MIC CAVAZZINI: The dramatic headlines about the opioid crisis are all-too familiar by now, and prescribers might be feeling under criticism. If it’s any comfort, liberal use of opiates in medicine goes back at least as far as the 4th Century BC. In the Hippocratic texts there are over twenty treatments that include poppy extracts, some of which mention pain among the symptoms being treated.
One such passage, filed under "Diseases of Women" [II, 10, 119L, p 289], deals with abnormal discharges, edema and shortness of breath. It comes with two florid pages of dietary recommendations, douches, purgative potions and contraindications, before this advice is offered;
“If after all this, the woman says that the cervix is hard and painful, flush again with butter until the uterus dries and the patient recovers. On the days between these douches, have her drink a tonic of elder berries, rennet from a hare, poppy capsules, fruit of the Gnidian daphne, and the shell of a sweet pomegranate, all in equal parts. Mix this with barley meal and maidenhair. To be taken on an empty stomach with fragrant red wine.”
Who knows if the the Hippocratic authors really knew what they were doing, but it makes for a good segue to introduce today’s show. Welcome to Pomegranate Health. I’m Mic Cavazzini, and over the next couple of episodes, we’ll take a look at the science and the modern culture around use of opioids for relief of chronic pain.
Let’s start with an epidemiological snapshot of the last thirty years. In line with the skyrocketing rates of pharmaceutical opioid use in the US, Australia experienced a fourfold increase between 1990 and 2014 as calculated in defined daily doses of opioids per capita. Another way to look at this is that 10 percent of adults in Australia start opioids each year, and the prevalence of use is around 16 percent.
I have to thank Dr Natasa Gisev from the National Drug and Alcohol Research Centre for guiding me through some of this literature, which can all be found linked in the podcast transcript. There aren’t as many publications available from the New Zealand setting, but the rise in dispensing there has followed a parallel trajectory. New Zealand is now the fifteenth biggest pharmaceutical opioid user in the world and Australia is eighth. But this isn’t a trans-Tasman rivalry you want to win.
Opioid poisonings recorded in Australian hospitals have tripled since 1998 and today, prescription opioids kill more people than heroin. There’s also a detectable increase in the risk of heart attacks, falls and road accidents within a few months of opioid initiation. Later in this episode we’ll discuss weaning dependent patients off opioids and what a holistic approach to pain therapy looks like.
Some of the increase in opioid prescribing has been appropriate. As stated in the guidelines of the Faculty of Pain Medicine, there is high-quality evidence to support opioid analgesia in cancer pain and palliative care. Certainly, many patients with these conditions will have benefited from the emergence of strong opioids in slow-release formulations over the past few decades. And opioids, of course, do have a proven analgesic effect in acute non-cancer pain.
But much of their use in the community is for non-cancer conditions that persist longer than three months. A study of data collected between 2010 and 2011 found that 44 percent of opioid prescriptions written by Australian GPs were associated with chronic non-cancer conditions. Back problems made up a third of these scripts, and osteoarthritic pain another 10 percent.
Systematic reviews will tell you that that there are no decent trials that would warrant long-term use of opioids for such indications. In fact, there are barely any studies that have even observed patients for more than four months—but despite this lack of evidence, guidelines have been all too permissive according to pain specialist Dr Chris Hayes.
CHRIS HAYES: So if you look at the guidelines from the Faculty of Pain Medicine Australian and New Zealand College of Anaesthetists, that guideline admits that there is no clear evidence for opioid use in chronic non-cancer pain, but sets out some recommendations that the clinician might follow when they are prescribing. The American guidelines, do raise a lot of cautions about the issue but then they undermine those cautions by saying that opioids should only be prescribed where the clinician expects that the benefits will outweigh the harms. Which is a nonsense statement, as far as I’m concerned, that undermines the value of their previous boundaries that they’ve been attempting to set.
The NICE guidelines from the UK are the most forthright that I’m aware of. This is guidelines for low back pain, where they just simply say don’t “prescribe opioids for chronic low back pain”. I think that is cutting to the chase more, and this is what we need to be saying, in my opinion.
MIC CAVAZZINI: Dr Hayes is Director of the Hunter Integrated Pain Service in Newcastle, and past Dean of the Faculty of Pain Medicine within the Australia and New Zealand College of Anaesthetists. I asked him to help me unpack the results of on a study published last year in JAMA that was the first to rigorously examine the efficacy of long-term of opioid analgesia.
In the SPACE trial conducted by US Veterans Affairs, patients with severe chronic back pain, hip or knee osteoarthritis were randomised to either opioid or nonopioid therapy. After 12 months of treatment the groups didn’t differ on pain-related function. The secondary outcome of the study was self-reported pain intensity, and this was actually lower in the nonopioid patient group.
CHRIS HAYES: I think this was a brilliant trial. For a long time in the sector, we felt there was a gap, because as you say, randomised control trials only went to, generally, a maximum of 12 weeks, and to extrapolate from those trials to chronic pain would be inappropriate. So, Erin Krebs and colleagues have done an outstanding job in putting together what they describe as a pragmatic randomised controlled trial, meaning that it was randomised, but not blinded. It might not be the ultimate nail in the coffin, but it certainly points, I think, to what we do see in day to day clinical practice.
MIC CAVAZZINI: Maybe you can help me understand some of the details of the study. The 106 patients that were randomised to opioid treatment went through three steps. The first involved immediate release morphine, hydrocodone or oxycodone. Step two involved sustained-action morphine, or oxycodone, and step three involved transdermal fentanyl. What’s the point of swapping in or out these different formulations?
CHRIS HAYES: So, those were options. Not all patients went through all of those stages, but the prescriber might step the patient through from a shorter-acting to a longer-acting opioid, and then potentially if the initial long acting opioid doesn't work, they might rotate to another opioid. So, these are fairly standardly used interventions for those that are using opioids in chronic non-cancer pain, which is undoubtedly a strength of the trial design.
MIC CAVAZZINI: Right, and similarly in the non-opioid group, they first received paracetamol and non-steroidal anti-inflammatories, and then they were offered a range of drugs, better known in the treatment of anxiety, depression or seizures, but more recently trending for neuropathic pain and fibromyalgia. Things like nortriptyline, amitriptyline, gabapentin. The patients receiving these reported half as many adverse side effects on average, than the opioid group. But they don’t sound like mild drugs, are they?
CHRIS HAYES: No, they’re not mild drugs, but very familiar to generalists in the pain sector. Again, there are questions about whether those drugs are actually helpful or not, over the long term, in chronic non-cancer pain. But nevertheless, for the sake of this trial, I think it was a useful comparator group to look at what opioids do add in clinical practice.
MIC CAVAZZINI: Now, as well as the SPACE study, Veterans Affairs also published another paper in the journal, Pain. That study looked at around 500 patients who had been on opioids long-term, mostly with musculoskeletal pain, but some with neuropathic pain and headaches. After these patients had been stopped opioids for a year, their reported pain intensity was not worse. So, what do we know about tolerance to opioids and pain sensitisation in response to long term use?
CHRIS HAYES: This is, again, a fascinating study by McPherson and colleagues from 2018. Yes, essentially as you described, the pain intensity either didn't change or reduced slightly. Although opioids might have a measure of modest benefit in the short term when initiated for chronic pain, tolerance soon kicks in, or perhaps even beyond tolerance, opioid-induced hyperalgesia, and that therefore, we wouldn't expect, medically, that their pain would escalate with removal of the drug. And again, this is a research trial that very much mirrors what we see in clinical practice.
MIC CAVAZZINI: The symptoms of opiate withdrawal may have been first described in the 2nd century by the Roman physician, Galen. His VIP patient, Emperor Marcus Aurelius, was taking a potion called theriac every day as a prophylactic to being poisoned. Historian Thomas Africa tells how during a wearying military campaign on the Danube, the Emperor increase the dose to calm his nerves, but then at one point tried to go cold turkey.
Galen observed, “When he found himself getting drowsy at his duties, he had the poppy-juice removed…. But, then, he was unable to sleep at night… So he was obliged to turn again to the theriac which contained poppy-juice, since this had now become a habit with him.”
The symptoms that Galen attributed to an abundance of dry humors, today we would recognise as opioid dependence. When the opioid pathways adapt to regular dosing, abrupt cessation causes symptoms that are sometimes described as a bad flu; insomnia, muscle aches, sweats, nausea, diarrhoea, as well as drug-opposite effects like hyperalgesia and anhedonia. These might sound like trivial side-effects, but the consequences can be to disrupt families and job opportunities and persistent use of opioids ultimately results brain damage and disability.
So how prevalent is dependence on prescription opioids in Australia? A reliable estimate comes from the 2015 POINT study in which people filling opioid scripts were sampled from pharmacies distributed across the geographic and socio-economic spectrum. Over 1400 participants were surveyed, and of these 8.5 percent met criteria for dependence on pharmaceutical opioids in their lifetime.
Dependence sometimes escalates to addiction, but it’s important to distinguish the two. This synopsis I’m about to give you is largely thanks to a 2017 review in the journal Pain by Professors Ballantyne and Sullivan of the University of Washington School of Medicine.
We all have some concept about the “reward centre” of the brain. It’s not dependent on opioid signalling, but on dopamine projections between the midbrain and limbic system that motivate behaviours like searching for food, water or a sexual partner. Without these drives, we wouldn’t get very far as a species.
But “wanting” stuff is intrinsically different from “liking” stuff. You don’t get addicted to opioids just because they feel good or because they relieve pain—in fact, both effects are dulled by repeated use—you get addicted to the drug-seeking itself. The repetition of goal-seeking behaviour trains the dopamine pathways about all the contextual cues that can lead to a hit.
An example of this are the colourful lights and sounds of poker machines, which are enough to trigger gambling behaviour in someone addicted to that past-time. Addiction therapy requires unlearning those associations, and might need the help of addiction specialists and allied health.
You probably won’t observe classic drug-seeking behaviour in patients that have a ready supply but there are screening tools that can assess risk of problematic analgesic use. Look up the “pain medication questionnaire” or SOAPP with a double P. Conversely, patients trying to get their hands on opioids to avoid withdrawal symptoms aren’t necessarily addicted. Their doses can be stepped down in a gradual way designed to manage symptoms.
Many clinicians these days are wary of prescribing opioids, but also want to give patients the benefit of the doubt. Professor Adrian Reynolds describes some of the yellow flags associated with addiction. He’s the clinical director of Tasmania’s Alcohol and Drug services, and immediate past President of the RACP’s Faculty of Addiction Medicine.
ADRIAN REYNOLDS: In the chronic pain setting, I always watch for the patient’s behaviours in the context of what they say. And so if I walk into a hospital room and note the patient is chatting with someone, reading a magazine, and then they report they’ve got a pain score of eight, nine, ten, or even twelve out of ten, that is inconsistent. And I know immediately there is something more going on here that needs attention. And they may present early for scripts, one or two days earlier than anticipated initially, and then they may start to ask their doctor to increase the dose.
They may report one or two episodes of lost supplies, which can indicate they may be over-using them, and if the patient reports using the medication for its affect modulating properties, that is, they just report they feel good, or feel better when they take it. Then that’s a signal of risk, and it’s not the reason these medications are prescribed. Quite commonly leads to escalation of problems, and ultimately to dependence.
MIC CAVAZZINI: I guess by the time you’re seeing them, they are already seeking help, whereas for the average physician or general practitioner who suspects something might be going on, is it hard for them to confront a patient with the fact of their addiction? Is addiction so stigmatised that this topic is avoided?
ADRIAN REYNOLDS: So, it’s only hard if we as the medical profession believe it’s hard. It’s not hard—it should be a normalised part of everyday clinical practice. I think we underestimate that patients actually want us, the medical profession, to ask about their innermost sensitive and difficult life problems. In fact, patients share those problems with us, like no other. And that’s a privilege, but it’s also a responsibility for the medical profession. So, I think we’ve got to be careful to avoid what I call learnt helplessness and clinical nihilism.
MIC CAVAZZINI: Let’s talk a little bit about weaning patients off opioids. I’ve variously read that in the sort of step-down process you should reduce it by 10 percent or 25 percent or 50 percent a month. What is your recommended strategy?
ADRIAN REYNOLDS: Look, the first thing to say is these opioid equi-analgesic tables are based on acute dosing. They have their limitations when applied to long term dosing. The fact that you’ve read widely ranging options or guidance around how to do it, I think is instructive, and it says that it’s not an exact science, and it really does depend on patient context drug, how long they have been using it, whether there is a history of dependence or aberrant or problematic use of other substances, their psychosocial circumstances.
I’ve treated many patients who, doctors have tried over years to taper, and I’ve said let’s just admit them, and I will stop the medicine and I’ll treat them symptomatically. But I put some boundaries as well and I’ve never found it useful to string the reduction out more than three months, in general.
MIC CAVAZZINI: And of course weaning off opioids is associated with side effects, such as increased anxiety, insomnia, abdominal pain, diarrhoea, tremor, tachycardia. How do you deal with these?
ADRIAN REYNOLDS: Depends on the drug. I titrate to clinical effect, I observe how the patient responds to particular doses, and I titrate accordingly. If we’re weaning them off an agonist opioid like morphine or oxycodone, if we’re going to put them on opioid substitution or treatment in lieu of that other agonist opioid, we would simply stop the full agonist, wait for withdrawal to occur, treat the most problematic symptoms symptomatically with medications, and not a heavy touch in what we do. And when they start to show withdrawal, we would commence them on, usually buprenorphine would be my preferred initial medication, and restabilise them on that new medication.
MIC CAVAZZINI: There’s a very good edition of Medicine Today, I think it was in 2016, which you contributed to. In another article, Apo Demirikol warns against treating insomnia with sedatives in a detoxing patient.
ADRIAN REYNOLDS: Yes, Apo’s advice is good. We have to be very careful in this context of the very high risks associate with combining opioids with other sedative medications, in particular the benzodiazepine class, but also some of the antipsychotics and other psychotropic medicines that can add to the risk of opioid-induced ventilatory impairment. I hasten to add that we don’t in general offer opioid detox, if you like, or withdrawal management in isolation, because it increases the risk of opioid poisoning, overdose death.
I’ve found that confidence and clarity around your approach, and explaining it to the patient all the way along the process, is really critical. Explaining it to family and other carers, including other health professionals is critical to get the patient on a safer evidence-based clinical management pathway.
MIC CAVAZZINI: We haven’t yet asked what chronic pain is, and how it comes to affect some 20 percent of the population. This overview is borrowed from the Ballantyne and Sullivan review I mentioned earlier, and Professors Baliki and Apkarian from the Feinberg School of Medicine in Chicago, writing in the journal, Neuron.
Rene Descartes had the idea that the pain withdrawal reflex was caused by threads and valves and the release of animals spirits. Not a bad go for 1664. Over the 19th and well into the 20th Century anatomy and physiology supported this idea that pain was a hard-wired response to keep us from hurting ourselves. There were specific pain receptors and pain nerves that formed a feedback loop in the spinal cord to cause instant withdrawal of injured limbs. And this pathway continued up to the thalamus where the pain was processed just like any sensory input, and made conscious.
In 1973 opioid receptors were identified in mushed rat brain tissue using radiolabled naloxone, and soon after, endogenous agonists were also discovered—the endorphins, enkephalins and dynorphins. Opioid receptors have since been found in a variety of central and peripheral neurons but in the context of pain relief, the periaqueductal grey matter is a major target. This region then makes descending projections back down the spine that dampen nociceptive input.
This tidy explanation for the powerful effect of therapeutic opioids provided a rationale for their increasing use in the nineties. But the focus on pharmacology drew attention away from other psychological factors that are equally important to the pain experience. Already in 1957, Henry Beecher had noted how a seriously injured soldier could persist in battle without the pain becoming overwhelming and in 1965, Melzack and Wall laid out the ‘gate control theory.’ This suggested that the perception of pain was influenced by attention, past experience and mood.
The periaqueductal grey is a good fit for this proposed gate, as it receives not just nociceptive input, but also projections from the limbic system that encapsulates memory, emotion and the reward pathways we described earlier. As Baliki and Apkarian put it; “Pain perception can reflect moment to moment shifts in value judgments regarding the self… and the relationship between the self and the environment.”
Less resilient than Beecher’s soldier was a builder who presented to emergency with a 15cm nail sticking up out of his boot. The guy was in agony and medics couldn’t touch him until they’d administered fentanyl and medazolam. When they finally got his boot off, they found the nail had passed right between his toes without injury. But his panic and the stark visual feedback had been enough to create an emergent sensation of pain.
Ballantyne and Sullivan say that, “Such calculations depend on constant adjustments between punishment and reward… Both the motivational salience and the motivational valence (positive or negative) of pain are adjusted by the dopamine system.”
In this understanding, the network is not just concerned with immediate injury, but with predicting threats in the environment so that future strategies of avoidance or approach can be planned. This can explain some unexpected overlaps between chronic pain and addiction, or indeed other disorders of maladaptive learning.
Most acute nociception resolves within three months of a tissue injury, but neuroimaging shows that the brain’s representation of pain shifts as the experience becomes chronic. In an fMRI study of people with back pain, brain activity was recorded mainly in sensory areas during the first months of symptom onset. But a year into their chronic back pain, it was the limbic areas that had taken up the torch.
By some perverse logic, the brain has decided that the pain experience and the cues and behaviours associated with it deserve to be reinforced. Baliki and Apkarian go so far as to say that this lowered threshold of pain perception, “functionally renders the brain addicted to pain.”
Another pathology associated with chronic pain is downregulation of endogenous opioid signalling, also seen in fibromyalgia. People with these disorders have a reduced responsiveness to opioid analgesia and also higher than average rates of depression. How could that be?
There’s good evidence that endorphins would normally support social cohesion and that their release is triggered by behaviours like laughter and song. That might explain why singing can help relieve pain, or why ‘laughter is the best medicine.’
Conversely, people carrying a specific mutation of the mu-opioid receptor don’t just experience high levels of surgical pain that’s hard to manage with opioid therapy, but they exhibit stronger neural and behavioural responses to social rejection. People describe getting dumped or fired with the same visceral language as they do physical pain. If you think about it in in an evolutionary context, it would favour your survival to fear being cast out of the safety of the clan and to appreciate the rewards of social connection. Endogenous opioids may well be fundamental to this.
I’ve gone down a bit of a rabbit hole here, but I hope I’ve convinced you why management of chronic pain would benefit from what Dr Chris Hayes likes to call a socio-psycho-biomedical approach. He describes how active self-management therapy emphasises mind-body influence, social connection and safety, physical activity, and nutrition.
CHRIS HAYES: Often the sociological and psychological components are more powerful drivers of the pain experience than what’s happening in the biological. We are specifically targeting our interventions about hypersensitivity in the nervous system, and a lot about the issues of threat and safety. There are aspects of threat in opioid reduction. The more they perceive their condition or their treatments as threatening, the more their nervous system stays in alert, overdrive mode and avoids recovery.
MIC CAVAZZINI: I look at this with a sort of synaptic plasticity lens, because that’s what I studied for my PhD. We’re now comfortable with the idea that post-traumatic stress disorder is the result of maladaptive learning between visual stimuli and emotional responses. So, you are saying that chronic pain is due to misfiring of overzealous emotional pathways and sensory pathways, all sort of triggering perhaps to the wrong cues.
CHRIS HAYES: Yes, that’s right. I mean, the nervous system seems to play a key role in that, and nervous system plasticity, issues of muscle tension, and issues related to triggering episodes. You know, what else was happening at the time the pain came on. Often there are times of life stress around that, and perhaps also this may echo back to earlier life experiences. Certainly, those who have had adversarial childhood experience are more prone to chronic pain.
You know, hence opioids and other sedating drugs being unhelpful, in that they cloud consciousness and blunt a patient’s awareness and perception of what’s happening in their body. It blunts their capacity to analyse what the pain is really telling them. It blunts their capacity to engage with active self-management strategies, and it's likely I think, over time, to prove that even short-term use is quite unhelpful in that setting.
MIC CAVAZZINI: Of my back pain, my physiotherapist says the longer you stay at home nursing your injury, the more your body is afraid of doing anything. So, getting back into physical activity, yes, there will be some discomfort, but then just tuning that down, and your body learning that actually, that minor nociception is not a threat, it’s not a serious threat, and that can be turned down.
CHRIS HAYES: That’s exactly right. You know, the connection word we use quite often. So if we’re isolated, staying home alone, then that tends to make us feel less safe as a human being. If we are interconnected with others in a positive way, that is a measure of safety, and gets our nervous system into something that is a more recovery mode of operation.
Having said that, there can, in some examples, be ongoing nociception coming in from the joints in rheumatoid arthritis, for example. You know, obviously, the immune system is wrapped fairly tightly around the nervous system. That can play a role. Nutritional factors can play a role in setting the immune system on edge, so to speak, which can then in turn put the nervous system on edge. So, we don’t want to be too unimodal in focussing on the nervous system.
MIC CAVAZZINI: So, how do you achieve this in your clinics at the Hunter Integrated Pain Service? How are they structured to tap into all of those elements?
CHRIS HAYES: We are a multidisciplinary team. So we have under the one roof physiotherapists and psychologists, along with doctors and nurses. We use a lot of our treatment in a group setting. So we start with just talking about the neuroscience, talking about the importance of social engagement. And we’re wanting people to accept, to some degree, the pain which they have, and maximise function with that level of pain.
Figures are at least modestly encouraging about what can be achieved if people stick with us. One of the challenge points that we are aware of is that only about 10%, in fact, of patients that are referred to our team will participate in that group process. So this is confessions of our weakness in terms of patient engagement, I suppose, but there are a lot of factors around that.
Alternatively, be would refer back to the GP where people are not wanting to engage with our team and suggest that that intervention could happen in the community as well, so the principle is going broad. But really, this is a systems challenge. So it speaks to community expectations, it speaks to what GPs say to patients before they are referred in.
Any of those five points, mind, body, connection, activity and nutrition can make a difference in pain specifically but there is also the bigger picture about chronic disease management in general, because all of those things can help. And I think this is a big question for us as a health sector at the moment, is how much is the role of the GP in advocating a generic approach, how much is best driven by the specialist sector. This is slow medicine rather than fast medicine. We’re not wanting to preach quick fixes—there is a place for specialist intervention, we just need to be very clear and selective about the use of those specialist interventions.
MIC CAVAZZINI: If the systemic reform we’ve been talking about sounds too much like hard work, bear in mind these parting figures. According to a study by Deloitte, the total financial cost of chronic pain in Australia in health expenditure and loss of productivity amounts to a figure of 73 billion dollars. That’s not far behind the entire federal health budget.
Thanks to Chris Hayes and Adrian Reynolds for their insight. They’ll be back in the next episode where we talk about regulation and monitoring of pharmaceutical opioids and which ones to worry about in particular. Thanks to all the physicians on the editorial group who provided feedback on this episode, and also to Iain Muir for throwing himself into the roles of Hippocrates and Galen.
There is heaps of supporting material at our website, racp.edu.au/podcast. For patients, there are also the Brainman videos that explains the basic principles of chronic pain and the active self-management approach.
Please share this episode of Pomegranate Health with anyone who might find it interesting. You’re welcome to send me your feedback via firstname.lastname@example.org. I’m Mic Cavazzini. Until next time.