Ep52: Opioids Part 2- Regulation and Marketing

Ep52: Opioids Part 2- Regulation and Marketing
16 September 2019

Fellows of the RACP can claim CPD credits via MyCPD for listening to this episode and reading the resources below.

In the previous episode we talked about the science of pain, opioid analgesia and dependence. Now we look at the influence of culture, regulation and marketing on opioid prescribing for chronic non-cancer pain. First we ask which are the prescription opioids most commonly leading to dependence and why are they prescribed. Then we discuss the mixed messages that prescribers are getting from guidelines and pharmaceutical regulation. Ever-relaxing indications for pharmaceutical subsidies can nudge prescribing behaviour in the wrong direction.

Tasmania was for many years the worst performer on measures of opioid use and harm, but this all began to turn around from 2006. Addiction medicine specialist Professor Adrian Reynolds explains how education, regulation and real-time prescription monitoring were brought together in that state.

Finally, an undeniable influencer of prescribing behaviour are the promotional campaigns organised by pharmaceutical companies. Pain medicine specialist Chris Hayes explains that those within the medical profession will not be surprised by this, but can be vigilant about having their professional judgement compromised. A couple of case studies provide context for the RACP's Guidelines for ethical relationships between health professionals and industry.


Dr Christopher Hayes FFPMANZCA (Director Hunter Integrated Pain Service)
Clin Assoc Prof Adrian Reynolds FAChAM (Clinical Director Alcohol and Drug Service, Tasmania)

Written and produced by Mic Cavazzini. Music: Chris Zabriskie ‘Out of the Skies, Under the Earth’ and ‘What True Self Feels Bogus Lets Watch Jason X’;  Borrtex 'You Are Not Alone', Jahzzar 'Missing You' courtesy of Free Music Archive. Gunnar Johnsén, 'Task At Hand 2', 'Task At Hand 5' licenced from Epidemic Sound. Image courtesy of WikiCommons. Voice acting by Iain Muir, Bob Kotic and Phillipe Soulaine.
Editorial feedback for this episode was provided by members of the RACP’s Podcast Editorial Group; Stella Sarlos, Lisa Mounsey, Michael Herd, Atif Slim, Rhiannon Mellor, Leah Krischock, Angela Chen, Genevieve Yates, Adrienne Torda, Philip Gaughwin, Rosalynn Pzcsola, Nele Legge, Marion Leighton, Oscar Russell, Jenae Valk, Li-Zsa Tan, Alan Ngo, Leah Krischock, Seema Radhakrishnan



***updates since publication of podcast
WHO retracts opioid guidelines following pharma influence controversy
[Australian Doctor]

Overviews and Guideline Documents
Position statement on the use of slow-release opioid preparations in the treatment of acute pain [ANZCA]
The cost of pain in Australia [Deloitte]
Prescription opioid misuse: contemporary challenges 2017 [Medicine Today]
Prescribing drugs of dependence in general practice - Part C1: Opioids [RACGP]
Prescription Opioid Policy  [RACP]
Guidelines for ethical relationships between health professionals and industry [RACP]

Opioid Harm in Australia [AIHW]
An overview of the patterns of prescription opioid use, costs and related harms in Australia [Br J Clin Pharmacol]
Prevalence and incidence of prescription opioid analgesic use in Australia [Br J Clin Pharmacol]
Twenty‐five years of prescription opioid use in Australia: a whole‐of‐population analysis using pharmaceutical claims [Br J Clin Pharmacol]
Current Opioid Access, Use, and Problems in Australasian Jurisdictions [Current Addiction Reports]
Predictors of persistent prescription opioid analgesic use among people without cancer in Australia [Br J Clin Pharmacol]
Pregabalin misuse‐related ambulance attendances in Victoria, 2012–2017: characteristics of patients and attendances [MJA]

Research on Opioids in Chronic Non-Cancer Pain
Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial [JAMA]
Changes in pain intensity after discontinuation of long-term opioid therapy for chronic noncancer pain [PAIN]
The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop [Ann Intern Med]

Deprescribing and Active self-management therapy
Opioid Conversion Calculator App [ANZCA]
Systematic review to determine which validated measurement tools can be used to assess risk of problematic analgesic use in patients with chronic pain [BJA]
Rethinking Opioid Dose Tapering, Prescription Opioid Dependence, and Indications for Buprenorphine [Ann Intern Med]
Prescribing wellness: comprehensive pain management outside specialist services [Australian Prescriber]
Better Pain Management [Faculty of Pain]
The behaviour change wheel: A new method for characterising and designing behaviour change interventions [Implementation Science]
Using social media to challenge unwarranted clinical variation in the treatment of chronic noncancer pain: the "Brainman" story [the Journal of Pain Research]
Understanding Pain: Brainman videos

State-based legal requirements for Schedule 8 prescriptions: why so complicated? [MJA]
Real-time prescription monitoring: lessons from Tasmania [Australian Prescriber]

Popular Media
A tangled web: as a new doctor it was easy to be influenced by the opioid industry [Ranjana Srivastava, The Guardian]
The Promotion and Marketing of OxyContin: Commercial Triumph, Public Health Tragedy [Am J Public Health]
No pain, no gain: How to handle New Zealand's opioid epidemic [Dr Mark Lane on Radio NZ]
How oxycontin was sold to the masses [the New Yorker podcast]
Why US life expectancy is falling [The Signal podcast, ABC]
Real Time Prescription Monitoring [NPS Medicinewise podcast]
Sackler Embraced Plan to Conceal OxyContin's Strength From Doctors, Sealed Testimony Shows [Medscape]
From Teddy Roosevelt to Trump: How drug companies triggered an opioid crisis a century ago [Washington Post]

***Updates since publication of the podcast Prescription opioid dispensing in Australian children and adolescents: a national population-based study [Lancet Child and Adolescent Health]
Interpreting trends in paediatric opioid prescribing [Lancet Editorial]
Mundipharma fined $300,000 for GP ads [Australian Doctor]


THE WORKS OF THOMAS SYDENHAM [p166]: “So necessary an instrument is opium [in the hand of a skilful man] that medicine would be a cripple without it; and whoever understands it well, will do more with it alone than he could well hope to do from any single medicine. To know of it only as a means of procuring sleep, or of allaying pain, or of checking diarrhoea, is to know only the half of it. [Like a Delphic sword, it can be used for many purposes besides.] Of cordials, it is the best that has hitherto been discovered in Nature. I had nearly said it was the only one.”

MIC CAVAZZINI: As much as this sounds like the latest advertising brochure from Big Pharma, it’s actually the words of 17th Century English physician, Thomas Sydenham. His text “Observationes Medicae” became go-to medical textbook for two hundred years, but Sydenham is best known for introducing laudanum to medicine, a spiced mix of opium and sherry. Another of his favourite remedies was Venice treacle. This expensive concoction contained not just opium among its 64 ingredients, but also frankincense, Indian nard and viper’s flesh. Sydenham doesn’t tell us whether this was a controlled-release formulation, however.

I’m Mic Cavazzini, for the Royal Australasian College of Physicians. Today on Pomegranate Health we’re going to talk about the influence of culture, regulation and marketing on opioid prescribing. I suggest you go back to the previous episode to hear about the science of pain and dependence. To start today’s story, it’s useful to ask where patients are most likely to get onto the slippery slope of opioid dependence. To answer this, I’ll be referring to findings from the Monash Centre for Medicine Use and Safety, UNSW Medicines Policy Research Unit and the National Drug and Alcohol Research Centre, all of which are embedded in the online transcript to this podcast.

According to a 2018 publication, almost 9% of Australians filling new opioid scripts for a non-cancer condition were still getting repeats twelve months later. A daily dose of 250-500mg oral morphine equivalents doubled the risk of persistent use. For transdermal patches the risk is twice as high again. This is worrying, given that an earlier study showed that 15% of patients given opioids are prescribed daily doses of 200 mg OME or more. [Forty percent of users are prescribed 90 mg or higher] But according to the Faculty of Pain Medicine the maximum dose outside of cancer pain and palliative care should be 40mg OME per day.   

On the potency ladder, codeine and tramadol are less than a third as strong as orally-administered morphine by weight. By contrast, oxycodone is 1.5 times stronger, and fentanyl is more than 50 times stronger. Most of the growth in opioid use over the last three decades has been in potent opioid compounds. [In 1990, opioids stronger than tramadol accounted for less than 10% of defined daily doses dispensed in Australia, but by 2011 this had risen to 40%]. If data are standardised by oral morphine equivalent dose, a third of use is now in the form of oxycodone and 10% is fentanyl.

Prescribers may well be getting mixed messages from guidelines and pharmaceutical subsidies. For example, fentanyl patches were listed on Australia’s PBS in 1999 for use in chronic and disabling cancer pain, but in 2006 the listing was changed to include chronic non-cancer pain that was unresponsive to non-narcotic analgesics. These days the product information on transdermal fentanyl simply reads, “This medicine is used to relieve chronic or long-lasting pain which requires strong painkillers.” [Sandoz, APO, Durogesic]. After lobbying from some professional organisations, the Minister for Health has just announced that non-cancer indications for fentanyl patches would be reigned back in.

Oxycodone has undergone the same sort of indication creep that fentanyl has. But research shows that a third of patients had not been prescribed any non-narcotic painkiller before initiating opioids. Every time a new long-acting opioid compound has been listed on the PBS it has greatly overtaken consumption of the basic formulation and even the most recently combination of long-acting oxycodone with naloxone has seen dispensing at a greater rate than would be expected if it were simply taking the place of the monotherapy.

Professor Adrian Reynolds is clinical director of Tasmania’s Alcohol and Drug services, and immediate past President of the RACP’s Faculty of Addiction Medicine. I asked him if these trends in opioid use were to do with the nature of the drug, or the behaviour of prescribers trusting a little too much in the latest greatest thing.

ADRIAN REYNOLDS:        Look, there’ll be a range of factors, but I think that last factor you raised would have to be a significant factor in the scheme of things. There’s going to be recommendations for smaller pack sizes of the immediate-release preparations.  We don’t want to be discharging patients with the large pack sizes when we only want them to be taking them for one, two or three days after discharge.  Although doctors have the option to prescribe lesser quantities now, in practice they’re not doing so very frequently. So we’ve got to move to a more effective structural arrangement. And if I take hydromorphone for example Jurnista, the lowest dose, four milligrams, is too low for an initial dose if someone is opioid naive.  And the highest dose of 64 milligrams is way above the maximum OMEDD that is now recommended.  And so that is illogical, it is risky, and we need to address those structural errors through regulation if we’re to get population level changes in clinical practice.

MIC CAVAZZINI:               And in terms of the long-acting formulations which in theory were supposed to produce a more rounded off dose—less of a spike that could be addictive—

ADRIAN REYNOLDS:        Lower levels. Yes.

MIC CAVAZZINI:               —that theory is still sound? That’s still within the guidelines?

ADRIAN REYNOLDS:        Look, there’s been a shift if you like among the pain specialists.  There’s an acknowledgement in acute pain we should be using short-acting, immediate release opioid formulations where they are indicated, and not the long-acting formulations.  But then if we are going to treat longer term, then yes, we should transfer the patient to a sustained-release preparation, for the reasons you’ve just described.

But we’ve certainly seen significant problems with the sustained-release preparations, haven’t we, and I think we’re in an active phase now of reappraisal of for whom, when, for how long and so on.  I think it’s a moving target right now, a moving, an issue that is constantly being discussed amongst doctors and reconsidered.

MIC CAVAZZINI:               So where do most people start on the slippery slope to addiction?  Is it with a high-dose codeine, is it with oxycodone, is it with something stronger?

ADRIAN REYNOLDS:        Look, I think the question is a bit more complex than just the drug and dose itself, but they are relevant in the scheme of things.  Look, I think we can say that higher dose, stronger opioids may increase the risk of dependence when compared to codeine.  But on the other hand, codeine, if you’re an ultra-rapid metaboliser, you’ve got two doses of the the cytochrome P450 gene, you may get an almost equivalent effect of milligram for milligram compared to morphine. 

Two things I highlighted at the Congress, as did Chris Hayes; that dose and duration of prescribing of opioids matter.  And so we know there are thresholds.  If you take these medications for more than three days, there is a statistically identified increase relative risk of long-term prescribing.  Seven days is another threshold, and one month is another threshold, in which you see a significant measurable increase in risk of being on these medicines long-term.  So the literature and evidence is taking us further away as the years go by from being able to support the use of opioids for long-term treatment of chronic non-cancer pain.


MIC CAVAZZINI: So who is prescribing all these opioids for chronic non-cancer pain? GPs have often been asked to answer for the widespread use in the community. If you just look at PBS prescribing, general practice account for about half of opioids initiated, dental clinics another 6%, and cancer care 1 or 2%. But that database doesn’t include dispensing in state-funded public hospitals or discharge meds from NSW and ACT. Also bear in mind that two thirds of new opioid scripts written by GPs are for codeine, while specialists more commonly prescribe oxycodone. This might be appropriate in the context of acute trauma or post-operative pain, but I could imagine that some patients are discharged without a clear strategy for deprescribing or alternative pain management. Then they end up at the GP clinic asking for the one thing that has helped them so far. 

[There’s evidence from a large cohort of patients in the US that persistent use of post-surgical opioids isn’t related to the severity of the surgery, and as the authors writing in JAMA conclude, “patients are likely continue opioids for reasons other than intensity of surgical pain.”]  It’s hard to join all these dots into a tidy picture, but I put this question to Dr Chris Hayes, Director of the Hunter Integrated Pain Service in Newcastle, and past Dean of the Faculty of Pain Medicine of the Australia and New Zealand College of Anaesthetists.

CHRIS HAYES:    I think that is right.  There has often been blaming of the other, and if it is a situation around hospital discharge, there needs to be very transparent communication about intention of duration of prescription and opioid deprescribing as the patient transitions from hospital to primary care. We haven’t necessarily done hugely well to date at the specialist end. 

I think that unwarranted clinical variation in a way is a measure of an immature sector, so there is a need for us to build a more consistent style of practice, so I think the finger pointing and the blaming is unhelpful, I think it’s good if we tackle this as a systems issue and recognise that there is work to do in both the hospital sector and general practice both, and we need integration across both arms of the health service.

MIC CAVAZZINI: Allow me one final historical indulgence. In 1805 a German pharmacist's apprentice extracted an alkaloid from the poppy plant that induced “a state of reverie.” He was named it after Morpheus, the Greek god of dreams, and it became instrumental to the early growth of the Merck pharmaceutical company. Morphine was a godsend for soldiers fighting in the American Civil war, but it was also given widely to middle-class house wives for menstrual cramps and nervousness. Or indeed to their teething children [One 1885 advert for Mrs Winslow’s Soothing Syrup promised “it produces natural quiet sleep, by relieving the child from pain, and the little cherub awakes as bright as a button.”]

By the end of the century it’s estimated that 1 in 200 Americans were addicted to morphine and opium, and several products were taken off the shelves. In any case, an alternative had been discovered. It was found to be even more effective at killing pain and at sedating coughs, during a dire period of tuberculosis and pneumonia epidemics. It was reasoned that as lower doses would be needed, so there would be less chance of addiction. The drug was named Heroin, for the heroic feelings it gave the Bayer employees who tried it. It began appearing at pharmacy counters in 1895 and a few early adopters wrote of its merits in the academic journals of the time.

No harmful symptoms whatever, especially as I observed no abstinence symptoms whatever”; “Drs Brown and Tompkin upon the ground of their experiments pronounce it a very safe and reliable analgesica very safe and reliable analgesic.”; “It possesses many advantages over morphine as a respiratory sedative. Two. it is not a hypnotic. Three; absence of danger of acquiring the habit.”

But already by 1902, articles were being published with titles such as “The heroin habit another curse” and “Héroïnomanie.” The more things change, the more things stay the same.

Back to the present time. You might be wondering why I haven’t mentioned the use of naloxone to mitigate the risk of overdose in people that are being weaned off high doses of opiods. This approach has been adopted in the US particularly for patients with a history of substance abuse use but there isn’t to date any evidence to show that this would have a protective effect at the population level. Both Adrian Reynolds and Chris Hayes argue that the very idea of take home naloxone can undermine the fundamental deprescribing message. Like I said earlier, behaviour change is all about sending the right signals. It’s useful to focus on Tasmania as a case study because in the early two thousands it was in last place for its stats on opioids use and harm. Deaths from methadone misuse were the highest in the country.Tasmanian opioid use was 30 to 40% higher than the Australian average until 2006.

At that point the Tasmanian curve began to flatten, and by 2012, use had dropped below the Australian average which was still rising. This shift was due in large part to the real-time prescription monitoring system. But as Adrian Reynolds explains, you need to pull many different levers to turn around behaviour of both the public and prescribers.

ADRIAN REYNOLDS:        As in a number of other states, if you want to prescribe a Schedule 8 medicine for more than two months continuously, you require an authority to do so through the regulators, the Pharmaceutical Services Branch.  If the patient is already identified as drug-dependent, you need an authority immediately.  So yes, that has been an important part we believe in monitoring and being across the issues before they become too significant, and gives us an opportunity to prevent.  Some states have an after-the-fact approach, they’ve had if you get up to 200 milligrams on OMEDD, which is way, way too late.

MIC CAVAZZINI:               So DORA implemented in 2009 was Australia’s first real time prescription monitoring program.It allows a prescriber to check whether their patient has been to see someone else.


MIC CAVAZZINI:               How is it different from the federal Prescription Shopping Program, which records patients who in any three month period have received a PBS item from more than six different prescribers?  And that’s updated within 24 hours of a script being filled.

ADRIAN REYNOLDS:        Well, that project is too little, too late in the scheme of things.  And in fact, we identified in Tassie that doctor shopping isn’t an issue.  But you don’t need, the problem is patients realise they didn’t need to doctor shop to get their high doses of opioids.  And so it missed the point, the Medicare system for monitoring missed the point. The other thing to say is DORA is mandatory, it’s not an opt-out, and it captures both private and PBS prescriptions, and it’s real time.  And so if a patient does present with a script perhaps early, ahead of time, the pharmacist enters it into the system.  There is an algorithm that will go ‘bing, bing’ down the line to the regulator’s side of things immediately if there’s a breach, if you like. And so they can pick up the phone immediately and talk to the pharmacist. 

And we’ve had occasions where we’ve retrieved the medications before they go out the pharmacy door.  Similarly with doctors, if they’re prescribing, or they’re seeing a patient and think an opioid might be indicated, they can look on the system, and they can see if this patient has been declared drug-dependent or a drug-seeker, if they are on an opioid pharmacotherapy program or not, if another doctor has an authority already to prescribe a Schedule 8 medicine, they can see what Schedule 8s or other reportable drugs have been dispensed, the quantities, and when.  So they can then make a better judgement about what they do next.

MIC CAVAZZINI:               So in May last year the federal Health Minister promised a nationwide RTP system by the end of that year. But the stalling block for the states was which IT platform to use, and whether it was a deal with Schedule 4 drugs as well as Schedule 8.  So now Victoria’s gone on to develop their Safe Script system at a cost of $30 million.  There’s a national program that New South Wales is trialling, but they’re considering adopting Safe Script as well. Meanwhile, the ACT’s developing their own program.  Is it really necessary to reinvent the wheel several times over?

ADRIAN REYNOLDS:        Well, I was disappointed to see another state do its own thing, and my assessment is the national system was superior.  But no matter what system we settle on, it has to be a nationally integrated and coordinated system if this is going to be maximised in its effectiveness.  But we need to build the clinical regulatory interfaces to respond to what those systems cough up.  And Tasmania, I say, has led the country, in fact is probably world’s best practice in the way we address that clinical regulatory interface. 

It’s not just the real time reporting, we can look at specialist reports, we can look at ambulance reports and so on, and form general views about the clinical status of the patient, their safety and their best clinical management into the future, and help and guide and support the medical profession towards safer, better care.  So it’s been a really carefully thought through, well-executed, not perfect, but a well-executed approach.

So we’ve got a very proactive collegiate relationship between lead clinicians and the regulators, and we focus on education and we ramped up medical education and training.  We went from one lecture in the whole course, I understand, to dozens of hours of interface with the medical students through their years.  Similarly, with the College of GPs and the physicians and the psychiatrists. 

So I think the responsibility is on the broader profession, on systems reform, rather than on individuals, if we’re really going to take this anywhere.  It’s a bit like with any other unhealthy commodity, if you say it’s up to individual choice and responsibility, you can say that for the next 100 years and we won’t address obesity and smoking and drinking and other related unhealthy endeavours.  You need structural reform to change population behaviour at the population level.


MIC CAVAZZINI: Now this story wouldn’t be complete without addressing the influence of marketing, and the oxycodone story in particular. The drug itself, [was discovered in 1916] and was introduced to the American market in 1939. Already in the sixties and seventies there was some concern over abuse of the combination drugs, Percodan and Percocet. But these were just a warning of what was to come with Oxycontin, brought out by Purdue Pharmaceuticals in 1996. Before we put our cynical hats on, it’s important to understand the scene in which this took place.

Morphine and other opioids had been legitimised for the management of cancer pain in the 1980s. I mentioned in the previous episode how the discovery of endogenous signalling pathways cemented the idea of that this was rational and evidence-based. This came on the back of the golden decades of psychopharmacology which had seen the discovery of drugs to treat depression and psychosis. Why shouldn’t pain be just another treatable disease?

There also emerged a conception of that “the relief from pain should be a human right”. That’s how it was put by the World Health Organisation’s Global Day Against Pain, but Australia may have been the first to enshrine this in law with the 1994 Medical Treatment Act. Around the same time, the American Pain Society was promoting the idea of pain as “the 5th vital sign” that demanded a physician’s attention.  

[Remember the mind-body discussion from the last episode? It has been speculated that an exaggerated focus on the sensation of pain has contributed to the increasing prevalence of some unexplained or functional pain syndromes. But that’s a whole different story.]

In the environment of the time, clinicians might be forgiven for having a embraced a bit overzealously the new formulations that were being released. Controlled-release oxycodone, marketed as Oxycontin, was approved in the US in 1996 and four years later in Australia. This was supposed to produce a more steady dose throughout the day and it certainly was rational to imagine it would be less addictive.

This is exactly how Oxycontin was promoted in the US and abroad, and this is where things get murky.  Purdue’s salesmen, executives and clinical champions like Dr Russell Portenoy argued that the risk of addiction to narcotic analgesia was “less than one percent.” They could do so with a straight face on the back of two citations from the 1980s. One was a letter describing a retrospective audit of patient records, and the other was a survey of staff from various American burns units. [From over twenty thousand patients captured, only 4 were defined as ‘actual iatrogenic addiction’ since the didn’t have a prior history of drug misuse.] Both papers were talking about inpatients treated for acute pain and said nothing about the risk of addiction in a wider community setting over long-term use.

Russell Portenoy had himself published a case series from 38 patients treated chronically with opioids. The two cases of dependence observed were brushed aside with the conclusion that, “opioid maintenance therapy can be a safe, salutary and more humane approach to the options of surgery or no treatment in those patients with intractable non-malignant pain and no history of drug abuse.”

I have to acknowledge that I’m drawing mostly from a chronicle of these events in the Journal of Public Health authored by Dr Art Van Zee. He’s the small-town GP who blew the whistle on Purdue’s predatory marketing to socio-economically deprived patients. One example of this was the distribution of vouchers for a free supply of Oxycontin of up to a month.

Despite the marketing promise that consumers would “get their life back” from pain, it turned out the tablets could be chewed to release doses as high as 160 milligrams. Dr Van Zee argues that even after the company learned of this potential for misuse, it steered its sales machine towards doctors with high-prescribing rates.

Between 1996 and 2001, Purdue Pharma organised more than 40 clinical conferences to expand what they called “the non-malignant pain market.” They spent 200 million US dollars in one year alone, that went not just to fancy hotels, but also to fishing hats and CDs with the catchy title “Get in the Swing With OxyContin.” There’s evidence that such influence does work. One study in the BMJ reports that a treat of even just $13 can encourage long-term prescribing of the promoted drug over others. 

By 2004, Oxycontin was the most prevalent prescription painkiller in the US and also [a leading prescription drug of abuse]. Some people were found to be causing grievous self-harm to justify continued prescriptions. In 2010, Purdue reformulated OxyContin to make it more difficult to misuse but it's suspected that this led to some addicts switching to heroin, which was easier to obtain and to use [This was associated with a five-fold increase in heroin-related overdose deaths in the US] and deaths from all opioids overtook those from motor vehicle crashes.

Dr Van Zee’s campaigning resulted in a massive class action against Purdue Pharma, and the state of Oklahoma sought 20 billion US dollars in damages. [The court heard that a company director had promised “a blizzard of prescriptions that will bury the competition”]. Dr Russell Portenoy himself was the target of lawsuits until he agreed to provide testimony that the company had knowingly and “understated the … risk of abuse, addiction and overdose.’’

In March this year Purdue settled for 270 million US dollars, and [a few months later, Israeli company Teva settled a smaller suit over its a generic form of Oxycontin.] at the end of August, an Oklahoma judge ruled Johnson and Johnson guilty of causing “public nuisance” in the way they marketed their tapentadol and fentanyl products. The company have been ordered to pay the state $572 million dollars.

We might scoff at the naivete of American regulators and physicians, but we’ve got our own demons to wrestle with in Australia. Chris Hayes’ collaborator Dr Simon Holliday has accused Purdue’s Australian arm, Mundipharma, of providing GPs with misleading information about Targin. That’s a combination or controlled-release oxycodone and peripherally-acting naloxone that has been demonstrated to have fewer constipatory effects.

But in a report to the ABC, Dr Holliday said that brochures suggested Targin was less addictive than immediate-release oxycodone, an unproven statement. He also reckoned that the conversion chart provided for weaning patients onto the drug was out by 25 per cent in some cases, and that Mundipharma cited decade-old treatment guidelines rather than the most recent ones. [To top it off, they attributed these to the RACP for these instead of the College of General Practitioners.]

This is sloppy behaviour at best, but Chris Hayes says that before pointing the finger at Big Pharma, the medical profession needs to examine its own place in this environment.  

CHRIS HAYES:    I think in terms of the current times and the Simon Holliday challenge to Mundipharma, they do need to quote the appropriate guidelines.  But it would be unjust I think for us doctors to be throwing stones too much at the pharmaceutical industry before we get our own house in order.  It’s the doctors who write the prescription for medication.  So we did prescribe maybe out of undue optimism-we interpreted the evidence that we had at that time incorrectly, I would say.  It’s always easy with the retrospectoscope, hindsight is a wonderful thing.  But I think it’s reasonable for us to do medical sorry statements.

MIC CAVAZZINI: In another investigation, this time published by The Age last March, the bad guy was Pfizer and their drug Lyrica.  Not an opioid, but the GABA analogue Pregabalin.  According to the journalist, the drug was originally confined to specialist pain clinics, but eight years later it’s one of Australia’s most prescribed drugs.  RACP epidemiologist, Professor Rachelle Buchbinder was quoted as saying “Now everyone is on it for everything”.  Have you also observed this increasing use of pregabalin?

CHRIS HAYES:    Not to generalise totally, but yes, I would agree with Professor Buchbinder.  I think she has her finger much on the pulse, and I know certainly some days in clinical practice it does seem like everyone is on Pregabalin for everything, almost, certainly many patients we see in the pain clinic. It is licensed for treatment of neuropathic pain, but we see many people who are prescribed Pregabalin without having clearly defined neuropathic pain.

I think from the point of view of doctors that are becoming more cautious about prescribing opioids, but still haven’t the confidence to prescribe active lifestyle management, pregabalin has become a go-to medication, despite again evidence of long-term efficacy.  If you look at the research trials even for clearly defined neuropathic pain, numbers needed to treat, you need to treat between four and 10 patients to get one person with a 30% reduction in pain.

MIC CAVAZZINI:               And more concerning is the fact that it does have some dangerous side effects, including insomnia and suicidal thoughts.  Now, the manufacturers did warn that it would double the risk of suicidal thoughts to one case in every 530.  But when it was being used at Gold Coast pain clinic in 2013, reportedly three of the first 50 patients reported a sudden onset of suicidal thoughts, and according to a study in the journal Addiction, there have been 88 pregabalin-associated deaths, almost all of them since it was PBS listed in 2013.  How comfortable are you with prescribing this drug?

CHRIS HAYES:    In terms of my clinical practice, pregabalin is not a helpful drug in the treatment of chronic non-cancer pain.  I think generally the harms outweighs the benefits and deprescribing is our recommended treatment.

MIC CAVAZZINI:               And that same study estimates that one in seven people prescribed the drug is at high risk of dependence, so yes, alarm bells should be ringing, perhaps.

CHRIS HAYES:    Yes, indeed.

MIC CAVAZZINI:               In the US, Pfizer has paid actually $1 billion US in fines for false advertising of Lyrica.  But when Dr Simon Holliday wrote to the TGA with his concerns about Mundipharma’s advertising of Targin, their comment was that marketing to doctors isn’t subject to false advertising laws, and that doctors are, quote, “Have the critical analytical skills to interpret scientific information and question claims in promotional materials that may be perceived to mislead a consumer”.  Why the kid gloves approach, considering that we were the first country in the world to implement plain packaging for cigarettes, for example?

CHRIS HAYES:    That’s the complicated issue, I think.  I mean, there’s no doubt that the pharmaceutical industry have been influential in terms of medical thought process, and I think that has been subtle and not so subtle.  But they would argue that they’re simply following current specialist views.  I think the pharmaceutical industry only has power insomuch as doctors allow them power.  We are the primary group that needs to interpret the evidence and develop guidelines, and if we are absolutely clear on what we think the indications are for these drugs, then it leaves the pharmaceutical industry little room to wriggle.  Where we are vague, as we often are, in our guidelines, the pharmaceutical industry have a lot of wriggle room, and in a sense I don’t blame them for taking advantage of that space.

MIC CAVAZZINI:               Yes, we shouldn’t be surprised by the motivations of a business, we know what their bottom line motivations might be.  But it is such a complicated space.  I mean, in Australia pharmaceutical companies aren’t allowed to advertise a specific drug to the public.  But there were adverts to the public suggesting that patients ask their doctor about pain that won’t go away.  If doctors then have more and more patients pushing that button and saying, “This is what I’ve got, nothing else will fix it”, is it likely to nudge them in the direction of that script?

CHRIS HAYES:    Absolutely it is.  I mean, this is why Professor’s Buchbinder’s quote reflects reality.  Many people out there in the community do have pain that won’t go away and those people often it seems are going to their GPs or other doctors raising the question of nerve pain, and in a short consultation the obvious solution is prescribe pregabalin.  The point has been made by the pharmaceutical industry that they would expect doctors, GPs, specialists, to evaluate through their own professional lens any marketing information that comes forth, and perhaps that’s the highest ideal in this situation. 

But nevertheless, I think we as professional colleges, need to wrestle with this, because if I as an individual doctor, or as a doctor as part of a broader organisation like the Faculty of Pain Medicine do receive pharmaceutical industry funding, it is then difficult, I think, for me to be totally arm’s length from that in developing a guideline.  And I think this is a challenge to us as a medical profession.  Perhaps there may be less controversial sponsors that could be engaged, and perhaps we could pay more money for our conferences. It’s not necessarily a good look if the public were to know that wealth doctors are receiving cheaper conference registration because of support from the pharmaceutical industry and particularly, the opioid pharmaceutical industry.

MIC CAVAZZINI: [In another great column for the Guardian, oncologist Dr Ranjana Srivastava describes her shock at being offered a bowl of soup by a chatty drug rep while she was a junior doctor. “On the subject of medical ethics,” she says, “my education had been silent. What constituted lobbying? How did one distinguish marketing from evidence? How did one learn that a free lunch was in fact very costly to patients?”]

To help navigate this minefield I want to point out the RACP’s updated Guidelines for ethical relationships between health professionals and industry . These makes it clear that not all funding arrangements present a conflict of interest, and in many cases they can further patient care and population health. But the guidelines help clinicians identify those relationships which could bias professional judgement. The cliché, of course, is the product familiarisation junket to a tropical island or a ski resort, but there are many subtler influences to be aware of such as subsidised conferences or training programs, or donations professional societies.

There’s a link to this document at our website, racp.edu.au/podcast as well as lots more reading and resources. Check out, for example, ANZCA’s phone app for dose conversion of opioids. Thanks to Chris Hayes and Adrian Reynolds for their contribution to this story. The views expressed are their own, and neither has declared conflicts of interest with regards to their comments for this story.

All the people who provided feedback to me are listed on the website, but I want to especially thank Natasa Gisev of NDARC and Samanta Lalic from Monash for their help with the epidemiology. And last but not least, the voice of Thomas Sydenham;

IAN MUIR: “Now if shall have done anything towards diminishing the risk, or even towards lightening the difficulties which occur in the treatment of these diseases—and I allow myself the hope that something has so been done—I have gained the object I had in view.” THE WORKS OF THOMAS SYDENHAM [p166]

I’m Iain Muir—I thank you kindly for lending your ears to this Episode of Pomegranate Health. It was produced by that good Doctor of Philosophy, Michele Cavazzini, for the Royal Australasian College of Physicians. I beseech you share this ripe fruit with your peers, and to carry forth the conversation at our comments page. Godspeed.


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18 May 2024
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