly disposed of to prevent over piling.

13% of Australians above the age of 18 years old describe moderate to high stress levels and there is a lower socioeconomic predominance to this.

But first, what is stress? There are many ways to define it but put simply, it really comes about when the demands placed on a person is so overwhelming that she/he is thrown into a state of worry. The right amount of stress can sometimes lead a person to being more productive. However, when the factors that cause stress are ongoing, this leads to distress whereby one can experience feelings of headaches, nausea and insomnia etc.

The Yerkes-Dodson Law (the inverted U model of arousal) describes this quite well. This is a law that describes the relationship between stress and work performance as pictured below:

Stress at unhealthy levels can have a negative impact on our health such as:

• Mental health: Depression, Anxiety, Forgetfulness
• Cardiovascular: Cardiomyopathy, Hypertension, Tachycardia, low HDL (good cholesterol)
• Respiratory: Hyperventilation, exacerbating pre-existing lung conditions e.g. asthma, chronic obstructive pulmonary disease
• Gastrointestinal: Irritable Bowel Syndrome, stress ulcer
• Endocrine: Poor diabetes control, Metabolic syndrome
• Genitourinary: Low sperm count, reduced libido
• Immune function: Reduces immunity predisposing to infections
• Pain: Reduces pain threshold
• Musculoskeletal: Increases risk of injuries

When one undergoes stress, they can also develop some maladaptive patterns to cope. These include an erratic eating pattern. e.g over or undereating and substance abuse. 38% of people engage in emotional over- eating, while another 38% are ‘starvers’. The remainder have unaffected eating pattern. Women tend to turn to food whilst men on the other hand use tobacco or alcohol to cope with stress. We know the effects of these substances on our health which have been discussed in the previous episodes.

A British study in 2007 demonstrated that people who responded to stress with a higher cortisol level tend to be emotional eaters. The food group of choice is usually a highly caloric food such as simple sugars or carbohydrates as they increase good feeling hormones (endorphins)

As outlined, stress has many effects on our health, and we ought to learn how to manage it better so that we can find a way to use it as a positive influence in our lives. We will discuss this further in the next episode.

Buvidal vs Sublocade
Cracking Addiction, Global Awareness, Healthcare

Buvidal vs Sublocade

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.

Suboxone
Cracking Addiction, Global Awareness, Healthcare

Suboxone Pt2

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.

Buvidal vs Sublocade
Cracking Addiction, Global Awareness, Healthcare

Understanding Buprenorphine Treatment

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.

Suboxone
Cracking Addiction, Global Awareness, Healthcare

Suboxone Pt1

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.

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