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Preference: Statistics, epidemiology and research design

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Morphine use increases pain severity, doubles duration

By Alannah James, The Lead South Australia
Morphine can more than double the duration of pain and amplify its severity in the long term, according
to new international research on its effects as a painkiller.
But the study team, which included researchers from Colorado, South Australia and China, has also discovered how
to switch off this pain-amplifying mechanism, offering hope for millions of pain sufferers world wide.
Author of the study and University of Adelaide Research Associate Dr Peter Grace said the results, published in the
journal Proceedings of the National Academy of Sciences (PNAS) , further questioned the use of opioid-based
painkillers and treatments.
“Prior studies have looked at the effect morphine has on pain sensitivity short term, but in this study we looked at the
weeks and months after morphine use,” Dr Grace said.
“What we found is that the opioid painkiller activates spinal immune cells, causing a further inflammatory response.”
“The pain is effectively transitioned to a chronic state, making the pain itself both more severe and longer lasting.”
The research team found that rats with chronic nerve pain that had been treated with morphine for just five days
experienced prolonged pain sensitivity than their control group counterparts.
“This extended period of chronic pain has followed from just five days of treatment with morphine, which in itself is
very significant,” Dr Grace said.
The study was led by Professor Linda Watkins at the University of Colorado Boulder.
Chronic pain affects 10 per cent of the world’s population, about 60 million people, with estimates of closer to 20-25
per cent in some countries.
Dr Grace, who is also a Research Assistant Professor with the University of Colorado Boulder, said the study had
huge implications for the treatment of pain worldwide.
“Our results add weight to the growing body of science suggesting that treatment with opioids such as morphine
may in fact be a contributor to people’s chronic pain,” Dr Grace said.
“It means we need a more sophisticated approach because what we found is that opioid pain killers such as
morphine activates spinal immune cells, causing further inflammatory response.”
The research team discovered a way of switching off this pain-amplifying mechanism using a new technology known
as Designer Receptor Exclusively Activated by Designer Drugs (DREADD).
By using DREADD, researchers were able to isolate the spinal immune cells and prove their involvement in this
response to opiate use.
“Importantly, we’ve also been able to block the two main receptors involved in this immune response, including Toll-
Like receptor 4 (TLR4) and another one called P2X7R, which have both been separately indicated in chronic pain
before,” Dr Grace said.
“By blocking these receptors, we’re preventing the immune response from kicking in, enabling the painkilling
benefits of morphine to be delivered without resulting in further chronic pain.”
Dr Grace said chronic pain sufferers could take opiate-based medicine as well as the receptor-blocking drug to
reduce likelihood of long-term effects.
“It means they would need to take two drugs instead of one – they would still be able to use morphine or other
opiate-based drugs as well as the additional drug.”
Novel drugs are currently undergoing testing and are not expected to be on the market for 10 years.
Dr Grace said the team would like to further investigate how broad the receptor-blocking drug was and whether it
had similar effects for other opiate-based drugs such as oxycodone and fentanyl, and for other types of chronic pain
including low back pain.
 

Gene discovery sparks hope for type 2 diabetes

By Andrew Spece, The Lead South Australia
Researchers have identified the gene they believe is responsible for the onset of type 2 diabetes,
sparking hope for treatments to prevent and possibly reverse the progressive condition.
The researchers from Flinders University in South Australia collaborated with international research teams from the
United States, Sweden and the United Kingdom to narrow down the possible field of 5000 candidate genes to one,
known as RCAN1.
Study leader and Flinders University cell physiologist Professor Damien Keating said a cross-referencing approach
using genes from individuals with Down syndrome was crucial to the result.
Professor Keating said people with Down syndrome were prone to a range of health disorders, including diabetes,
resulting from the overexpression of particular genes because Down syndrome occurred when people had an extra
copy of chromosome 21.
“Many individuals with Down syndrome experience lower insulin secretion, mitochondrial dysfunction and increased
oxidative stress in the insulin-producing beta cells of the pancreas, which are all conditions that also appear in
people with type 2 diabetes,” Professor Keating said.
To identify genes duplicated in Down syndrome that contribute to problems with insulin secretion, scientists
screened the genes of four mouse models of the disorder – two had high blood sugar and two did not, with the
variation enabling a short-list of 38 implicated genes to be identified.
The scientists then narrowed down the list by comparing it to genes overexpressed in beta cells from humans with
type 2 diabetes.
“The comparison identified a single gene, RCAN1, which, when we overexpress it in mice, causes them to have
abnormal mitochondria in their beta cells, produce less cellular energy and secrete less insulin in the presence of
high glucose,” Professor Keating says.
According to the World Health Organisation, the number of people with diabetes in 2014 was 422 million, up from
108 million in 1980. In 2012, an estimated 1.5 million deaths were directly caused by diabetes and another 2.2
million deaths were attributable to high blood glucose.
Type 2 diabetes, which accounts for the majority of diabetes cases, is a progressive condition in which the body
becomes resistant to the normal effects of insulin and/or gradually loses the capacity to produce enough insulin in
the pancreas. The cause of type 2 diabetes is unknown.
“Given that we’ve identified this gene as important for reducing insulin secretion in type 2 diabetes, we are now at a
stage where we have a series of drugs that target RCAN1 and we are now going to test to find whether these drugs
can improve insulation secretion in type 2 diabetes,” Prof Keating said.
“We don’t understand what changes in our pancreas or in our insulin secreting beta cells to cause that transition
from just being insulin resistant and having metabolic syndrome to transitioning to full-blown type 2 diabetes.
“RCAN1, this gene we identified, is certainly a candidate now for that.”
Prof Keating said none of the available treatments for type 2 diabetes targeted the primary cause of the condition.
“All the drugs out there simply alleviate the symptoms,” he said.
“So we have to test these drugs that we have because we feel like that may be able to go straight to the cause of the
reduced insulin secretion that causes Type 2 diabetes … prevent it and possibly reverse it.”
The results of the study led by Prof Keating have been published in the international journal PLOS Genetics.

Study finds 5:2 diet is useful weapon in fight against diabetes

A popular diet is proving to be effective for improving the health of people with type 2 diabetes.
In a pilot trial conducted by the University of South Australia, use of the 5:2 diet resulted in a significant reduction of
blood glucose level and weight loss.
In the three-month trial involving 35 people, participants reduced their haemoglobin A1C (HbA1c) by an average of
0.6 per cent and also reduced their bodyweight by 6-7kg.
The results have prompted a larger year-long study to begin in the coming months, which aims to involve 100
participants.
University of South Australia PhD candidate Sharayah Carter said there had been a lot of research to support the
new diet, but none that looked into its potential benefit for people with type 2 diabetes mellitus (T2DM).
“One of the major struggles with weight loss is people’s ability to stick to a daily-restricted calorie diet,” she said.
“On top of that, people with T2DM have medication to consider. A person with diabetes is not going to be able to take
the same amount of medication on those two days because they’re not eating enough food to support that
medication.
“What we found was that two days of severe energy restriction basically achieves similar results to a daily restriction
diet.”
The UniSA trial was the first of its kind and tested the effects of a two-day intermittent energy restriction (IER) diet
with 5-days of habitual eating for people with T2DM. This was compared to a daily restricted diet.
The results showed that while the IER diet has less of an impact on lifestyle and medication, both diets achieved
similar reductions on weight and in haemoglobin A1C levels.
The standard calorie restriction diet consisted of 1200 calories a day for women and 1500 calories for men. All
participants were asked to walk an extra 2000 steps per day to increase their level of exercise.
People who are obese are up to 80 times more likely to develop type 2 diabetes than those with a Body Mass Index
(BMI) of 22. Weight loss can help control and possibly halt the disease.
According to the World Health Organisation, the number of people with diabetes in 2014 was 422 million, up from
108 million in 1980. In 2012, an estimated 1.5 million deaths were directly caused by diabetes and another 2.2
million deaths were attributable to high blood glucose.
Type 2 diabetes, which accounts for the majority of diabetes cases, is a progressive condition in which the body
becomes resistant to the normal effects of insulin and/or gradually loses the capacity to produce enough insulin in
the pancreas. The cause of type 2 diabetes is unknown.
“IER uses short periods of severe energy restriction – 500 calories for women and 600 calories for men – followed by
periods of habitual eating to achieve similar health improvements as daily dieting but unlike some IER diets, does
not require non-fasting days to involve restricted dieting,” Carter said.
“We achieved a 0.6 per cent drop in HbA1c in both groups which was a significant drop in that time frame and
importantly all our participants who were on medication reduced their dosages which is important for both the
individual and the health budget.
“Essentially you are achieving the same total energy restriction after seven days by following the two-day restriction
and getting the same results.”
The study was conducted in collaboration with the Sansom Institute for Health Research. It is a consortium of
leading researchers with the aim of intervening early to prevent illness, improve health systems and services,
creating more effective therapies and advancing health equality.

Malnourished das linked to underdeveloped kids

By Caleb Radford, The Lead South Australia
Malnourished fathers could avoid passing on poor health to their children by taking vitamin supplements
and antioxidants before conceiving.
Researchers from the University of Adelaide in South Australia conducted a laboratory study using under-nourished
male mice and found a direct correlation between the health of the offspring and the father’s health at the time of
conception.
University of Adelaide researcher Nicole McPherson said previous studies had looked at the affect of malnutrition in
mothers but new evidence suggests that paternal influences could play a more direct role.
“Malnutrition is a serious issue and affects hundreds of millions of people around the world,” she said.
“The biggest issue is that people dismiss men’s health and it’s impact on the health of their children, whether that is
under-nutrition or over-nutrition.
“However, we now know that the parents’ health at the moment of conception is incredibly important. What we’re
seeing from our research is that some form of dietary supplementation may also benefit fathers-to-be.”
There are about 2 billion people in the world who suffer from various forms of malnutrition. About 2.6 million children
die from malnutrition each year, which accounts for a third of child deaths globally.
Under-nutrition is considered to be the number one risk to health worldwide and accounts for 11 per cent of the
global burden of disease.
The research study found that the offspring of malnourished male mice were born underdeveloped and showed
evidence of abnormal gene expression and metabolic markers.
These offspring were prone to health conditions including increased risk of non-communicable diseases,
cardiovascular disease and type 2 diabetes, mirroring the situation for human children born in the developing world.
Researchers responded by altering the diet of the male mice to include additional zinc, folate, iron and other vitamin
supplements.
This resulted in improved fertility rates, healthier children and normal metabolic markers.
“A father’s health at the time of conception is really important – their particular dietary quality and nutrient
sufficiency,” Dr McPherson said.
“We hope that these findings could eventually be translated into interventions, to help reduce the health burden of
under-nutrition to the world.”
“This is however a laboratory study and we still need to do more research.”
The study titled Paternal under-nutrition programs metabolic syndrome in offspring which can be reversed by
antioxidant/vitamin food fortification in fathers has been published in the Nature journal Scientific Reports.

World told to get ready for plain packaging

Australia has received a big filip in its fight to protect its tobacco plain packaging laws after the World Health Organisation launched an international campaign declaring that all governments had to “get ready” plain packaging.

Since it introduced the world’s first plain packaging laws in 2012, Australia has been playing virtually a lone hand in a global battle with major tobacco companies determined to have the laws overturned.

So far, Britain, Ireland and France have joined Australia in passing plain packaging legislation, and both, Canada and New Zealand have announced plans to introduce plain packaging legislation.

Tobacco companies have failed in successive bids to have the laws overturned by national courts and international tribunals.

The latest setback came last month when the highest court of the European Union ruled in favour of regulations that give its member states the option of implementing plain packaging for tobacco products.

This followed the acceptance of the Permanent Court of Arbitration sitting in Singapore of Australia’s argument that it did not have jurisdiction to hear a claim by Philip Morris Asia that the legislation breached trademark protection laws.

The WHO used World No Tobacco Day to join the fight, launching its “Get ready for Plain Packaging” campaign for more effective health warnings on tobacco products around the globe.

The WHO said tobacco packaging was a form of advertising and promotion, often misled consumers and served to hide the deadly reality of tobacco use.

Plain packaging requires tobacco products be sold without marketing gimmicks and with clearly displayed health warnings. Australia was the first country in the world to introduce the legislation. Introduced in 2012, research has indicated that Australia has seen a reduction of 100,000 fewer smokers as a direct result from the plain packaging legislation.

The AMA has been a loud supporter of plain packaging legislation. Past AMA President Dr Andrew Pesce was alongside Federal Health Minister Nicola Roxon as she released the world-first draft Bill and the proposed design for the plain packaging packs.

The WHO said that plain packaging built upon other measures as part of a comprehensive multi-sectoral approach to tobacco control. For more information about the campaign, visit http://www.who.int/campaigns/no-tobacco-day/2016/en/

Kirsty Waterford

 

Committee backs AMA on primary care

A parliamentary committee has called on the Federal Government to consider reforms to the Medicare Benefits Schedule to help GPs better manage chronic disease in patients.

The House of Representatives Standing Committee on Health handed down its report on Chronic Disease Prevention and Management in Primary Health Care last month, noting that the groundwork for improvements to the primary health care system already existed.

“It is clear, however, that this cannot occur without cooperation, coordination, evaluation and adequate data and records to support Primary Health Networks in fulfilling their important role as coordinators of care,” the committee said.

“Performance measurements, expansion of chronic disease items, improved referral and rebate claiming processes and encouraging private health insurers to manage their members in cooperation with the primary health care system is a clear goal.”

The AMA made a submission to the inquiry in August last year, noting that primary health care was critical to providing quality, effective and empowering health care for people with chronic disease.

“With more than half of all potentially preventable hospital admissions due to chronic conditions, costing more than $1.3 billion a year, there are significant benefits in ensuring access to timely, clinically necessary and well-coordinated health care,” the AMA said.

The AMA called for reform of the MBS to restructure specific chronic disease management (CDM) items to cut red tape and reflect modern clinical practice.

It also called for formal engagement protocols between Primary Health Networks (PHNs) and Local Hospital Networks (LHNs) to work together on areas such as transitioning patients out of hospitals and into aged care.

It recognised that there was scope for private health insurers to explore the potential for greater engagement with general practice, but urged caution on expanding their role into a managed care model.

The Committee picked up many of the AMA’s recommendations.

It recommended the Government investigate expanding the number of allied health treatments that can attract an MBS rebate within a year, on the proviso that the patient has the relevant General Practitioner Management Plan and Team Care Arrangements in place.

It also recommended that the Government examine reforms to the MBS to allow for a practitioner to claim a rebate for a chronic disease management consultation and a general consultation benefit, for the same person on the same day.

It recommended considering expanding the Practice Incentives Program to include programs for breast, bowel and skin cancer screening, as well as the Integrated Health Check developed by the National Vascular Disease Prevention Alliance.

“Preventive health promotion as well as expanded health checks will help to provide the awareness and early detection required to help combat these diseases,” the committee said.

“The Health Care Home trials which are expected to commence in 2017 will help to improve this outcome, and with appropriate funding, privacy considerations, capture and consolidation of data, and a focus on research and improvement, the cooperative care goals required to improve chronic disease primary care can become a reality.”

Maria Hawthorne

News

AMA award winners presented at national conference

At the recent AMA National Conference the following awards were presented: AMA President’s Award in recognition of outstanding contributions to the care of their fellow Australians — Dr Paul Bauert, who for 30 years has fought for better care for Indigenous Australians and, more recently, children in immigration detention, and Vietnam War veteran Dr Graeme Killer, who has devoted his life to improve the care of current and retired Defence Force personnel; Doctor in Training of the Year Award for outstanding leadership, advocacy, and accomplishments of a doctor in training — Dr Ruth Mitchell, a neurosurgery trainee currently in her second year of her PhD at the University of Melbourne, and a neurosurgery registrar at the Royal Melbourne Hospital, and chair of the Royal Australasian College of Surgeons’ Trainee Association; Woman in Medicine Award, presented to a woman who has made a major contribution to the medical profession by showing ongoing commitment to quality care, or through her contribution to medical research, public health projects or improving the availability and accessibility of medical education and medical training for women — Associate Professor Diana Egerton-Warburton, in recognition of her exceptional contribution to the development of emergency medicine, and her passion for public health; Excellence in Healthcare Award recognises ongoing commitment to quality health and medical care, policy, and research, and is awarded to an individual or individuals who have made a significant contribution to improving health or healthcare in Australia — Associate Professor John Boffa and Ms Donna Ah Chee, who have made an enormous contribution to reducing harms of alcohol and improving early childhood outcomes for Aboriginal children.

[Perspectives] Tom Potokar—helping burns climb up the international agenda

Tom Potokar was inspired to be a doctor after watching a Médecins Sans Frontières (MSF) documentary on Vietnamese boat people in the 1970s. Today, he is a consultant in burn injuries at Morriston Hospital in Swansea, Wales, and Director of Interburns (International Network for Training, Education and Research in Burns), a non-profit agency aiming to improve burns care and prevention in low-income countries, where most global burn injuries occur. According to Richard Nnabuko, President of the Pan African Burn Society, Enugu, Nigeria, “Tom has a passion for the burn victims of the low and middle-income countries of Africa and southeast Asia and for training dedicated men and women from these areas.”

Bad breath could be seriously unhealthy

Bad breath may not only be unpleasant for those around you, it could be seriously bad for your health, according to research into the link between oral bacteria and pancreatic cancer.

While an association between poor oral hygiene and pancreatic cancer has been previously established, researchers at New York University have for the first time found that an imbalance of bacteria in the mouth precedes the development of the cancer, opening up potential methods for early detection and the tantalising possibility of a causal link.

The study, which involved sequencing DNA extracted from the saliva of 361 pancreatic cancer patients and 371 healthy participants, found that those with porphyromonas gingivalis in their mouth were at 59 per cent greater risk of developing pancreatic cancer than those who did not, while those with aggregatibacter actinomycetemcomitans were at 50 per cent greater risk (though the association was not considered to be as statistically strong).

Significantly, the increased risk remained the same even after excluding pancreatic cancer cases that occurred less than two years after the samples were taken. Lead researcher Jiyoung Ahn says this means it is unlikely that the imbalance in oral bacteria has occurred as a result of the pancreatic cancer, and instead predates it.

The discovery provides for several promising new avenues for investigation.

It raises the potential for developing a screening test for pancreatic cancer using the two oral bacteria as markers – an important advance for a disease that often goes undetected until it reaches an advanced stage, contributing to its high mortality rate.

Researchers are also intrigued by the possibility that the two bacteria may somehow cause the cancer to develop, though Ahn cautions that it is premature to reach such a conclusion.

Ahn says it is possible that the imbalance of the two bacteria in the mouth is the correlate of systemic inflammation or other processes occurring within the body.

“Inflammation is related to cancer,” she says. “The bacteria could be causing inflammation in the pancreas – that’s one theory. But maybe the bacteria in the mouth is just a marker for the susceptibility of the body to inflammation.”

Ahn and her colleagues are planning further research, including injecting the two bacteria into the pancreas of mice genetically engineered to be susceptible to pancreatic cancer to see what effect this might have, as well as examining possible links between viruses in the mouth and pancreatic cancer.

In the meantime, the scientist says, it is too soon to advise people that flossing and brushing their teeth will help stave off pancreatic cancer.

Adrian Rollins