The opioid epidemic: do we need to rethink pain?

A landmark report has highlighted the link between opioid prescriptions in hospital and the long-term risk of dependence, prompting calls for more collaboration and conversation around pain management.

Released by the Society of Hospital Pharmacists of Australia (SHPA), the report found that more than 70% of hospitals frequently supplied opioids for patients to take home “just in case”, even when they have not required them in the 48 hours prior to discharge.

The paper also noted that pharmacists reported extremely high use of sustained-release opioids in the treatment of acute pain for opioid-naive surgical patients.

Based on data from 135 Australian facilities, the report outlined 33 recommendations to enhance local strategies to improve patient care nationwide.

Opioid prescription in hospitals now routine, increasing risk of dependence

Professor Michael Dooley, president of the SHPA, told doctorportal that the unnecessary use of opioids was particularly pronounced among surgical patients.

“They may come in for knee, hip and other procedures, and they’re in quick and smart. We’re trying to flow them through and they just get written up for a script of 20 Endone, just as routine.”

“The patients may not have needed anything over the last day or two, but we still tend to write them up for a packet of opioids, and they grab them and leave the hospital.”

He said that while the prescription of opioids as a precaution is well intended, there are proven dangers with this.

“There is clear evidence that giving patients opioids to take home, when they don’t need them, puts them at risk of continuing to take them.”

“This can then precipitate some pretty traumatic and tragic paths of dependence.”

Not all pain needs to be eliminated

Professor Dooley described current perceptions of pain as being caught in a pendulum. “We have probably swung too far in thinking that all pain is bad pain, and that we need to eliminate all pain.”

“We need to treat serious pain, but with mild pain, often patients will tolerate it. We actually don’t have a magic bullet for minor pain – it’s probably something that people can cope with.”

“If someone has done in their knee or ankle, the pain is telling them not to stand on it or to push themselves too hard.”

Professor Dooley said Australia’s current relationship with opioids stands in contrast to how it began.

“About 15-20 years ago, we had morphine, and everyone was really concerned about opioids and how to use them. Then we got oxycodone, and now we’ve got 130 opioids and people have become less aware of the potential downstream implications.”

Starting meaningful conversations about opioids is essential

Professor Dooley said that having conversations around opioids was the most important step to take in addressing the problem.

“We need to start having conversations with patients and tell them about their pain and analgesia.”

Professor Dooley added that patients need to be empowered to ask key questions around whether pain medication is needed, how long they should take it, and how long they can reasonably expect their pain to last.

“At the moment, no one really has that conversation with patients. As with all these things, there needs to be multiple people having those conversations with the patient, repeating the same message.”

He said that doctors, pharmacists and nurses all need to be involved in this. “For example, often nurses will approach a patient and ask them if they would like a painkiller, rather than asking how their pain is going, and if they are okay with that level of pain.”

[Perspectives] Mathuros Ruchirawat: leading light in pollution control

By the time she was in high school, Mathuros Ruchirawat had already figured out her professional calling. “I’m a scientist at heart”, says Ruchirawat, now Professor of Pharmacology and Toxicology at Mahidol University in Thailand and Vice President of Research and Academic Affairs at the Chulabhorn Research Institute (CRI) where she oversees nine research laboratories. Somehow she also finds time to direct a major research and educational enterprise at Thailand’s Center of Excellence on Environmental Health and Toxicology (EHT).

[Department of Error] Department of Error

Pearson M, Metcalfe C, Jayamanne S, et al. Effectiveness of household lockable pesticide storage to reduce pesticide self-poisoning in rural Asia: a community-based, cluster-randomised controlled trial. Lancet 2017; 390: 1863–72—In this Article (published online first on Aug 11, 2017), Martin Wilks (Swiss Centre for Applied Human Toxicology, University of Basel, Switzerland) should have been cited in the Data Monitoring Committee. This correction has been made to the online version as of Dec 7, 2017.

Codeine – the facts

The Theraputic Goods Administration has ruled medicines that contain codeine will no longer be available without prescription from 1 February 2018.

This will include codeine-containing combination analgesics (available under brand names such as Panadeine, Nurofen Plus, Mersyndol and pharmacy generic pain relief products).

Codeine-containing cough, cold, and flu products (available under brand names such as Codral, Demazin and pharmacy generic cough, cold and flu medicines) will also become unavailable as over-the-counter medicines.

High dose codeine (30-120 mg per dose), used for cancer pain, post-operative pain and other acute pain conditions, already requires a prescription.

There are a range of products available that do not require a prescription to help manage pain and will be available post-February 2018.

Most Australians are aware codeine used for pain relief offers very little additional benefit when compared with medicines without codeine.

The decision to re-schedule codeine is consistent with the Australian Government’s commitment to protect public health and safety for all Australians.

Codeine is closely related to morphine and, like morphine, is an opioid. Long-term use of low-dose codeine has been linked to opioid dependence, toxicity and abuse.

Codeine can cause opioid tolerance, dependence, addiction, poisoning and, in high doses, death. Codeine use can be harmful. Tolerance occurs when codeine becomes less effective and so the body needs higher and higher doses to feel the same relief from symptoms.

Severe withdrawal symptoms can result when the medicine is stopped; these include head and muscle aches, mood swings, insomnia, nausea and diarrhoea. Some of these withdrawal symptoms, such as head or muscle aches, mimic the symptoms that low-dose codeine products are often used to treat, leading to people incorrectly continuing to take the medicine longer or in higher doses.

Codeine poisoning contributes to both accidental and intentional deaths in Australia.

Unfortunately in Australia the most common class of drug identified on toxicology reports in drug-induced deaths are opioids, including opiate-based analgesics such as codeine.

The codeine-containing medicines that are currently available over-the-counter are usually combined with either paracetamol or ibuprofen. Regular use of medicines containing codeine, for example for chronic pain, has led to some consumers becoming addicted or tolerant to codeine without realising it.

Taking more than the recommended dose of combination products could result in serious side effects.

Though safe at recommended doses, long-term use of high doses of paracetamol can result in liver damage,

while the most severe adverse effects of long-term ibuprofen use include serious internal bleeding, kidney failure and heart attack.

CHRIS JOHNSON

Are we using the correct first aid for jellyfish?

The answer is predicated on our knowing what the correct treatment is — and we don’t

In this issue of the MJA, Isbister and colleagues report that hot water immersion was no more effective than ice packs for treating the pain of stings by the box jellyfish (Chironex fleckeri).1 This finding is surprising, as jellyfish venoms are heat-labile,2 but unsurprising, given that heat treatment for some patients did not begin until 4 hours after the patient was stung.

Managing jellyfish stings is generally subject to confusion, and official advice needs revising to make it clear, consistent and effective. The current Australian Resuscitation Council (ARC) guidelines for treating jellyfish envenoming3 encourage this confusion by suggesting that people stung while swimming in temperate waters (south of Bundaberg) should use heat immersion to reduce pain (based on a randomised controlled trial of treatment for bluebottle stings4), but those envenomed in tropical waters (north of Bundaberg) should be treated with ice. The guidelines also advise that vinegar should be used to minimise envenoming only in tropical areas — unless it is clear that the patient has been stung by a bluebottle, in which case vinegar should never be used. Which treatment should you use if you are stung while swimming at Bundaberg? The answer is, at present, uncertain, and urgently requires investigation.

Interestingly, the practice of applying vinegar is based on a single study that found that it deactivated undischarged stinging organelles of the box jellyfish (C. fleckeri).5 No direct evidence contradicting this finding has been published, but a recent study found that treating the discharged stinging organelles of C. fleckeri with vinegar could increase venom release by nearly 70%.6 Data indicating that applying vinegar saves lives has not been reported, nor any that it increases mortality or morbidity. There is, however, retrospective data suggesting it may increase both the level of analgesia required and the length of hospital stay for people presenting with Irukandji syndrome (caused by several species of small box jellyfish).7 Vinegar nevertheless remains the treatment of choice for these stings.

Non-evidence-based treatments dominate first aid for jellyfish stings. Once any of these treatments is entrenched, substantially more evidence is needed to abandon it than was required to establish it. For example, urinating on a jellyfish sting has been shown to aggravate jellyfish envenoming,5 but is still thought by many to be acceptable first aid.

Applying pressure immobilisation bandages (PIBs) to treat jellyfish envenoming is a further example. PIBs were first introduced as first aid for jellyfish stings because of their role in treating snake bites. Two published studies finding that applying them increases venom expression from jellyfish stinging organelles8,9 and several years’ lobbying were needed before this approach was removed from ARC guidelines.

The treatment of Irukandji syndrome with intravenous magnesium is yet another example, introduced on the basis of a single case report.10 Despite many subsequent published studies finding this procedure ineffective, including one randomised controlled trial,11 it is still standard practice for many medical professionals. Magnesium may be helpful in some situations, but may not be as effective as first thought, perhaps because of differences in the venoms involved.

There are significant differences between the venoms of jellyfish: differences between jellyfish from different geographic locations,12 between different species,13 between jellyfish at various ages, and between different parts of the jellyfish (tentacles and body).14 It is not unlikely that these variations lead to very different effects in people stung by jellyfish.

How should we proceed? As it is estimated that there are more than 150 million envenomings by jellyfish each year,15 we need to know our enemy. A more complete understanding of the ecology of these animals and their venoms would make the answer much clearer, but in the meantime treatments may be unsystematically selected in the hope that they might work. At the same time, we need to temper the determination by practitioners to persist with treatments that lack evidence of their effectiveness.

There is still much to learn about jellyfish venoms. We need a simple, consistent first aid approach that works, and this will require well designed investigations of the complexities of these venoms, how they operate, and how their effects can be mitigated. “Are we using the correct first aid for jellyfish stings?” is the wrong question; we should be asking, “What is the correct first aid for jellyfish stings?” The challenge is to design and conduct experiments that are sufficiently comprehensive to answer it!

Self-poisoning by older Australians: a cohort study

The known Self-poisoning is less common among older people, but the numerous medicines they often use provide a ready source of toxins. Further, multiple comorbidities may exacerbate their toxicity and hinder recovery.

The new Most self-poisoning by older people was intentional, but the proportion of unintentional poisonings increased with age. Hospital length of stay, rates of intensive care unit admission and cardiovascular adverse effects, and mortality were higher among older patients.

The implications As our population ages, self-poisoning by older people is likely to be an increasing problem. Although self-poisoning is associated with higher morbidity and mortality than in younger patients, the risk of a fatal outcome is low when patients are treated in specialist toxicology units.

As our population ages, self-poisoning and the associated morbidity are likely to be a growing problem. Self-poisoning is a burden on the health system and is a risk factor for subsequent suicide.1 Drug overdose is less common among older people than in younger adults,2 but is associated with higher morbidity and mortality.3–5 Distinct age differences in the nature and severity of self-poisoning have been reported.5 Stressors such as failing health, the death of a spouse, family discord, and loneliness may contribute to poisoning in older people.6 They often have several comorbidities and consequently take numerous medications, providing a ready source of toxins for self-poisoning. Further, multiple comorbidities and frailty may exacerbate the toxicity of these agents and hamper recovery from self-poisoning. Hopelessness and suicidality frequently increase with age, and depression is strongly associated with suicidality in older people. There is also a relationship between medical and psychiatric comorbidities and suicide by older people.7

While poisoning generally occurs in the context of deliberate self-harm or drug misuse, declining cognitive function can also be associated with unintentional overdose in older people.5 A recent report on self-poisoning in Australia8 provided only limited information about drug overdoses in older people, while an earlier, small study of deliberate self-poisoning by mature Australians included data only to July 1998.9

We examined the epidemiology and severity of self-poisoning by older people in a large regional centre in eastern Australia over a 26-year period, including in-hospital morbidity and mortality, and changes over time in the medications most commonly involved in self-poisoning. We compared these data with those for overdoses in a younger population.

Methods

We undertook a retrospective review of prospectively collected data for people presenting to the Hunter Area Toxicology Service (HATS) after self-poisoning during the 26-year period January 1987 – December 2012. Since 1987, HATS has provided a comprehensive 24-hour toxicology treatment service for a population of about 500 000 people. HATS currently has direct clinical responsibility for all adult poisoning patients in all hospitals in the greater Newcastle region, and provides a tertiary referral service to Maitland and the Hunter Valley.

HATS routinely records data for patients who present to hospital (even if the poisoning is uncomplicated) in a purpose-built database.10 A structured data collection form is used by HATS to prospectively capture information about patient demographics (age, sex), the drugs ingested, co-ingested substances, previous suicide attempts, whether the overdose was intentional or unintentional, management (including intensive care unit [ICU] admission), and complications of poisoning (hypotension, arrhythmias, ventilation requirement, death).11 At discharge, further information is collected, including hospital length of stay [LOS], and psychiatric and substance misuse diagnoses. Data are routinely entered into a fully relational Microsoft Access database distinct from the hospital’s main medical record system.

Data for all patients aged 65 years or more who presented following self-poisoning were extracted, analysed and compared with data for patients less than 65 years of age.

Statistical analysis

Continuous variables are reported as medians and interquartile ranges (IQRs) or ranges, and dichotomous variables as percentages. The statistical significance of differences in continuous variables was assessed in Mann–Whitney U tests, and of differences in dichotomous variables in χ² tests (with Yates correction) or Fisher exact tests. P < 0.05 was deemed statistically significant. All analysis and graphics were performed in GraphPad Prism 6.0h (GraphPad Software).

Ethics approval

The Hunter New England Human Research Ethics Committee has previously granted an exemption from formal ethics approval for analysing data from the HATS database and patient information for research purposes.

Results

There were 17 276 admissions for self-poisoning over the 26-year period 1987–2012; 626 patients (3.6%) were aged 65 years or more and 16 650 (96.4%) were less than 65 years old. The older cohort included 344 women (55%), the younger group 10 258 women (62%; P < 0.001).

Changes in the epidemiology of the admissions of older patients over the 26-year period were analysed by dividing it into one 6-year and four 5-year segments. The proportion of patients admitted to hospital for self-poisoning who were 65 or older (3–4%) was relatively constant across the entire period. The median age of the older patients was 73 years (IQR, 68–79 years); that of the younger patients was 31 years (IQR, 23–41 years). There was a steady decline in the number of admissions for overdoses with increasing age (Box 1). Five hundred admissions in the older cohort (80%) and 14 837 in the younger cohort (89%) involved deliberate self-poisoning (P < 0.001). While the absolute number of self-poisonings decreased with age, the proportion of unintentional and iatrogenic poisoning admissions among patients over 65 increased (65–74 years, 15%; 75–84 years, 25%; 85–97 years, 34%; P < 0.001).

The median hospital LOS for the older patients across the entire period was 34 hours (IQR, 16–75 h); for the younger cohort, 16 hours (IQR, 9–25 h; P < 0.001). There was a progressive decline in LOS for the elderly cohort over the 26 years, from 46 hours (IQR, 23–86 h) in 1987–1992 to 26 hours (IQR, 14–35 h) in 2008–2012; in the younger cohort LOS was relatively constant across time (Box 2, A). The fall in LOS for older patients did not appear to be related to any change in self-poisoning rates with a particular class of drugs (data not shown).

In the older cohort, 133 people (21.2%) were admitted to an ICU, compared with 1976 of the younger cohort (11.9%; P < 0.001). The proportion of older patients admitted to an ICU declined over the 26-year period from a peak of 26% in 1993–1997 to 14% in 2008–2012; there was also a decline for the younger group (Box 2, B). The decline in the proportion of older patients who were ventilated was similar to that for those admitted to an ICU (Box 2, C). There were 24 deaths (3.8%) in the older cohort and 93 (0.6%) in the younger cohort (P < 0.001). Mortality decreased over time in the older cohort, from 8% to 1%, but remained relatively constant (0–1%) in the younger cohort (Box 2, D). The most common drug/toxin groups involved in fatal self-poisoning in the older cohort were opioids (5 of 24 deaths) and organophosphates (3 of 24; Appendix 1).

The incidence of cardiovascular adverse effects was higher in the older cohort. Hypotension was present in 65 older patients (10.4%) and 813 younger patients (4.9%); 59 patients aged 65 or more (9.4%) had arrhythmias, compared with 217 patients under 65 (1.3%). There were no differences between the two groups in the incidence of delirium, serotonin toxicity, or seizures.

There were 356 single-drug ingestions (56.9% of admissions) in the older cohort, compared with 7009 (42.1%) in the younger cohort (P < 0.001), and 28 many multiple drug (ie, more than five) ingestions (4.5%) in the elderly cohort compared with 250 (1.5%) in the younger cohort (P < 0.001; Appendix 2). Benzodiazepines were the drug class most commonly ingested by older patients (24.2%), followed by paracetamol (8.1%) and alcohol (7.3%); in contrast, alcohol was the most common drug ingested by younger patients (16.2%), followed by benzodiazepines (15.6%) and paracetamol (14.0%; Box 3). The proportion of benzodiazepine ingestions among older patients decreased over the 26-year period from a high of 35% in 1993–1997 to 15% in 2008–2012 (Box 4, A). The proportion of cardiovascular drug ingestions (Box 4, B) increased threefold, from 4% to 11%, with about one-third of poisonings unintentional or iatrogenic. In contrast, only 2% of toxic benzodiazepine ingestions were unintentional or iatrogenic. The proportions of tricyclic antidepressant and first generation antipsychotic ingestions fell across the study period, with a corresponding increase in those of newer antidepressants and second generation antipsychotics (Box 4, C). The overall proportion of ingestions involving antidepressants or antipsychotics was unchanged over the study period, accounting for 12% of admissions. The proportion of poisonings with analgesic drugs (paracetamol, opioids or salicylates) increased by about 50% (from 10% to 16%); paracetamol accounted for 60% of toxic analgesic drug ingestions (Box 4, D), but there was a much greater increase in the proportion of poisonings with morphine and oxycodone. Only four admissions of older patients (0.6%) involved recreational drugs, compared with 1306 admissions (7.8%) in the younger cohort (P < 0.001).

A history of previous suicide attempts, psychiatric illness, hospital admission for mental health problems, or drug or alcohol misuse was respectively identified for 198 (32%), 241 (38%), 174 (28%) and 147 (23%) admitted older patients. Each of these proportions was significantly smaller (P < 0.001) than for patients under 65 (Box 5).

Discussion

For people aged 65 years or more admitted to hospital for self-poisoning, the average LOS was twice as long, admission to an ICU more likely, the incidence of hypotension and arrhythmia significantly higher, and mortality greater than for younger patients. Hospital LOS for older patients steadily declined over the 26-year period, and this decrease was associated with a similar decline in the rates of ICU admission, ventilation, and mortality. This may reflect changes in management over time, with an increasing emphasis on reducing LOS, as well as improvements in services that aid older patients during the discharge process. A reduction in the proportions of self-poisonings with more toxic agents, such as tricyclic antidepressants and conventional antipsychotics, may have also contributed to the decline in LOS, although the number of admissions of older patients for self-poisoning with these drugs was small. Further, the reduced number of more toxic ingestions by the younger cohort did not affect their mean LOS over the study period (data not shown).

The proportion of patients admitted to hospital for self-poisoning who were at least 65 years old in our study (3–4%) was lower than the proportion of older people in the Australian population (11–14%) during the study period. Lower rates of admission of people over 65 years of age for poisoning with recreational drugs and the lower prevalence of psychiatric co-factors and alcohol and drug misuse probably explain this difference. Although the proportion of the population who were 65 or older increased during the study period, the proportion of self-poisonings involving older people remained relatively constant. This is reassuring, but underscores the importance of specialist toxicology services.

Among those aged 65 or more, the proportion of non-deliberate or unintentional self-harm admissions increased with age; the proportion was more than twice as great among the oldest patients as in the 65–74-year age group. In a profile of calls to a large American poisons information centre, therapeutic errors resulting in self-poisoning were increasingly prevalent among older people, rising from 14.5% in 50–54-year-old people to 25.3% in those aged 70 years or more.2 Psychiatric illness is associated with suicide at all ages,7 and 38% of older patients in our study had a history of psychiatric illness. Other risk factors for suicide include depression, alcohol misuse, prior suicide attempts, higher age, being male, living alone, and bereavement (especially among men).12 While in our study a history of psychiatric illness, a prior suicide attempt, and alcohol or drug misuse were all more frequent in patients under 65, one-third of older patients also had a history of attempted suicide, and almost one-quarter reported alcohol or drug misuse. Social isolation and loneliness, family discord, and financial trouble are also risk factors for suicide.6

In our study, opioids were the drugs most commonly associated with fatal self-poisoning by older patients. The rising proportion of opioid overdoses in this group is worrying, and may be reflect the increasing use of these agents, particularly for the treatment of non-malignant pain. While paracetamol was the second most commonly ingested drug in poisonings, the proportion has remained constant over time, and there were no fatalities, probably because a highly effective antidote, N-acetylcysteine, is available.13

Benzodiazepines were the drugs most frequently implicated in self-poisonings by older patients in our study, consistent with other reports. A Canadian study of 2079 people aged 65 or more found that benzodiazepines, opioids, other analgesics and antipyretics, antidepressants, and sedative hypnotics were the drug classes most frequently used in suicide attempts.5 In a Swedish study, a benzodiazepine was implicated in 39% of drug poisoning suicides by older people, and this proportion was rising despite a reduction in prescription sales.14 Both the prescription and ingestion of benzodiazepines have been reported to be associated with self-poisoning by older Australians.9 Benzodiazepines may exacerbate undiagnosed depression and impair impulse control in some individuals, leading to suicide attempts. The decline in the proportion of admissions for self-poisoning with benzodiazepines over the study period is therefore reassuring.

Self-poisoning with cardiovascular drugs by older people increased threefold over the study period, and probably contributed to the higher incidence of hypotension than in the younger cohort. In an American study of calls to a poisons information centre, there was a relatively high number of self-poisonings with β-blockers and calcium channel antagonists by older callers.2

The number of drugs taken by older patients appears to have a bimodal distribution, with the proportions of admissions for ingesting one drug or more than five drugs both being higher than among younger patients. The higher frequency of toxic ingestions of more than five drugs may reflect the increased use of Webster-pak and dosette boxes by older patients.

The data in our study have inherent limitations. The HATS database does not capture the number of people who died outside hospital, nor those with less severe poisonings; that is, people who visited their primary care physician rather than presenting to an emergency department. Other poisoning studies in Newcastle have also not included patients treated only by their local medical officer or in private hospitals.15,16 Further, despite the use of a prospective data collection form, retrospective review of medical records is often required to complement prospectively collected data. However, this is rarely required for the minimum dataset we analysed; almost all data were recorded at admission. Finally, the HATS database does not capture medical comorbidities, so that we were unable to correlate these with the outcomes we reported. The key strengths of our study include the fact that the longitudinal data were gathered over an extended period, and that core data fields were consistently recorded.

Education strategies for preventing poisoning have traditionally focused on children, but the morbidity and mortality for this age group is extraordinarily low.2 Although less common in older people, self-poisoning can be a highly significant clinical event. Suicidal intent is more common, as is a lethal outcome. Some prevention efforts may be better directed to protecting our expanding population of older citizens. The importance of potentially remediable factors, such as depression and rates of benzodiazepine prescribing, should not be overlooked. The overall low mortality among older people presenting to hospital after self-poisoning reflects the standard of care received by these patients.

In summary, self-poisoning by older people is likely to be an increasing problem as our population ages. Self-poisoning by older people is associated with higher morbidity and mortality than in younger patients, and unintentional self-poisoning is also more common. The steady decrease in LOS over the 26-year period and the declines in the rates of ICU admission and death are encouraging. Despite the higher overall rate of completed suicide by older people, our data indicate that the risk of a fatal outcome following self-poisoning is low when the patient is treated in a specialist toxicology unit.

Box 1 –
Number of admissions for self-poisoning, greater Newcastle region, 1987–2012, by 5-year age bands*

* Age group labels indicate the starting age for each band; eg, 15 years = 15 to less than 20 years of age.

Box 2 –
Median hospital length of stay (A), proportion of admissions to intensive care units (B), proportion of patients requiring mechanical ventilation (C), and in-hospital mortality (D) for patients admitted to hospital for self-poisoning, greater Newcastle region, 1987–2012

Box 3 –
Types of drugs most frequently ingested by patients admitted to hospital for self-poisoning, greater Newcastle region, 1987–2012, by age cohort*

Drug class/name	Patients≥ 65 years	Patients< 65 years

Total number of patients	626	16 650
Total number of ingested substances	1198	33 205
Benzodiazepines	290 (24.2%)	5180 (15.6%)
Paracetamol	97 (8.1%)	4633 (14.0%)
Opioids	37 (3.1%)	1221 (3.7%)
Salicylates	24 (2.0%)	335 (1.0%)
Alcohol	87 (7.3%)	5374 (16.2%)
Tricyclic antidepressants	54 (4.5%)	1332 (4.0%)
Selective serotonin re-uptake inhibitors	33 (2.8%)	1650 (5.0%)
Serotonin/noradrenaline re-uptake inhibitors	13 (1.1%)	767 (2.3%)
Antidepressants (other)	15 (1.3%)	428 (1.3%)
Angiotensin 2 receptor blockers/angiotensin converting enzyme inhibitors	42 (3.5%)	178 (0.5%)
β-Blockers	30 (2.5%)	259 (0.8%)
Calcium channel blockers	28 (2.3%)	111 (0.3%)
Digitalis glycosides	14 (1.2%)	20 (0.1%)
Vasodilators	13 (1.1%)	154 (0.5%)
Anticonvulsants	39 (3.3%)	1475 (4.5%)
Antipsychotics (typical)	35 (2.9%)	1200 (3.6%)
Antipsychotics (atypical)	22 (1.9%)	1673 (5.0%)
Lithium	22 (1.8%)	228 (0.7%)
Antihistamines	16 (1.3%)	727 (2.2%)
Proton pump inhibitors	15 (1.3%)	129 (0.4%)
Statins	14 (1.2%)	50 (0.2%)
Non-steroidal anti-inflammatory drugs	13 (1.1%)	1091 (3.3%)
Other drugs	85 (7.1%)	1356 (4.1%)
Nitrates	14 (1.2%)	22 (0.1%)
Other non-therapeutic substances	33 (2.8%)	516 (1.6%)

* Three drug groups frequently implicated in self-poisoning by people under 65 years of age were rarely involved in self-poisoning by older patients: amphetamines (1.9% of admissions of people under 65), antibiotics (1.1%), and anticholinergic agents (1%).

Box 4 –
Major drug classes implicated in admissions for self-poisoning of people aged 65 years or more, greater Newcastle region, 1987–2012. (A) Alcohol and benzodiazepines; (B) cardiovascular drugs; (C) antidepressant and antipsychotic drugs; (D) analgesics

Box 5 –
The proportions of patients admitted to hospital for self-poisoning, greater Newcastle region, 1987–2012, with a history of previous suicide attempt, psychiatric illness, admission to hospital for a mental health problem, or substance misuse, by age cohort

[Perspectives] Marie Vahter: the arsenic detective

Marie Vahter first came across the harm arsenic can do to the environment and health in her native Sweden during the early 1980s, when a large copper smelter was spewing the toxin into the air and sea. She did her PhD in toxicology, focusing her dissertation on the kinetics of inorganic forms of arsenic in relation to animal species. Today, she is a Professor in Environmental Medicine at the Karolinska Institutet, Stockholm, where she directs research into the immediate and long-term effects of early-life exposure to toxic metals such as arsenic, manganese, cadmium, and lead.

A decade of Australian methotrexate dosing errors

Methotrexate is a synthetic folic acid analogue used for its antineoplastic and immunomodulating properties. It competitively inhibits folic acid reductase, decreasing tetrahydrofolic acid production and inhibiting DNA synthesis. Low dose methotrexate (administered weekly in doses of 7.5–25 mg) is indicated for rheumatoid arthritis, psoriasis and inflammatory bowel disease.1

The unusual dosing schedule of low dose methotrexate is associated with a risk that it will be prescribed, dispensed or administered daily instead of weekly. Used appropriately, methotrexate is considered safe and efficacious; accidental daily dosing, however, can potentially be lethal. Higher or more frequent doses can result in gastro-intestinal mucosal ulceration, hepatotoxicity, myelosuppression, sepsis and death.2 Indeed, there are several literature reports of serious morbidity and mortality linked with methotrexate medication errors.3–7 A study of medication errors reported to the United States Food and Drug Administration over 4 years identified more than 100 methotrexate dosing errors (25 deaths), of which 37% were attributed to the prescriber, 20% to the patient, 19% to dispensing, and 18% to administration by a health care professional.8,9

Current efforts to reduce the likelihood of these errors include the guideline that a specific day of the week for taking methotrexate is nominated.10 Additional care in counselling is recommended to ensure that patients are aware of the dangers of taking extra methotrexate and of signs of methotrexate toxicity.4 In Australia, oral methotrexate is available in packs of 2.5 mg × 30, 10 mg × 15, and 10 mg × 50 tablets. In 2008, the 15-tablet pack was introduced to reduce the risk of toxicity, with the 50-tablet pack being placed on a restricted benefit listing for patients prescribed more than 20 mg per week.

Although overseas data have been published in the form of case reports3,6 and reviews of adverse event databases,9 Australian data on methotrexate medication errors are lacking. In this article, we describe cases of methotrexate medication errors resulting in death reported to the National Coronial Information System (NCIS), summarise reports involving methotrexate documented in the Therapeutic Goods Administration Database of Adverse Event Notifications (TGA DAEN), and describe methotrexate medication errors reported to Australian Poisons Information Centres (PICs).

Methods

This study investigated medication errors recorded in the NCIS, TGA DAEN and PIC datasets. For the purposes of our study, “medication error” was defined as an incident occurring anywhere in the medication process, including prescribing, dispensing or administration. For the error to be included in our study, methotrexate must have been taken by the patient on 3 or more consecutive days.

Data were collected from the NCIS to identify deaths linked with methotrexate medication errors. The NCIS database has a record of reportable deaths from July 2000 onwards for all states except Queensland, for which data are available from January 2001. This database was searched on 4 July 2015 for closed cases from the period 2000–2014, searching for methotrexate in the “cause of death” fields, and by searching for deaths caused by antineoplastic agents in “complications of health care” as “mechanism/object”. A keyword search of attached documentation (findings, autopsy reports) was not performed. Results were manually reviewed for inclusion.

Data were obtained from the open access TGA DAEN for methotrexate adverse events reported from January 2004 to December 2014. Cases coded as “accidental overdose”, “drug administration error”, “drug dispensing error”, “inappropriate schedule of drug administration”, “medication error”, or “overdose” were extracted and manually reviewed for inclusion.

There are four PICs in Australia that together provide around-the-clock poisoning advice to health care professionals and members of the public across Australia. We retrospectively reviewed the New South Wales, Victorian, Western Australian and Queensland PIC databases. South Australia, the Northern Territory, the Australian Capital Territory and Tasmania do not have PICs, but calls from these states are diverted to the New South Wales and Western Australian Poisons Centres. Data from the Victorian PIC were available from May 2005, and from the Queensland PIC from January 2005; other PIC databases were searched for 1 January 2004 onwards, with cases included if they occurred on or before 31 December 2015. Methotrexate cases were manually reviewed for inclusion.

Methotrexate dispensing data from January 2004 to August 2015 were obtained from the Pharmaceutical Benefits Schedule Item Reports website (http://medicarestatistics.humanservices.gov.au/statistics/pbs_item.jsp). Item numbers 1622J, 1623K and 2272N were included, corresponding to the oral methotrexate available in Australia. The price of 10 mg × 50 tablets is above the Pharmaceutical Benefits Scheme (PBS) co-payment threshold, while those of other pack sizes are below the threshold. The PBS dataset did not capture items under the co-payment threshold until April 2012. Data on the dispensing of 10 mg × 15 and 2.5 mg × 30 tablet packs during the study period is available only for concession card holders; that is, using PBS data for the entire population overestimates the proportion of scripts dispensed for the 10 mg × 50 pack size. As the price of the medicine of interest lies under the co-payment threshold, the study population was restricted to concessional beneficiaries to better reflect use of the medicine.11

We used medians and interquartile ranges (IQRs) to describe the data, and performed statistical analyses with Excel (Microsoft) and SPSS 22 (IBM).

Ethics

Ethics approval for the use of NCIS data was granted by the Victorian Justice Human Research Ethics Committee (approval number CF/12/19007); ethics approval for the use of PIC data was granted by the Sydney Children’s Hospitals Network Human Research Ethics Committee (approval number LNR-2011-04-06).

Results

We identified 22 instances in the NCIS dataset where methotrexate was listed as a cause of death, including 12 with documented bone marrow suppression. Dosing errors were recorded in seven cases (five men, two women); methotrexate had been taken for between 3 and 10 consecutive days. One further deceased patient took more than the prescribed dose of methotrexate (based on tablets remaining and dispensing date), but was not included because consecutive daily dosing was not conclusively established. Abnormal blood cell counts were documented for all seven deaths linked with dosing errors (median age, 78 years; range, 66–87 years). Reasons for the errors included dosette packaging errors by pharmacists (three cases), prescribing error (one), mistaking methotrexate for another medication (one), dosing error by carer (one), and prescriber–patient miscommunication (one). Causes of death without a documented dosing error included alveolar damage or pulmonary fibrosis (five cases), pneumonia (three), sepsis (three), pancytopenia (one), chronic liver disease (one) and gastro-intestinal haemorrhage (one).

The TGA DAEN included 16 reports of methotrexate-related adverse events meeting our search criteria, including five deaths. These were reviewed for inclusion, and unintended daily dosing was documented in ten cases (median age, 58 years; IQR, 42–74 years; range, 41–85 years; eight women), including two deaths (two women, aged 71 and 83 years).

The PIC dataset contained 92 cases of methotrexate-related medication error meeting our inclusion criteria. Between 2005 and 2013, the annual number of events was fairly stable (four to nine cases per year; Box 1). Interestingly, there was an increase during 2014–2015 (16 and 13 cases respectively). We compared PIC exposures with prescribing and dispensing habits, as increased supply might explain an increase in medication errors. The number of methotrexate concessional scripts dispensed during 2005–2015 is shown in Box 1. Most methotrexate was dispensed in 10 mg × 50 tablet packs, the rate of dispensing of which increased steadily during the study period, while that of 2.5 mg tablets had been decreasing. The rate of dispensing of the smaller pack size (10 mg × 15), introduced in 2008, has grown, but has not reached that of the larger pack size, which still accounted for 47% of scripts (and 79% of 10 mg doses) in 2014.

In the PIC dataset, exact ages were recorded in 51% of cases (median age, 65 years; IQR, 52–77 years; range, 28–91 years); at least 18 patients were over 75 years of age. Fifty-five of the 92 patients were women; sex was not recorded in seven cases. Call records documented a range of symptoms, including stomatitis, vomiting, reduced blood cell count and fever. The median number of consecutive days for which methotrexate was taken was 5 (IQR, 4–9 days; range, 3–180 days); the distribution was skewed (Box 2), with 20 cases involving methotrexate taken for 3 consecutive days. The median daily dose taken was 10 mg (IQR, 10–15 mg; range, 2.5–60 mg). Box 3 summarises data on the doses and durations of administration in medication errors reported to PICs.

Where documented, reasons for errors in the PIC dataset included mistaking methotrexate for another medication (11 cases), often folic acid (six cases) or prednisone (four); carer or nursing home error (five); methotrexate being newly prescribed for the patient (five); dosette packing errors by the pharmacy (four); misunderstanding instructions given by the doctor or pharmacist (two); the patient believing it would improve efficacy (two); prescribing error (one); and dispensing or labelling error (one).

There was little overlap in the cases recorded in the three datasets. One DAEN case was a match for one in the NCIS dataset, and there was one possible match of a DAEN case with PIC data. Two of the NCIS deaths were also recorded in PIC databases.

Discussion

This study examined methotrexate dosing errors captured by a range of reporting systems. This included seven deaths in the NCIS dataset (2000–2014), ten cases in the TGA DAEN (including two deaths, 2004–2014) and 92 PIC cases (2004–2015). These datasets had little overlap, with 91 unique reports of methotrexate medication error identified in the three datasets for 2004–2014. Although these events are relatively rare, they can have serious consequences, and all are preventable. Serious toxicity (including death) was noted after as little as 3 consecutive days of methotrexate administration.

This study highlights the benefits of searching both the coronial and TGA datasets, as there was only one case common to these two datasets (with the NCIS capturing more cases than the TGA). Deaths are reported to the coroner according to legislation that defines a “reportable death”, and there is no requirement to report deaths caused by adverse drug events. Indeed, a recent study by our group found that there is little cross-reporting of drug-related deaths by the TGA and the coroner (unpublished data). This raises the question of whether there might be more deaths related to methotrexate dosing errors that are not reported to either body. Similarly, although our PIC dataset includes all Australian poisons calls, not all methotrexate medication errors result in a call to a PIC. Methotrexate medication errors causing toxicity and death may thus be more common than our study suggests.

Further limitations of our study include the delayed release of findings by the coroner. At the time of data extraction, case closure rates for 2013 and 2014 averaged about 75% and 50% respectively. Our study may therefore underestimate the numbers of deaths, especially those occurring during 2013–2014. The TGA dataset documents occasions of methotrexate dosing errors, but the DAEN does not establish causality, so that the deaths recorded in the TGA DAEN represent associations with the medication (rather than causal links). The PIC dataset has limitations, including non-standardised methods for coding calls and the fact that it lacks outcome information (Australian PICs do not routinely conduct follow-up calls). As the PBS dataset did not capture items under the co-payment threshold prior to 2012, we analysed only dispensing data for the concessional population. Although this provides an indication of prescribing trends, it may not be generalisable to the entire population.

The variability in the amount and duration of methotrexate administration prior to a toxic reaction is interesting. The NCIS database showed that taking methotrexate for 3 consecutive days can be fatal, but a small proportion of PIC patients took the drug daily for weeks before they presented to hospital. Such diversity of response could be caused by the marked variability in genes involved in methotrexate absorption, transport, metabolism and excretion.2,12 Variability in renal function and hydration could also affect methotrexate clearance.2 The median age of patients in the NCIS dataset was more than 10 years higher than that in the PIC dataset, suggesting that increased age may be a risk factor for death related to methotrexate dosing errors.

These data revealed a worrying increase in methotrexate medication errors in the PIC dataset for 2014–2015, despite the mentioned efforts to reduce the incidence of these events. It is difficult to explain this increase, but the risk of methotrexate medication error may be increasing as the population ages. Older people may be at increased risk because of a range of problems that includes confusion, memory difficulties, and age-related decline in visual acuity.

This study indicates that ongoing harm is occurring as the result of methotrexate errors. More needs to be done by the manufacturers, the TGA and health professionals to reduce these risks and to improve the harm–benefit balance of weekly methotrexate. One possibility would be to adjust the packaging. A further reduction in pack size may be warranted; for example, each box of the Rheumatrex Dose Pack8 in the United States contains doses for 4 weeks only (similar to the manner in which the weekly dosed bisphosphonates are packaged). Current methotrexate pack sizes in Australia can exceed a year’s supply, depending on the prescribed dose. Although supply of the largest methotrexate pack was changed to a restricted benefit in 2008, this did not result in a reduction in the number of scripts dispensed (Box 1). In addition, uptake of the new, smaller pack has been slow (Box 1). More must therefore be done to discourage prescribing of unnecessarily large quantities of methotrexate.

Further, because it is recommended that folate be co-prescribed with methotrexate, folate and methotrexate could be packaged together in a manner similar to that for oral contraceptives/sugar pills or combination calcium/vitamin D with bisphosphonates. This would be particularly useful given that one of the reasons for methotrexate medication errors we identified was confusion of the medication with folate. The limitations of this approach include the lack of national consensus on the ideal regimen for folate supplementation, with insufficient evidence to justify strongly recommending a specific dose.13 This approach would also require an industry partner to develop such a product,8 and with current prices there may be a limited return on this investment.

Formulating methotrexate as a distinctively coloured tablet could reduce the risks of medication errors by pharmacists, pharmacy technicians and patients; the documented confusion of methotrexate with folic acid tablets is probably related to both being small yellow tablets. Further packaging changes could be made, including clear labelling of the box with a statement such as “Warning: this medicine is usually taken weekly. It can be harmful if taken daily.” Similar labelling changes have been recommended in Australia14 and elsewhere,15 and the results of this study suggest that more needs to be done to mandate sponsors (the companies supplying methotrexate in Australia) to enact these changes.

As some of the dosing error events can be attributed to prescribing or dispensing errors, warnings in prescribing and dispensing software could be improved. Prescribing software could include a pop-up alert when methotrexate is prescribed daily, with the manual entry of an oncological indication needed to override the warning.16 Dispensing software could include alerts if methotrexate is being dispensed too frequently. We identified at least three fatalities caused by daily methotrexate included in pharmacy-filled dosette boxes. Education of pharmacists and their assistants could be improved to increase vigilance and checking of dosette packs containing methotrexate. Further, patients who are prescribed methotrexate for the first time are at particular risk, and extra care in counselling these patients is needed. This includes providing clear verbal and written instructions about dosage.

In conclusion, our study found that methotrexate medication errors, some resulting in death, are still occurring despite a number of safety initiatives. The increase in the number of events during 2014–2015 is particularly concerning. Methotrexate use is likely to continue increasing as Australia’s population ages, so that additional measures are needed to prevent these errors. We have outlined some potential strategies, including altering the packaging, improving education, and including alerts in prescribing and dispensing software.

Box 1 –
Methotrexate medication error events reported to Australian Poisons Information Centres, and the quantity of each methotrexate pack size dispensed to concessional patients through the Pharmaceutical Benefits Scheme, 2005–2015

Box 2 –
Number of consecutive days for which methotrexate was administered in events reported to Australian Poisons Information Centres, 2004–2015*

* Data from the Victorian Poisons Information Centre were available from May 2005, and from the Queensland Poisons Information Centre from January 2005.

Box 3 –
Dose and duration of 84 methotrexate medication errors reported to Australian Poisons Information Centres, 2004–2015*

Each point represents a unique event; eight of the 92 reported events are not included because the amount of methotrexate taken each day was ambiguous or not included in the call record. * Data from the Victorian Poisons Information Centre were available from May 2005, and from the Queensland Poisons Information Centre from January 2005.

Drug checking to improve monitoring of new psychoactive substances in Australia

Drug checking may need to play a part in future public health interventions

As has been reported previously in the Journal,1 novel psychoactive stimulant drugs are now increasingly prevalent in patients presenting to hospital emergency departments. A further cluster of 11 patients showing confusing hallmarks of sympathomimetic poisoning but no identifiable substance presented to St Vincent’s Hospital in Sydney over a public holiday weekend in April 2015. Also, the start to the 2015–2016 summer festival season has included multiple deaths and hospitalisations following drug use at festivals, leading to calls for novel actions to protect public health.2 Here, we take the opportunity to describe a method of harm minimisation that has been deployed in Europe and could potentially be deployed locally to tackle this problem.

Monitoring new psychoactive substances

New psychoactive substances (NPS) are emerging rapidly into the market, with more than 100 identified in the past year by European monitoring systems.3 Existing psychoactive drug monitoring systems have limited capacity to identify NPS. Their limitations are detailed as follows:

self-reports (eg, household surveys and regular interviews with sentinel groups, as reviewed by Burns et al4) can identify what users think they are taking, but not necessarily what they are actually taking;
web vendor monitoring (eg, analyses of surface web and dark web [also see Burns et al4]) can identify what vendors report they are selling, but not what is actually sold; and
pharmacological analyses (eg, wastewater analyses5) can provide more accurate information about what is actually being consumed, but not what people believe they are consuming.

These monitoring systems have been used to identify NPS and track their use in Australia, but they are not able to characterise the congruency between what people believe they are taking and what they are actually taking. Combining all three of these methods and providing an innovative drug-checking service would strengthen surveillance of drugs being used in festival settings. Accurate and tailored information can facilitate an open dialogue between health care providers and drug users at the point of consumption. Identifying emerging trends in NPS will provide opportunities to prevent harm, and enable our services to respond more effectively to the harms arising from both intentional and unintentional NPS use.

Drug-checking services

Several European countries now provide drug analysis services,6 whereby individuals submit samples of their drugs to have their contents identified and analysed for purity. The results are provided to the consumer. The analytical facility can be based either on-site (eg, at large parties or festivals) or off-site. In some of the European services, brief health interventions aimed at reducing harm are offered to consumers simultaneously. Fast turn-around drug analysis services may have reduced harms resulting from recent episodes of mass intoxications at festival settings by:

identifying the NPS and other contents of the pills or powders;
monitoring NPS availability and use trends to enable an effective public health response;
identifying emerging hazards from specific NPS and the formulations available;
improving the knowledge base for effective clinical management of acute and chronic presentations;
providing an opportunity for users to seek help, obtain health information to reduce potential harms and to offer options for individual behaviour change; and
providing intelligence that could influence supply dynamics.

The optimal method for providing analytical services will depend largely on the social and legal context. In Austria and Switzerland, field workers from a non-government organisation conduct on-the-spot drug analysis to patrons at dance parties via a field laboratory equipped with high-pressure liquid chromatography machines. Samples are received directly from consumers and results are available to them within 20 minutes, accompanied by a brief intervention with referral if required.7 In the United Kingdom, amnesty bins are placed in party venues and a private, not-for-profit laboratory undertakes the analyses to add to a library of NPS. In larger nightclubs, on-site field workers use infra-red mass spectrometry to compare the drugs received with the database. Local accords between police, public health officials and the nightlife venue operators are required to ensure successful integrated services. A network of 26 drug-checking sites in the Netherlands is incorporated into the Ministry of Health as part of a national surveillance system.8 This service offers immediate results of quick office tests to potential users, with intervention and referral if necessary. Subsequently, samples are sent for more accurate spectrometric analysis, and results are available within a week. Most importantly, results are incorporated into the national surveillance system and are monitored for trends in emerging substances, and results are used to inform public policy and practice. While the direct prevention of deaths has not been documented, dangerous pills or powders identified by checking systems in the Netherlands have quickly disappeared from the Dutch markets following the launch of warning campaigns.9

Discovering new compounds that endanger life is unlikely to benefit the user after he or she has taken the drug except in ruling out other causes for developing severe syndromes. However, as more becomes known about the psychopharmacology of specific compounds, best-practice treatment algorithms can be created. If backed up by a sensible brief intervention, such a service might see users of drugs more engaged in caring for their health, recognising problem substance use, and seeking help. From a public health perspective, information on new compounds can be used to monitor emerging trends and inform prevention activities.

Problems to overcome

Several hurdles need to be overcome before drug checking can be established in Australia. Drug sellers may view the service as an opportunity to have their drugs checked before they distribute them. As in Europe, drug-checking services would need to ensure they are not complicit in aiding drug distribution. There may also be a misconception among users of the service that by having their drugs “checked”, their use is condoned or seen as safe. Existing drug-checking services deal with this misconception through careful engagement with service users to explain that all drug use is risky and that the only completely safe option is to avoid drug use. This message is more likely to be heeded by users of drug-checking services who are receiving advice about harm reduction that is individually tailored to their personal characteristics and the known characteristics of the drugs they may consume.

As happens overseas, Australian drug-checking services will need to be provided in multiple sites in both metropolitan and regional locations. Transport problems would need to be solved to provide access to services outside metropolitan areas.

Effective laboratory testing is expensive; without adequate investment, the drug-checking service may be restricted to ad hoc sites or subject to unreliable testing techniques. Indeed, drug-checking interventions were conducted in Australia over a decade ago,10 but, at that time, on-site testing technology was restricted to colour reagent test kits, which are not reliable enough nor able to detect the larger number of substances currently available. In 2016, for an investment of under $200 000 (based on the costs of a high-performance liquid chromatography machine and employing a Scientist and Drug and Alcohol Counsellor), a mobile laboratory could be set up and attached to existing peer-run harm-reduction services, supported by existing full laboratories providing in-kind support. While there are expenses associated with the ongoing running of such a service, the costs of trialling this kind of intervention are relatively low with the use of currently available technology that has been field-tested in other countries.

In addition, handling materials that are suspected of being illegal substances is prohibited by law; there are harm-reduction services currently operating in Australia that have been provided with an exemption for service staff and clients, such as Sydney’s medically supervised injecting centre. Therefore, providing a drug-checking service would not require a radical shift in national drug policy, but would require cooperation between health and police stakeholders.

Conclusions

An important public health need in Australia could be met by providing an easily accessed drug-checking service that provides reliable and fast information to consumers about the content of drugs, along with non-judgemental harm-reduction advice. A further advantage is the ability of such a service to track the appearance of NPS on the market rapidly,8 which is helpful and sometimes necessary if we are to respond more effectively to NPS-related harm. Such a service could mitigate the severity and impact of situations that commonly overwhelm emergency departments around Australia by rapidly disseminating information about NPS to (a) potential consumers, warning them about specific products and batches, and (b) clinicians, guiding them on the predicted toxidrome and management of affected patients.

Concerns about the unintended consequences of providing a drug-checking service include legitimisation of the use of drugs, civil responsibility of the drug checkers towards consumers of tested drugs, and the use of the service by drug sellers as a quality control mechanism. Such concerns have not been supported by evidence in the European context.11 In Europe, the service is used in tandem with opportunistic brief interventions that provide a moment for education on health and harm reduction, and reduces the delay to treatment for problem drug use. Further experience with services of this kind is required to ascertain the feasibility, acceptability and effectiveness in inducing behaviour change of various models of drug checking in the Australian context, which is different from the Dutch context (eg, there is no threat of prosecution for using these drugs in the Netherlands). Therefore, it is very important that a high-quality research trial of drug checking in Australia be conducted.

ADHD medication overdose and misuse: the NSW Poisons Information Centre experience, 2004–2014

In 1984, dexamphetamine became available in Australia as a subsidised medicine for treating attention deficit hyperactivity disorder (ADHD). Immediate release and long-acting methylphenidate, atomoxetine and modafinil have since been added to the Pharmaceutical Benefits Scheme. Apart from atomoxetine (a noradrenaline re-uptake inhibitor), these medications are all psychostimulants. With the exception of dexamphetamine, the rates of prescribing of these medications continues to grow significantly in Australia and elsewhere.1,2 This can largely be attributed to the increasing acceptance of ADHD as a diagnosis.3,4 However, these trends in prescribing are occurring amid increasing concerns about the diversion and misuse of these drugs.5 Further, there is increasing public anxiety about prescription stimulant dependence and misuse, including warnings about illicit injection of methylphenidate (Ritalin) following two recent deaths in Tasmania.6 This is in the context of much wider concerns about the relatively high prevalence of methamphetamine dependence in Australia7 and the increased use of methamphetamine by existing drug users,8 which may be related to recent increases in the purity of illicit crystal methamphetamine.9 There is also growing unease about the overdiagnosis and overtreatment of ADHD, as well as about the increasing off-label use of these medicines to treat conditions for which the evidence base is weaker.10

The factors described here contribute to the increasing public availability of ADHD medications that can be diverted, misused and lead to overdoses. In this article we describe trends in intentional exposures to ADHD medications (overdoses and recreational use) reported to the New South Wales Poisons Information Centre (NSWPIC) over an 11-year period.

Methods

Data sources

We conducted a retrospective study of calls to the NSWPIC from 1 January 2004 to 31 December 2014. The NSWPIC receives about 110 000 calls from the public and from health care professionals each year, accounting for around 50% of Australian PIC calls. Between 6 am and midnight, the NSWPIC receives calls from NSW, Tasmania and the Australian Capital Territory, and it also handles after-hours calls from across Australia for seven nights each fortnight.

The defined daily dose per 1000 population per day (DDD/1000/day) is a measure of the national use of a drug, and this information is published annually in Australia.11 We extracted the data for the medicines of interest during the study period (2004–2014).

Search strategy and inclusion criteria

We searched the NSWPIC database for “methylphenidate”, “dexamphetamine”, “modafinil” and “atomoxetine”. We also searched for “methamphetamine” to allow comparison of the number of calls about prescription medications with that of calls related to definite illicit amphetamine use. Since our focus was intentional exposures, we excluded exposures in children under the age of 10 years to remove paediatric ingestions of accidental or undetermined intent. We therefore included in our analysis only exposures coded as “intentional” in people aged 10 years or more. The co-ingestion of alcohol or illicit street drugs, such as ecstasy, marijuana or cocaine, was used as a proxy measure of illicit use. Characteristics, including age, sex, co-ingestants, route of exposure and symptom disposition, were extracted. The presence of symptoms at the time of the call was coded as “present” or “absent”.

Definitions

For the purposes of this study, misuse was defined as using the drug for a purpose other than that for which it was prescribed. This included taking the drug in excessive quantities or by non-oral routes, and the use of diverted medicines. Diversion was defined as the transfer of drugs from legal sources to an illicit channel or marketplace.

Statistical analysis

Statistical analyses were performed with the Joinpoint regression program, version 4.2.0.2 (Statistical Methodology and Applications Branch, Surveillance Research Program, National Cancer Institute)12 and SPSS for Windows 22.0 (SPSS Inc). Continuous data were summarised as medians and interquartile ranges (IQRs). Time trends in the ratios of calls to all intentional poisoning calls (to adjust for annual call fluctuations) and of calls to DDD/1000/day (to adjust for changes in dispensing) were analysed with the Joinpoint program. This program tests for joinpoints (points where there is a significant change in trend); it provides measures of annual percentage change (APC) for each trend segment and an average annual percentage change (AAPC) for the entire study period. The program then tests whether these measures differ significantly from zero (α = 0.05). In addition to examining overall trends, analysis was stratified by age category (children, 10–14 years; adolescents, 15–19 years; adults, 20–75 years) and sex.

Ethics approval

Ethics approval was obtained from the Human Research Ethics Committee of the Sydney Children’s Hospitals Network (approval number, LNR-2011-04-06).

Results

During the 11-year study period, 1735 calls were received by the NSWPIC about intentional exposures to ADHD medications (dexamphetamine, 575 calls; methylphenidate, 1059; atomoxetine, 83; modafinil, 18). Intentional exposures constituted 42% of all exposure calls for these drugs. Characteristics of the subjects in this study are summarised in Box 1. Their median age was 17 years (IQR, 15–23 years). Only 4% of exposures were by injection and 1% by inhalation or other nasal ingestion; 95% were by oral ingestion. Injected use of methylphenidate increased during the study period (three cases in 2004, ten in 2014). At the time of the call to the NSWPIC, 60% of cases were symptomatic and 26% asymptomatic; symptom status was not recorded for 14% of calls. At least 93% of calls resulted in hospitalisation (the call originated from a hospital, or the subject was referred to hospital). Consultant toxicologists were involved in the management of 60 cases (3% of calls).

A summary of the unadjusted exposures over time is shown in Box 2. Most intentional exposures were to methylphenidate and dexamphetamine. There was a 210% increase in the annual number of exposures to methylphenidate during the study period, while dexamphetamine exposures declined by 25%. Modafinil and atomoxetine exposures were infrequent. Box 3 depicts the trends in dispensing of these medications (DDD/1000/day).

Methylphenidate exposures (expressed as a ratio of all calls about intentional exposures) increased significantly over the study period (Box 4; Appendix 1, A), with an AAPC of 9.8%. Dispensing of methylphenidate also increased significantly (Box 4; Appendix 1, B), with an AAPC of 10.8%; one joinpoint was identified, with the rate of increase slowing from 2008. When call numbers were adjusted for DDD/1000/day, there was no significant trend in the number of intentional calls about methylphenidate (Box 4), suggesting that trends in call numbers were associated with changes in the rate of medical dispensing.

Dexamphetamine exposures declined significantly from 2004 to 2014 (Box 4; Appendix 2, A), with an AAPC of −6.6%. Dexamphetamine dispensing (Appendix 2, B) decreased significantly between 2004 and 2012, with an APC of −2.7%, with no significant trend for 2012–2014 (Box 4). As with methylphenidate, there was no significant trend when the number of calls to the NSWPIC was adjusted for DDD/1000/day.

Results stratified by age and sex are shown in Box 5. The trends are similar to those in the unstratified data. The reduction in dexamphetamine exposures was only significant in adult women, adolescent men, and boys. The increase in the number of methylphenidate calls was significant for both sexes and for all age categories, with the exception of boys.

We also examined trends in illicit use, defined as use of the medication together with alcohol (146 calls) or any street drug (43 calls). Illicit use increased by 429% across the study period. Joinpoint analysis identified a significant increase in illicit use from 2004 to 2014 (Box 4; Appendix 3, A), with an AAPC of 13.8%. Further, there was also a significant increase in the number of reported exposures to methamphetamine (Box 4; Appendix 3, B), with an AAPC of 23.4%.

Atomoxetine and modafinil exposures and intravenous exposures were excluded from detailed joinpoint analysis because of the low numbers of calls about these drugs.

Discussion

The number of calls to the NSWPIC about ADHD medication exposures increased dramatically during the study period, driven mostly by calls about methylphenidate. While our joinpoint analysis showed a significant increase in the number of methylphenidate exposures and a significant decrease in that of dexamphetamine exposures, there were no significant trends after call numbers were adjusted for the dispensing rates for each medicine, indicating that call frequency had changed in line with prescribing rates. This finding was consistent with other PIC studies in which exposure trends were correlated with the sale or prescribing rate (and thus with the availability) of dexamphetamine and methylphenidate, but not of atomoxetine.5,13,14

This study was unable to capture whether the individual was prescribed the medicine involved in a call, or the reasons for an overdose. However, a Danish PIC study found that methylphenidate had been prescribed at the time of exposure in 65% of overdose cases; of these, attempted suicide (54%) and recreational use (40%) were the most frequent reasons for exposure.15 A further study, comparing exposures related to the non-medical use of atomoxetine and methylphenidate, found that recreational use was more frequent in methylphenidate (40%) than atomoxetine exposures (19%), with suicide attempt or emotional strain more common in atomoxetine (62%) than methylphenidate exposures (54%).13

The number of symptomatic patients in our study is consistent with the findings of other international studies. In the Danish PIC study, 323 patients (86%) were symptomatic; the symptoms presented were predominantly central nervous system/constitutional (altered psychomotor activity, mood symptoms, perceptual disorders; 81%) or cardiovascular (70%) in nature.15 A Swiss PIC study found a similar spectrum of toxicity for methylphenidate, with most people reporting mild to moderate symptoms.14 In our study, most calls resulted in hospitalisation, suggesting a high degree of overdose severity. A report from RADARS, an American prescription drug monitoring system incorporating PIC and diversion surveillance methods, found significant increases in the severity of overdoses associated with extended release amphetamine and methylphenidate.5

Our study found that the route of administration of these drugs was oral in most cases, but rates of intravenous administration were increasing. This is concerning because of the greater morbidity associated with intravenous use, and raises the question of whether those who inject these drugs are new or existing injecting drug users. The potential for harm associated with injection of these agents is reportedly comparable with that of amphetamines or cocaine.16 Other PIC studies have found similar trends in exposure routes, with oral ingestion being the most common, followed by injection (5–10%) and snorting (4–13%).14,15 In contrast, a study of regular ecstasy users found that up to 43% reported snorting the drug, but only a small number described injecting or smoking it.17

There has been a dramatic increase in the number of calls to the NSWPIC about incidents in which alcohol or illicit drugs were co-ingested with ADHD medicines, predominantly with methylphenidate, suggesting that misuse of this drug is increasing in Australia. In our study, this increase in suspected illicit use has been most marked since 2012, corresponding to a rise in the number of methamphetamine-related calls. This may be related to an increase in supply and demand for amphetamines for misuse, or with increasing toxicity among existing amphetamine users. Increases in methamphetamine purity were also seen around this time.8 Similar rates of co-ingestion were found by previous PIC studies.14,15 The United States National Survey on Drug Use and Health data for 2002–2009 indicated that 3.4% of those aged 12 years and over had used ADHD medications for non-medical purposes.18

Unfortunately, no equivalent national data are available for Australia. A recent systematic review of the misuse of prescription methylphenidate and amphetamine found that young adults (16–25 years), people being treated for ADHD, and known illicit substance users are at particular risk of misusing these medications. However, these studies were not population-wide, and may have been biased by focusing on specific populations. Studies of pharmaceutical stimulant misuse among US university and college students have yielded lifetime prevalence estimates of 7–17%, compared with a general population lifetime prevalence of 0.3–2.1%.19 In terms of current drug users, the results of a 2013 Australian survey of people who inject drugs found ADHD medication misuse to be uncommon.20 Conversely, half of a sample of regular ecstasy users reported illicit use of pharmaceutical stimulants at some point, and 30% reported using them in the past six months. Most of this misuse was of diverted rather than of prescribed medications.17 A US study found that two-thirds of those who used illicit drugs in addition to ADHD medications had begun using them before they had started an ADHD medication.18

Misuse has been described in people who are prescribed ADHD medications.19 In one study, as many as 14.3% of 545 respondents from an ADHD treatment clinic indicated that they had misused prescription stimulants at least once. Further, 39.1% of respondents also used non-prescription stimulants, particularly cocaine (by 62.2% of those who misused stimulants), methamphetamine (4.8%), or both cocaine and amphetamine (31.1%).21 However, another study found that people treated for ADHD in childhood do not appear to be at increased risk of illicit substance-related death, crime, or hospital visits later in life than children diagnosed with ADHD diagnosis who were not treated with stimulant medications.22

In studies examining reasons for misuse of ADHD medications, the most frequently reported were to improve attention, concentration and alertness, to improve study habits and academic performance, and to “get high”.19 However, the frequencies of these responses tend to reflect the populations most commonly studied, including college students and people with ADHD. A minority of people also report self-medication of undiagnosed ADHD symptoms.19 Of those who misuse these medications, the most common source is diversion from a friend, relative or dealer.20

According to reports by a group of regular ecstasy users, the median age of first use of ADHD medications by recent users was 18 years (range, 6–30 years) and the median amount taken in an average session was two tablets (range, 0.33–30 tablets).17 Other than this, little is known about the natural history or prevalence of ADHD medication misuse in Australia. The relatively young median age of first use found by this and other studies may be related to ease of access within peer networks.

The effectiveness and tolerability of atomoxetine are comparable with those of methylphenidate,23 but it is often prescribed only as a second-line drug, or for those perceived to be at risk of psychostimulant misuse.15,24 Atomoxetine exposures in our study appeared to result in less severe toxicity and to not be associated with illicit use, but the number of calls was too low to reach any conclusions. Significant toxicity associated with atomoxetine overdose has been described by other authors.25

Australian PIC data (together with data from other sources, such as hospital presentation data, police data, and wastewater analysis) are underutilised in detecting emerging trends in substance use. However, limitations of this retrospective study include the lack of outcome data, as Australian PICs do not routinely conduct follow-up calls. As specific symptoms were not coded, we were unable to construct a comprehensive symptom severity profile. Further, this study was limited to exposures in people aged 10 years or more, so that we are unable to comment on intentional poisonings in younger persons. Our data comprised a collection of all intentional exposures reported to the NSWPIC that does not allow further sub-categorisation into self-harm, recreational use, and other forms of misuse, so that co-ingestion of alcohol and illicit drugs were used as a marker of illicit intent. Alcohol is unlikely to be a specific marker, as it may also be taken with a self-harm overdose. A deeper understanding of these aspects of toxicity could be gained from examining poisoning cohorts, such as the Hunter Area Toxicology Service database.26 In addition, as PIC data collection relies on voluntary calls, our study is likely to have significantly underestimated the true frequency of the toxicity and misuse of ADHD medications. However, benchmarking to methamphetamine calls at least allows us to comment on trends. Our study predominantly reflects the NSW experience, with limited data from the rest of the country (resulting from the on-call system), so it may not be possible to generalise our findings to the rest of Australia.

Clinical implications

The incidence of poisoning exposures appears to be correlated with community prescribing rates. Misuse of these medications mostly involves diverted drugs, so that increasing prescribing of these medications is likely to increase their availability for diversion. There also appears to be an increased risk of misuse and overdose in people who are prescribed ADHD medications, but such misuse is often related to a past history of other drug misuse. In a similar vein to opioid management, care should be taken when initiating these medications to complete a full risk assessment for misuse, which includes taking an addiction history, and ensuring that they are used safely, appropriately and in an evidence-based manner, including considering non-medical or non-stimulant alternatives. Atomoxetine may be an alternative for those at risk of misuse. There may also be scope for regulatory measures and guidance. An example of this is the Stimulant Regulatory Guidelines developed in Western Australia in response to one of the highest global rates of stimulant use disorder.27

Box 1 –
Characteristics of 1735 intentional exposures to ADHD medication reported to the New South Wales Poisons Information Centre, 2004–2014

	Dexamphetamine	Methylphenidate	Modafinil	Atomoxetine	Total

Number of reports (percentage of all exposures to ADHD medications)	575 (32%)	1059 (62%)	18 (1%)	83 (5%)	1735
Median age (interquartile range), years	19 (16–31)	16 (14–20)	30 (21–36)	16 (14–19)	17 (15–23)
Sex
Male	269 (47%)	503 (47%)	6 (33%)	42 (51%)	820 (47%)
Female	273 (47%)	499 (47%)	12 (67%)	32 (39%)	816 (47%)
Not recorded	33 (6%)	57 (5%)	0	9 (11%)	99 (6%)
Treatment
Hospitalised	533 (93%)	966 (91%)	17 (94%)	78 (94%)	1594 (92%)
Referred to toxicologist	22 (4%)	35 (3%)	0	3 (3%)	60 (3%)
Co-ingestants
Illicit	49 (9%)	133 (13%)	7 (39%)	8 (10%)	197 (11%)
Non-illicit	73 (13%)	312 (29%)	9 (50%)	60 (72%)	454 (26%)
Route of exposure
Ingestion	557 (97%)	987 (93%)	18 (100%)	81 (98%)	1643 (95%)
Parenteral	15 (3%)	56 (5%)	0	1 (1%)	72 (4%)
Inhaled/nasal	3 (1%)	16 (2%)	0	1 (1%)	20 (1%)
Symptom assessment
Symptomatic	352 (61%)	626 (59%)	14 (77%)	45 (54%)	1037 (60%)
Asymptomatic	143 (25%)	286 (27%)	3 (17%)	24 (29%)	456 (26%)
Unknown	80 (14%)	147 (14%)	1 (6%)	14 (17%)	242 (14%)

All percentages are column percentages, with the exception of the first row (number of reports).

Box 2 –
Intentional exposures to methylphenidate, dexamphetamine, modafinil, atomoxetine and methamphetamine reported to the New South Wales Poisons Information Centre, 2004–2014

Box 3 –
Pharmaceutical Benefits Scheme prescriptions for dexamphetamine, methylphenidate, modafinil and atomoxetine, expressed in defined daily doses (DDD)/1000/day, 2004–2014

Box 4 –
Results of joinpoint regression analysis of trends in exposures to methylphenidate, dexamphetamine and methamphetamine reported to the New South Wales Poisons Information Centre, 2004–2014

Time segment

AAPC or APC (95% CI)

Methylphenidate

Exposures

2004–2014

AAPC, 9.8% (7.5 to 12.3%)*

Dispensing

2004–2014

AAPC, 10.8% (10.0 to 11.5%)*

2004–2008

APC, 15.7% (13.8 to 17.6%)*

2008–2014

APC, 7.6% (6.7 to 8.6%)*

Calls adjusted for DDD/1000/day

2004–2014

AAPC, −2.0% (−4.4 to 2.9%)

2004–2011

APC, 4.5% (−1.1 to 10.4%)

2011–2014

APC, −15.7% (−31.4 to 3.6%)

Dexamphetamine

Exposures

2004–2014

AAPC, −6.6% (−10.7 to −2.3%)*

Dispensing

2004–2014

AAPC, −1.4% (−3.2 to 0.3%)

2004–2012

APC, −2.7% (−3.8 to −1.7%)*

2012–2014

APC, 4.1% (−5.8 to 15.1%)

Calls adjusted for DDD/1000/day

2004–2014

AAPC, −4.3% (−9.0 to 0.5%)

Illicit use of ADHD medication^†

Exposures

2004–2014

AAPC, 13.8% (8.1% to 19.7%)*

Methamphetamine

Exposures

2004–2014

AAPC, 23.4% (2.5% to 48.5%)*

2004–2012

APC, 2.3% (−8.9% to 14.8%)

2012–2014

APC, 161.5% (−9.5% to 665.9%)

AAPC = average annual per cent change; APC = annual per cent change; DDD/1000/day = defined daily dose per 1000 population per day. * APC or AAPC is significantly different from zero (P < 0.05). † Inferred (alcohol or illicit drugs were co-ingested).

Box 5 –
Results of joinpoint regression analysis, stratified by age category and sex: trends in exposures to methylphenidate and dexamphetamine, 2004–2014

AAPC (95% CI)

Methylphenidate

Adults (20–75 years)

8.6% (2.1 to 15.4%)*

Male

8.2% (1.0 to 15.8%)*

Female

9.5% (2.6 to 16.8%)*

Adolescents (15–19 years)

13.0% (8.1 to 18.0%)*

Male

8.2% (1.0 to 15.8%)*

Female

9.5% (2.6 to 16.8%)*

Children (10–14 years)

8.9% (3.5 to 14.6%)*

Male

6.0% (−2.7 to 15.5%)

Female

11.4% (6.5 to 16.5%)*

Dexamphetamine

Adults (20–75 years)

−2.8% (−7.9 to 2.5%)

Male

1.2% (−3.9 to 6.6%)

Female

−7.5% (−14 to −0.4%)*

Adolescents (15–19 years)

−11.9% (−21.4 to −1.3%)*

Male

−17.4% (−24.1 to −10.2%)*

Female

−7.6% (−20.8 to 7.9%)

Children (10–14 years)^†

−18.1% (−27.7 to −7.2%)*

Male

−21.5% (−30.6 to −11.3%)*

AAPC = average annual per cent change. * APC or AAPC is significantly different from zero (P < 0.05). † Joinpoint analysis not performed for exposures to dexamphetamine in female children (missing data).