The problem with opioids

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Opioids, including both illicit and pharmaceutical agents, are the most harmful drugs to human health (see Table 1). Use of opioids increases the risk of overdose, infectious diseases, and the onset of other medical and psychiatric conditions. 1

Table 1. Types of illicit and pharmaceutical opioids 7

Heroin Opium

Alfentanil Buprenorphine Codeine Dextropropoxyphene Fentanyl Hydromorphone Methadone Morphine Oxycodone Pethidine Remifentanil Tapentadol Tramadol

There is increasing global misuse of pharmaceutical opioids resulting in rising accidental deaths. 1 Evidence from the United States suggests that while the prevalence of chronic pain has remained stable over the past 15 years, the amount of prescription opioids sold has quadrupled. 2 Although opioid use in Australia is not at the epidemic proportions of the United States, similar patterns have also been documented. There has been a four-fold increase in the use of opioids in Australia over the past 25 years (4.6 to 18.0 DDD/1000 pop/ day) and the rates of accidental deaths due to opioids (namely, pharmaceutical opioids) have doubled in Australian adults aged 35 to 44 years over the past decade. 3,4

Not all opioid use is considered misuse. There are clear indications for pharmaceutical opioids in individuals with acute and cancerrelated pain. However, evidence to support efficacy in chronic pain is inconclusive. 5 The Australian Pain and Opioids in Treatment (POINT) study demonstrated that opioid use in individuals with chronic pain did not improve workplace functionality and was associated with a high risk of adverse outcomes including abuse, dependence, overdose, and death. 6 Despite this, studies have shown that almost 44% of opioid prescriptions in Australia are for chronic pain. 7 This suggests there is room for further regulation and a greater emphasis on guidelines for prescribing opioids and nonopioid interventions for the management of chronic pain.

There are 13 different types of opioids available for use in Australia (see Table 1). They act on opioid receptors in the central nervous system and the gastrointestinal (GI) tract to reduce the transmission of pain. They also cause respiratory depression, sedation, and GI complications like constipation, nausea, and vomiting. 8

The most commonly prescribed opioids in Australia include codeine (in combination with paracetamol), oxycodone, and tramadol. 3 Buprenorphine, morphine, and fentanyl are also common. 3 Each type of opioid has a different dose equivalent (compared to morphine) and duration of action. Many opioids are available under different trade names, in variable doses, and as combination agents, meaning there are hundreds of different formulations available. 5 Variable

use of multiple opioids, including immediate and/or controlled release formulations, and use of opioids in combination with other psychoactive substances has resulted in many opioid-related deaths. 1

A wide range of explanations have been cited for the increasing use of prescription opioids. They include demographic changes, patient characteristics, and factors related to physician prescribing. Demographic factors include longer cancer survival periods and an ageing population, with increased rates of arthritis. 10

Individual risk factors for prescription opioid abuse include; • Obtaining multiple prescriptions from different providers and pharmacies

• Daily use of high dose prescription pain relief • History of substance abuse • Current mental illness

• Living in rural areas • Low income 9

Some suggest that there is a medical culture towards pain that prevents practitioners from questioning an individual’s experience of pain and equates pain management with compassion for patients. 5 Other factors, such

Table 2. Comparative doses of opioid analgesics 8

Codeine Oxycodone

200mg oral 15-20mg oral

Tramadol

Buprenorphine

Fentanyl 100-120mg IM or IV (intravenous) 150mg oral 0.4mg IM 0.8mg sublingual 100-150mcg SC

3-4 hours 3-4 hours

12 hours (CR (controlled release) 3-6 hours 12/24 hours (CR) 6-8 hours

1-2 hours

as systemic under-treatment of mental health conditions and aggressive promotion of opioids by pharmaceutical companies may also influence opioid prescribing. 10

Regulation of opioids is essential to reduce individual risk and improve public safety. Scheduling opioids under the National Poisons Standard ensures safe storage, dispensing, and administration across Australia. Individual states and territories can also implement regulations, such as real-time dispensing monitoring for controlled drugs. 5 Examples of the use of regulation to curb opioid use and improve safety in Australia include;

• Change of codeine from a Schedule 2/3 to Schedule 4 drug to improve patient safety and prevent abuse (in place since 1 February 2018)

• Availability of over-the-counter naloxone to support greater access to life-saving, overdose treatment in the community (commenced 1 February 2016)

• Electronic Recording and Reporting of Controlled Drugs (ERRCD), Tasmania’s realtime dispensing monitoring system. Appropriate prescribing, dispensing, and administration of opioids are also required. First, it is important to determine if there is a clinical indication for opioids. Before considering opioids a plan of management and goals of treatment should be nominated. Non-pharmacological interventions and nonopioid analgesics may be safer and improve outcomes for patients with chronic pain. If opioids are indicated, psychosocial factors, the potential for drug interactions, and risk factors for dependence should be considered. Prescribers may require authority from a state-based pharmaceutical services unit in order to prescribe two months or more of some opioids. Central to gaining authority is an assessment of drug dependence. Drug dependence is defined differently in each state and Territory but usually requires identification of drug seeking behaviour. 5 Unfortunately, drug seeking behaviour is poorly defined and often difficult to identify.

When opioid use is supported, regular monitoring, promotion of nonpharmacological interventions, and exit strategies for opioid cessation, may improve safe and effective pain management. 5

Increased use and misuse of opioids is a problem that is affecting Australia and much of the rest of the world. Without intervention, the rates of overdose and accidental deaths associated with pharmaceutical opioids may continue to rise. National and statewide regulation, in combination with appropriate prescribing, dispensing, and administration of opioids is required to improve outcomes for Australians.

REFERENCES 1. United Nations Office on Drugs and Crime,

World Drug Report 2017. (ISBN: 978-92-1- 148291-1, eISBN: 978-92-1-060623-3, United

Nations publication, Sales No. E.17.XI.6). 2. Centers for Disease Control and Prevention.

Opioid overdose: Understanding the epidemic [Internet]. Atlanta: CDC; 2016 Dec 16 [cited 2017 Aug]. Available from: https://www.cdc.gov/ drugoverdose/epidemic/index.html. 3. Karanges EA, Blanch B, Buckley NA, Pearson SA.

Twenty-five years of prescription opioid use in Australia: a whole of population analysis using pharmaceutical claims. Br J Clin Pharmacol. 2016 Jul;82(1):255-67. UNSW; 2017 Jul [cited 2017 Aug]. Available from: https://ndarc.med.unsw.edu.au/news/ more-australians-dying-accidental-overdosepharmaceutical-opioids

5. Jammal W, Gown G. Opioid prescribing pitfalls: medicolegal and regulatory issues. Aust Prescr. 2015;38:198-203.

6. Ballantyne JC. What can the POINT study tell us? Pain. 2015 Feb;156(2):201-2.

7. Harrison CM, Charles J, Henderson J, Britt H. Opioid prescribing in Australian general practice. Med J Aust 2012;196:380-1.

8. Australian Medicines Handbook 2017 (computer program). Adelaide: Australian Medicines Handbook Pty Ltd; 2017 July.

9. Centers for Disease Control and Prevention. Opioid overdose: Prescription opioids [Internet]. Atlanta: CDC; 2016 Mar 16 [cited 2017 Aug]. Available from: https://www.cdc.gov/ drugoverdose/opioids/prescribed.html.

Alteplase is a recombinant tissue plasminogen activator (rt-PA, Alteplase). Generic name: Alteplase Trade name: Actilyse Drug Class: Thrombolytics / Fibrinolytics

Alteplase is a thrombolytic agent, used to breakdown a thrombus (blood clot) in patients with acute ischaemic stroke, acute ST segment elevation myocardial infarction (STEMI), and massive pulmonary embolism. In patients with acute ischaemic stroke, it has been shown to reduce disability at three months. 1

In Australia, many states and Territories have their own indications and eligibility criteria for the use of thrombolysis in the treatment of an acute ischaemic stroke. Examples of eligibility criteria include;

• Onset of ischaemic stroke within 4.5 hours • Presence of a potentially disabling neurological deficit • CT that rules out haemorrhage or non-vascular cause of stroke

Thrombolytic agents enhance the process of fibrinolysis. Fibrinolysis is the body’s natural way of breaking down a thrombus (see Box 1). 2 It involves producing tissue plasminogen activator (t-PA), which binds to and breaks down fibrin within a blood clot. The clot breaks apart as the fibrin strands disintegrate. Alteplase is a synthetic form of t-PA. It is an exact copy of naturally produced t-PA and binds directly to fibrin and fibrinogen to dissolve a clot. 2

Alteplase is associated with an increased risk of bleeding including intracranial haemorrhage. There is

Box 1. Normal physiological fibrinolysis. Alteplase is a synthetic t-PA that induces fibrinolysis. High doses are required to overcome the inhibitory effects of plasminogen activator inhibitors 2

Thrombus is formed which contains fibrin and plasminogen

Damaged blood vessels release tissue plasminogen activator (t-PA)

t-PA binds to fibrin and breaks down plasminogen into plasmin Plasmin activator inhibitors inactivate t-PA

Acute ischaemic stroke IV bolus: 0.1mg/kg Followed by Infusion (over 60 minutes): 0.8mg/kg To a maximum total dose of 90mg Acute STEMI IV bolus: 10mg Followed by Infusion (over 60 minutes): 50mg Then Infusion (over 120 minutes): 40mg (reduce dose to less than 1.5mg/ kg for patients under 65kg) OR Accelerated version (over 90 minutes total) IV bolus: 15mg Followed by Infusion (over 30 minutes): 0.75mg/kg (maximum 50mg) Then Infusion (over 60 minutes): 0.5mg/kg (maximum 35mg) Pulmonary embolism IV bolus: 10mg Followed by Infusion (over 120 minutes): 90mg (reduce dose to less than 1.5mg/ kg for patients under 65kg) Table 1. Indication and dose of alteplase 1

limited data to support the use of alteplase in people over the age of 80 with acute ischaemic stroke as it has been associated with worse outcomes, including an increased risk of intracranial haemorrhage and mortality, compared to younger people. 1

Caution should be observed when using alteplase in patients taking angiotensin converting enzyme (ACE) inhibitors as concurrent use may increase the risk of allergic reactions. 1

Absolute contraindications to alteplase include;

• Active, suspected, or known bleeding disorders • Co-morbid conditions with an increased risk of bleeding such as severe uncontrolled hypertension, severe liver disease, or thrombocytopenia 1 There is limited data to support the use of alteplase in pregnancy. However, as it is indicated for the treatment of life-threatening conditions it may be used as required. 1 Many protocols for the administration of alteplase in emergency departments have additional evidence based relative precautions and contraindications.

Most adverse effects of alteplase are related to bleeding. Bleeding at the injection sites, intracranial bleeding, and/or internal bleeding may arise. Transient hypotension may also occur. 1 Infrequent and rare adverse effects include allergic reaction and cholesterol embolism. 1

The recommended dose of alteplase is dependent on the indication and weight of the patient (see Table 1). It is delivered via intravenous administration, with an initial bolus followed by an infusion over 60 to 180 minutes. 1 Nursing considerations include ensuring that patients have two reliable and well secured intravenous cannulas in situ, and that patients are regularly monitored for the onset of bleeding. If severe bleeding occurs and cannot be controlled with direct pressure, the infusion should be stopped. 1

At present, alteplase is the only thrombolytic agent used to treat acute ischaemic stroke in Australia. 1 One barrier to timely treatment in rural areas is that patients may not be able to safely transfer while alteplase is running. A multisite, randomised control trial is currently underway in Australia to determine whether tenecteplase, which is administered as an IV bolus, could be used as a superior alternative to alteplase to improve clinical outcomes. 3 Tenecteplase is well established as a single IV dose thrombolytic treatment for STEMI.

1. Australian Medicines Handbook 2017 (computer program). Adelaide: Australian Medicines Handbook Pty Ltd; 2017 July.

2. Waller DG, Sampson AP. Medical pharmacology and therapeutics. 4th edition. London: Elsevier Health Sciences; 2014. 744p.

3. Heart Foundation. Tenecteplase versus alteplase for stroke thrombolysis evaluation trial [Internet]. Phillips, ACT: Heart Foundation; n.d. [cited 2019 Nov]. Available from: https:// www.heartfoundation.org.au/research-project/ tenecteplase-versus-alteplase-for-strokethrombolysis-evaluation-trial