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03 SEPTEMBER 2020

August 31 was international overdose awareness day, a joint initiative highlighting the personal and societal toll of drug overdose; an issue affecting both urban and regional communities throughout the developed world.   

While illicit opioid misuse was the initial scourge, over the last decade there has been greater demonstration of other drugs involved, specifically stimulants, prescription opioids and other sedatives.   

What is this hidden ‘epidemic’? 

In response to the ‘opioid epidemic’ a range of regulatory responses has been introduced: in Australia this has involved opioid reforms at Therapeutic Goods Administration (TGA) and Pharmaceutical Benefits Scheme (PBS) level, in order to reduce opioid prescribing (in both numbers and doses involved) in the belief that tighter regulation on prescribing will reduce deaths due to prescription opioids.   

Part of the prosecution of these reforms is the view that opioids are not indicated for chronic non-cancer pain, based on population studies demonstrating limited or no benefit and significant harm; these arguments overlook systematic reviews demonstrating benefit (although short to medium term studies only) and limited understanding as to why opioids may fail.   

Indeed, in one longer-term trial of opioids alone (not ideal) versus multimodal therapy, benefit compared to baseline was demonstrated over the longer term; what’s relevant here is the study cohort involved recruitment of participants with musculoskeletal pain and functional impact, presumed predominantly nociceptive pain, where opioid use in the short term has consistently demonstrated benefit. 

What do the numbers tell us? 

The overdose statistics and their interpretation in Australia remain a concern. The Pennington Institute’s recent report on overdose related deaths reports the majority (75 per cent) to be unintentional, two thirds of these being heroin or methadone related (half of all overdose deaths), with a recent reduction in pharmaceutical opioid-related deaths. Regional differences are noted, including higher death rates in regional areas compared to urban areas (per capita) and interesting variations between the states.   

Polypharmacy (concurrent use of multiple medications) remains prominent, reported in near 60 per cent of deaths, commonly sedatives, benzodiazepines, antidepressants, alcohol and cannabis. Of interest, the 40–60 year age group and male predominance (two thirds) is noted, suggesting older opioid dependent persons are at particular risk of drug-related death. 

Monitoring systems have been or are in development, to better inform clinicians of dispensing of opioids and associated at-risk medications, including sedatives and psychoactives. Modest reductions in opioid-related deaths have been reported in those jurisdictions with mandatory monitoring systems, although prescribing rates may be reduced to a greater extent.   

Two prospective investigations from the US have demonstrated an increased risk of death in those tapered/withdrawn from opioids. While causes of this increase haven’t been well defined, they include loss of tolerance to opioids (with subsequent overdose death) and self-harm.   

What are the safeguards in place? 

The Victorian system (safescript) has now entered a mandatory stage and we await data examining any impact, in terms of prescribing rates and coronial findings. One national issue requiring clarification is how monitoring system data is to be used in health system regulation, specifically in identifying and potentially prosecuting prescribers. Users of the safescript system note a recording of who checks the system and when, such that in the event of a bad outcome relating to prescription medications, prescribing practice will be open to inspection.   

This fear of exposure will drive behaviour change, increase use of the system and potentially limit a prescriber’s willingness to engage and support those on monitored medications.  Indeed, while interviewing New York doctors, authors found a number willing to stigmatise patients and purge their practice of those on opioids. 

What are the risks of a narrow regulatory focus on opioids? 

Further to the emphasis on opioids, including on those that consume and prescribe, a similar focus on gabapentinoids, particularly pregabalin (Lyrica) has emerged. While studied and registered for neuropathic pain, its use has extended to the acute pain setting (where it has shown benefit in reducing opioid use), in those with sensitisation associated with chronic pain and to assist with sleep for those with pain.   

It has also been reported to be misused, particularly at high doses in the prison population and those with drug dependency. Concerns about over promotion, over prescription and lack of appreciation for potential adverse effects have been raised; it has emerged in the overdose statistics as part of the cohort associated with mixed drug toxicity.   

The 2020 Pennington report notes an increase in deaths associated with antiepileptics, from 11 in 2015 to 128 in 2018, but this remains less than deaths associated with antidepressants. A Victorian analysis, associated with safescript, also identifies a rise in gabapentinoid associated deaths (in association with opioids and benzodiazepines), although when considered in relation to high rates of prescriptions, it remains below the threshold for routine monitoring (being 100 deaths per million prescriptions). 

Pregabalin has also been identified as a drug of concern in relation to ambulance call outs in relation to drug overdose, although appears to have low toxicity when taken alone.  Another suggestion of concern is potential for pregabalin to contribute to mood disturbance, in particular, suicidal intent; while anti-epileptics as a class have been associated with suicidality, when assessed in persons with epilepsy, the gabpentinoids are reported to have a low risk (slightly less than controls), while other antiepileptics have a higher risk (notably topiramate). 

Indeed, in some pain studies, successful treatment with gabapentin was associated with improvements in mood (potentially to a greater extent than co-prescribed antidepressants for pain). 

So what is the real problem here? 

What we may be seeing in these reports and statistics is an indication of the distress associated with chronic severe disabling pain, known to be associated with depression and suicide rates at two to three times the average population.   

Rural areas, duration of pain, severity of pain (including neuropathic features) increase this risk; given doctors and patients often search for beneficial treatment, it is not surprising that overdose statistics identify prescription opioids in combination with benzodiazepines, antidepressants and gabapentinoids as a major concern.   

It’s not all about the drug, its promotion and prescribing practices, but can reflect the condition that the drug is being used for, namely pain. In an environment of heightened scrutiny of medication prescribing for pain, the potential is for increased stigma of both patients and health care professionals when living with and managing severe disabling pain.   

Given helplessness is an additional risk factor for suicidal intent in those with pain, withdrawal of opioids and gabapentinoids as viable treatment options may increase levels of distress and overdose risk.   

What should we really be focused on? 

Clinicians and regulators need to reflect on the role of a patient centred approach: assessing an individual’s mechanisms of pain, the impact on their physical and mental health and the need to tailor a personalised approach incorporating both medication and non-medication approaches.  

Assessing benefit to risk and regular monitoring for deteriorating mental health is crucial, especially in the setting of an opioid taper (which can exacerbate psychological distress as part of opioid withdrawal). Given the current push against the use of opioids and gabapentinoids, improving access to multidisciplinary care, particularly in rural areas, as part of a national plan for action on pain management should be the priority if we are to avoid a paradoxical increase in suicide, including intentional overdose deaths. 

A/Professor Malcolm Hogg,
Painaustralia Board Director
Associate Professor Malcolm Hogg is a specialist in Anaesthesia and Pain Medicine and Head of Pain Services, Melbourne Health, and a Board Director and Clinical Advisor for Painaustralia. He is a past president of the Australian Pain Society and fellow of Faculty of Pain Medicine, ANZCA, and member of the International Association for the Study of Pain.