The Hunter Region recorded 241 unintentional overdose deaths in four years, the annual Penington Institute report said - while raising alarm about the nation's "overdose crisis".
The report, released on Monday, recorded these deaths from 2017 to 2021 in Newcastle (88), Lake Macquarie (66), Cessnock, Singleton, Dungog (31), Port Stephens (25), Maitland (20) and Upper Hunter (11).
It said the drugs most involved in unintentional overdose deaths were opioids, benzodiazepines, stimulants, antidepressants, alcohol, anticonvulsants, neuropathic pain modulators, antipsychotics and synthetic cannabinoids.
The annual overdose report said drug overdose was "one of the top three causes of death" for adults under 50.
Drug overdose was behind only suicide and land transport accidents as the leading causes of death for people aged 20 to 29.
It was the second leading cause of death behind suicide for those aged 30 to 39.
In the Hunter New England and Central Coast Primary Health Network, unintentional drug-induced deaths rose from 53 in 2007 to 94 in 2021.
The rate of deaths per 100,000 people in the network rose from 4.8 to 7.7 over that period.
In the Hunter-Central Coast network, the report said "drug-induced suicides" rose from 13 in 2007 to 26 in 2021.
Penington Institute CEO John Ryan said the report's findings were "cause for concern for all Australians".
He called for action to address the nation's overdose crisis.
"It is no exaggeration to talk about an overdose crisis. Overdose deaths in Australia have exceeded the road toll since 2014, and we see little to no action to demonstrably change this," Mr Ryan said.
The report was released ahead of International Overdose Awareness Day on Thursday, which amounted to "the largest global campaign to end overdose".
Chronic pain research shows people often take drugs to self-medicate for physical and/or mental pain.
Chronic Pain Australia's vice president Fiona Hodson said "there can be unintended consequences", particularly when people were using multiple drugs - including illicit ones.
Ms Hodson, a Newcastle-based nurse, has specialised in pain management for 25 years.
She said opioid prescribing in the Hunter had been historically high, although this was being reduced due to prescriptions being tightened through regulation.
The region had a large number of people with "low socio-economic status", which was a factor in the complex nature of drug use.
"We have lots of blue-collar workers who work in the mines and get back injuries and we've previously had the steelworks," she said.
There were also "rural and remote issues", with people having limited access to specialists and GPs.
"It's all about not having access and support."
She said people sometimes turn to drugs so they can keep working through pain.
"They have to keep going and put food on the table," she said.
She said men "will hold their pain in and try to remain stoic", women face "medical misogyny" and the LGBTQIA+ community had their struggles.
"Alcohol is probably the biggest problem because it's so accessible. People have a bad day and go home and have a glass of wine or two or three."
Six Australians lose their lives to overdose every day.
In NSW, unintentional drug-induced deaths from benzodiazepines rose from 358 in 2007-11 to 953 in 2017-21.
Over that same period, deaths rose due to use of pharmaceutical opioids (364 to 706), stimulants (129 to 808), heroin (162 to 555), alcohol (388 to 525) and cannabinoids (34 to 413).
All the cannabinoid-linked deaths involved synthetic products, not natural ones.
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