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TWO leading pharmacologists have called for a boycott on prescribing dextropropoxyphene after its manufacturer successfully appealed the drug’s removal from the Australian Register of Therapeutic Goods.
Dextropropoxyphene, an opioid, was approved for mild-to-moderate pain more than 30 years ago. Since then evidence has accumulated that it is no more efficacious than paracetamol.
A “For Debate” article in the MJA said the drug also carried a significant risk of sudden death from cardiotoxicity in patients with renal impairment, drug interactions and accidental or deliberate overdose. (1)
Despite this, dextropropoxyphene remains on the market in Australia after an appeal to the Administrative Appeals Tribunal (AAT) by the drug’s manufacturer against the Therapeutic Goods Administration (TGA) decision to delist it, the authors wrote.
The drug has been banned in the UK (2004), EU (2009), US (2010), New Zealand (2010) and elsewhere, they wrote.
The TGA delisted dextropropoxyphene in 2011, with the decision reaffirmed in January 2012. (2)
The AAT upheld the appeal by the manufacturer, Aspen Pharmacare, allowing dextropropoxyphene to remain on the market provided “conditions were put in place directed at minimising the risk”. (3)
In its judgment, the AAT said that “the Tribunal has concluded that the quality, safety and efficacy of both Di-Gesic [dextropropoxyphene/paracetamol] and Doloxene [dextropropoxyphene napsylate] is not unacceptable. In consequence, the products will remain on the [Australian Register of Therapeutic Goods]”.
Professor David Henry, CEO of the Institute for Clinical Evaluative Sciences and professor in the Department of Medicine at the University of Toronto, told MJA InSight that more attention needed to be paid to Aspen’s role.
If the TGA and AAT were not able to protect the public, “doctors and pharmacists should take matters into their own hands and stop using this dangerous and useless drug”, Professor Henry said.
He said doctors might also consider whether to use other products from the same manufacturer.
Professor Andrew Somogyi, professor of clinical and experimental pharmacology at the University of Adelaide, said he was convinced the only way to keep the public safe from dextropropoxyphene was if Aspen now voluntarily removed it from the market.
“And the only way the company will remove it is if there are no sales”, Professor Somogyi told MJA InSight.
He called on medical educators to educate their students and peers about therapeutic guidelines that advised against prescribing the drug. “That’s the only way.”
A spokesperson for Aspen Pharmacare told MJA InSight the company’s policy was not to speak to the media.
Professor Somogyi said the AAT decision set “a very dangerous precedent” as well as damaging Australia’s reputation internationally.
“I’m quite embarrassed about it, actually”, he said. “Internationally, people are looking at us and saying ‘what’s going on?’. The TGA is being viewed as foolish and naïve, and the clinical investigators are being made to look foolish as well.
“I feel very sorry for the TGA”, Professor Somogyi said. “They’re doing the best they can to protect the public. They made a very good decision about dextropropoxyphene and then they get this ludicrous decision [from the AAT].”
A spokesperson for the TGA said each party would have an opportunity to consider an appeal to the AAT finding.
The authors of the MJA article said the case highlighted the need to reform the appeal process by drug manufacturers for the sake of public safety and interest.
“When registration can be contrary to TGA advice and based around civil court proceedings rather than scientific interpretation of evidence, the international reputation of Australia’s drug regulatory system could be at stake”, they wrote.
“[The case] should clearly highlight to our government the urgent need to revise the legal appeal processes that in our view inappropriately burden the TGA when it decides to take action to protect the Australian people.”
1. MJA 2013; 199 (4): 257-260
2. TGA 2012; Media release: Update on TGA decision to cancel prescription pain-killers, 6 Sept
3. Administrative Appeals Tribunal of Australia 2013; Aspen Pharmacare Australia Pty Ltd and Minister for Health and Ageing [2013] AATA 197
If you ever had shoulder surgery you would know that Digesic is far more effective as a pain killer than Paracetamol. A large study with a P>05 showing that the two are equivalent is not practical for individual use.
It would have been better to describe in short detail the scientific OBJECTIONS to Digesics use than to just say that decision to reinstate it in Australia was bad science. Criticising without stating evidence is poor science.
I am sure that scientific evidence was used to reinstate it although I am not privy to it.
Pacdoc, superior to what?
Andrew Byrne, alternatives are not more expensive
Interesting to see such a dicotomy of views
Really supporting the medication as efficacious by EXPERIENCE and against based on derived numbers.
I wish to add my support for the superior pain relieving property of dextro and my experience of lack of adverse effects used as used to be indicated, based on my own use and its use with my patients.
Personal experience is quoted above-I had bilateral sacral fractures S2,3,4,5-proven on MRI-with extensive haemorrhage -after being knocked over by a heavy horse-was prescribed Digesic-which induced slight euphoria due to the mu-opiod receptor and serotonin reuptake inhibition effects, I presume, but the resulting pain with every step I took, and pain everytime I rolled over in bed which lasted weeks-six I was told by the Orthopaedic Surgeon was the norm, I recall well. Those of you quoting post-operative analgesia, I ask, were you, your patients, or your wives taking some Benzodiazepine (which I was not) which has blunted your memory of the pain?
Digesic is not, in my experience, an effective analgesic for moderate to severe acute pain.
Not only was I prescribed an ineffective analgesic, there was no ECG, no examination of my heart , my blood pressure, nor my renal function, despite my having a systolic murmur diagnosed previously by a Cardiologist.
Drug-dependence in chronic pain and drug-trafficking are separate problems, seen with over the counter Nurofen Plus, seen with Dexamphetamine prescribed for children, and Panadeine Forte, sold by little old ladies, and Diazepam, worth one dollar per mg, as is Oxycodone. Methadone and Subutex prescribed by drug-dependence clinics are sold on the street. Misuse of these drugs does not support the case for Digesic, rather emphasises the need for multidisciplinary approaches to chronic pain and drug-dependence.
Drug company profits are the drivers of much of what we can and can’t do in our prescribing these days. UK psychiatrist Ben Goldacre (Google him) has a worrying but logical ‘take’ on prescribing pressures. The denigration of cheaper drugs over patented and therefore more profitable drugs is now very clear ‘business as usual’ for the drug industry and despite apparent competition, quiet collusion is also possible. Alarmist research cited against ‘old faithfuls’ may be far away from clinical medicine and often funded by drug companies who hold sway over many of the journals which we might have assumed were independent. There has been a scare campaign for over ten years about the ‘potentially fatal’ side effect of torsade de pointes tachycardia in methadone patients (associated with ubiquitous QT prolongation in this population). As with Debendox, I was sceptical at new and serious side effects being ascribed to a drug we had used for decades under close supervision without reports of the claimed problem (birth defects or torsade). There are still no reports of death due to confirmed torsade in a methadone patient … and nearly all ~100 reported non-fatal cases were multifactorial, often co-prescribed anti-virals (there may be one death from the French literature – as yet unconfirmed). Although I rarely prescribe it these days, I would also be disappointed to lose the combination propoxyphene option, knowing that most alternatives are far more expensive while not necessarily being safer – and for some of the newer drugs the safety data is not yet established.
As a GP who has also had to occasionally be a patient I would like to make a comment. I have had 2 hip replacements. I also am a non converter of Codeine due to a genetic predisposition and so Morphine and Fentanyl are the drugs of choice for severe pain. I was able to take Digesic in the postoperative period and found it at that time to be superior to paracetamol. I am sure it was not “all in the mind”. Under normal circumstances I find paracetamol is a very good analgesic but if I have more severe pain Digesic is definitely better despite what the experts say!
This issue nicely illustrates one of the unaddressed issues in evidence based medicine, of individual variability.
When a drug works for short term symptoms in a minority of patients, it may show no beneficial effect in an RCT which includes peope who are responders and non responders to the drug. If only 10% of the population are responders, and the drug has an excellent effect for them, it may still show no benefit in an RCT.
When a treatment is used for short term symptom based goals, the evidence base should focus on whether the drug is safe, and let patients work out if it is effective for them.
In this case it seems dextropropoxyphene fails on safety criteria.
The plural of anecdote is not data. I am a full time clinician and given the plethora of effective options available I have not needed to use dextropropoxyphene for many years, regardless of any clinical tradition or culture of use, personal or my patients personal experience. If you insist on using this drug, clearly shown to have greater risks than benefits and marginal effectiveness, then you might as well introduce homeopathy to your practice as well. You are clearly not practicing evidence based medicine.
It seems from the postings on this topic that many of our clinicians seem driven by personal preference rather than evidence. The evidence for the lack of efficacy and the toxicity of dextropropoxyphene is overwhelming. The reason other ‘toxic’ medications such as warfarin, penicillin and aspirin continue to be used is that the evidence overwhelmingly support their use.
This medication has already been discontinued in Europe, the USA and in our back yard, New Zealand. There is no cry from these markets that they must have the medication back! The suggestion that there are patients who can only benefit from this particular medication I find ludicrous.
I am appalled at the decision of the AAT and strongly support the suggestion that this drug should be driven from the market by refusing to use it.
Fantastic.
We have academics in an ivory tower who don’t have to sully their hands treating PATIENTS telling us how to treat patients . Clueless .
Notice you don’t see a lot of clinicians up in arms against it ?? Now why would that be ?
Digesic is the ONLY effective anaelgesic for moderate post-operative pain that NEVER causes nausea .
When it was unavailable all that was done was prescription patterns changed to supply stronger oxycodone/ codeine-based anaelgesics that DID cause nausea .
In some post-operative scenarios vomiting can be disastrous .
I worked in an ICU in my training . Got to say I never say a patients sick from Digesic ingestion . Saw it from Digoxin , aspirin , paracetamol, narcotics ……maybe we should get rid of them too ?
This drug is essential in the management of post-operative pain . If that is all it is available for , then it is still very worthwhile
Leave it alone.
TS
Capadex & Di-Gesic were useful drugs – not for everyone, but useful – and the only low level product that worked for some patients who could not tolerate the stronger narctics, yet were not helped by paracetamol alone. These products require care & cosideration in prescribing, and sensible clinical managment – AS DO ALL THE POISONS WE USE WITH EFFECT!. Consider the humble aspirin, or warfarin!
I agree with others above that dextropropoxyphene is no less safe than many other stronger painkillers available – the misbegotten unbalanced combo of Panadeine Forte that is widely overused because of its PBS listing, springs to mind as do the various narcotics. In practice, I have seen & treated many more disasters with Ibuprofen (freely, and in my opinion, wrongly otc even in supermarkets) than I have ever seen with dextropropoxyphene.
While respecting the work of the professorial pharmacological colleages above, they do not practice in the full cut & thrust world of the full time GP – we have to make these balanced decisions several times at least every hour for the benefit of the patient. Pharmacological input is useful, but it does not hold all the answers, and natre has a wonderful way of playing with averages & statistics. I recall listening to Prof Somogyi in a program years ago trying to make a decision where there was little clinical evidence, so he was stuck making a decision. Welcome to the everyday life of the practicing clinician, especially the GP.
By all means provide us with our data, but keep your fingers off the regulator switch – leave that to the clinicians, And finally, God protect us from phamaceutical regulation by lawyers.
AAT findings-“Conditions are put in place to minimise the risk”
Well, TGA, get your legal minds onto this-put the conditions in place-Cardiology review, renal function, no interacting drugs, clinical Psychologist assessment of risk of overdose, prior to each prescription, then see who will bother prescribing it.
Not me.
I and my colleagues prescribed Digesic widely in a surgical setting for years and, yes, it works. I do not know of a meaningful drug which cannot hurt anybody and if you take enough, Digesic will hurt too. So will water. Experience tells us that legal opinions are only worth the size of the cheque you write to pay for them and lawyers are probably the last port of call when trying to dispense health care. In practice there are very many drugs we use every day which would vanish were similar criteria applied to them. It’s a bit like the automobile – use it and some will come to grief but no-one is going to win an argument which says it should be banned.
My wife cannot tolerate opioids, including codeine, but has received good pain relief from DiGesic, over and above that provided by paracetamol alone, for several decades. Recently she was prescribed oxycontin and endone for intense muscle pain secondary to vertebral fracture because of osteoporosis. The pain was relieved but the hallucinatory side effects were intolerable. I am prepared to vouch for the clinical efficacy of DiGesic over many years in a patient who will be almost completely deprived of adequate pain relief if this drug is banned. This debate enhances my concern that some evidence-bsed medicine is flawed because the theoreticians have not tested all the evidence, such as this clinical experience which I know is shared by others. I am far more concerned that there has been any mention of boycott without first seeking whether or not the evidence is complete.
I am astonished that it is claimed that dextropopoxyphene is no more efficacious than paracetamol. I have had it prescribed for moderate acute pain on a couple of occasions in the past and have found it considerably more effective in quelling the pain than the codeine/paracetamol combinations that are commonly prescribed for this level of acute pain, let alone paracetamol alone. Many analgesics carry the risk of death if over-used or used in conjunction with other drugs; paracetamol, if misused or overused, can cause serious and permanent liver damage and yet is available over the counter from supermarkets in Australia. So while I believe that it is a matter of concern that a pharmaceutical company can use the courts to run roughshod over TGA decisions, I think, on this occasion, that the TGA got it wrong.
I am a registered medical practitioner and have both used Digesic myself and also prescribed it on occasions to patients who have been unable to tolerate other opioid analgesics, including panadeine forte.
To suggest that dextropropoxyhene is “no more efficacious than paracetamol” is completely laughable. Any doctor with even a modicum of clinical experience, let alone their own personal experience with it, could easily advise that that is not the case at all.
Like with every prescription drug, it comes down to how it is used, not whether it should be banned at the first suggestion of an adverse reaction without far more detailed studies being performed first.
Oh, and while you’re at it, why don’t we just all boycott isotretinoin and tramadol too?
These days I am suspicious when I read calls for ‘a boycott’ to ‘keep the public safe’, that something is ‘damaging Australia’s reputation’, and that we should ‘revise the law’. These people seem not to be busy enough. But then, ‘activity suggests a life filed with purpose’….
Are we going to ban penicillin? Many have died from unanticipated anaphylactic shock following injections of this medication. Dextropropoxephene has been around for decades bridging the gap between paracetamol and the opiate analgesics. There were few reports. making headlines about deaths from this medication. Aspen did not discover this drug and acquired rights to market it only fairly recently. They would not have done so had there been evidence that justified a total ban on its use. The Courts exist to discover the Law as it applies to a particular case where there is a dispute involving two or more conflicting interpretations of it. That is our remedy against abuse of the government monopoly on force where it is applied selectively without justification. In this instance, the Court has reached this decision after hearing all relevant evidence. It has not sought to practice Medicine but to settle a dispute where the plaintiff maintained that the law had been applied selectively. It you’ll behoves piqued academics to take to the barricades and call for a boycott on all medications marketed by Aspen. Have they not heard of ACCC?
We are witnessing what happens at the intersection of campaigns for better pain management, better safety-profiles and greater attention to evidence. We listened to the call for better attention to pain managment, and, we heard about the non-responders to codeine, and now there is concern about the greater use of strong opiates. Perhaps we need to go back to more non-drug modalities (heat, massage, water, ice, physio etc) – though this won’t be effective for all people or all conditions. All effective medications have adverse effects, and we need to be able to choose between a wide range. Having said that, many of us do not use dextropropoxyphene. Should we?
Interesting – those advocating the bocotting of ALL the drigs manufactured by the Company – does that include all the ‘very efficacious ‘ drugs as well ? Hmm ! Where is patient care factored in?
I am an intermediate metabolizer at CYP450 450 2D6, a genetically determined enzyme required to convert opoids (which are inactive prodrugs) to the analgesic morphine. Codeine and other opioid analgesic drugs do not work for me at all. Dextropropoxephene is an effective analgesic for me.
However I am well aware of the risks associated with dextropropoxephene as it is strong inhibitor of Cytochrome 2D6 which means the anyone taking psychiatric drugs metabolised by CYP450 2D6 (and that means pretty much all of them) will experience serious drug toxicity, akathisia and sucidality or aggression.
I have been unable to establish if it is dextropropoxephene on its own or the combination of dextropropoxephene and other drugs that causes neurotoxic or cardiac deaths. Dextropropoxephene is dangerous because of its inhibitory potential of CYP450 2D6 as are other drugs that do this, including Aropax (paroxetine) and Prozac (Prozac (fluoxetine). All drugs used in psychiatry are associated with excess deaths so should be used only in cases of mental illness not for stress. The problem of adverse drug reactions (ADRs) and interactions is not trivial. ADRs and interactions are the number four killer in USA, but this problem is poorly recognised in Australasia.
My concern is that in the clinical trials that got atypical antipsychotics licensed at the US Food and Drug Administration, one in every 145 clincial trial subjects died, most by suicide. Other medication use was controlled or not reported.
I believe doctors need a good explanation about the mechanisms of death and about how to use drugs and about drug-drug interactions.
How many deaths have ever been caused in Australia by the cardiac side effects of Dextropropoxyphene?
How many deaths have been caused by an overdose of Dextropropoxyphene in Australia?
How many deaths have been caused in the last 10 years by Oxycodone in Australia?
I would suggest that Dextropopoxyphene is probably a great deal safer than Oxycodone and is useful in those patients with mild to moderate pain where Codeine does not work or the patient is intolerant of such. It of course is usually combined with Paracetamol, as is Codeine. The current teaching seems to be to prescribe Oxycodone for any pain other than mild pain. This prescribing of Oxycodone must be of much more concern than prescribing Dextropropoxyphene.
Any Dr who posts anecdotal experience with this drug on here supporting it should be ashamed of themselves. PLACEBO effect. It doesn’t work in proper RCT studies, and it causes harm sometimes, not often but sometimes, full stop. We need to practise evidence-based medicine, otherwise we are no better than naturopaths, witch doctors and snake oil salesman. It is awful that a drug company can challenge the TGA, it is unethical, it is wrong. If I were a GP, where alternative drugs of equal efficacy existed manufactured by other companies, I would boycott all drugs manufactured by aspen pharmacare.
Several of my patients are appalled at the prospect of losing this medication from pharmacies. They all claim increased efficacy over paracetamol. None of them have contraindications. If an opioid is to be banned it should be oxycodone, which currently represents a far greater risk to public health in Australia than dextropropyphene.
This is not bypassing medical opnion – it is bypassing theoretical pharmacological opinion when it conflicts with real clinical experience – judicious use short term, especially post operatively, extremely valuable drug for patient. Originally removed upon the advice of inexperienced theoreticians to the detriment of patient care. This is being seen more frequently as a consequence patients are turning to alternatives. This leaves the clinicians with only dangerous opioids as an option which are more damaging – both in effect and side effects. The courts thankfully look at the eviidence then make a decision – so the courts had the benefit of looking at the evidence of all the experts – both theoreticaal and practical in an unbiased way. Thankfully the company had the commercial courage to challenge a bureaucratic decision.
I am an experienced and busy neurosurgeon who is active in both spinal and cranial surgery. Over the years, I have found that Di-Gesic was the medication of choice in treating post-op pain in the ssignificant group of patients who experience severe nausea and vomiting with other opiates. Our routine post-op regime is Panadol/oxycontin/endone/lactulose/coloxyl with senna, but some patients are intolerant, which often also applies to other opiates. We have a sophisticated acute pain service who do not have a good alternative answer for this patient group other than to lie still until their post-op pain settles. In this pattern of usage, I have not seen any adverse reactions to the drug, but I admit that patient numbers would be small. I have not reviewed all the evidence, but patients are not homogeneous. I believe that close clinical observation still has a role in the modern era.
This does indeed set a very worrying precedent. Bypassing considered medical opinion by referring the matter to a court will encourage others to do the same in search of profit. I agree that Australia urgently needs legislation to protect medical decision making in the interests of the public. This is all so more important with the rising abuse of opioid drugs and controversial treatments such as naltrexone implants.
Some years ago while working as a GP (now retired) I had 8 teeth removed. Post operatively I took Paracetemol for pain control with very little relief. After switching to Digesic I experienced a significant improvement in pain control. More recently I had a similar experience following TURP. I suffered no side effects on either occasion. The statement that dextropropxyphene is useless is not consistent with my own experience.
As a pharmacy student 20 years ago, I conducted a study which was instrumental in removing dextropropoxyphene from the formulary at Prince Henry Hospital, Sydney. I am surprised anyone is still prescribing this drug