The 2016 World Congress on Pain, meeting in Yokohama in late September, held a packed Special Session on Opioids. The theme was their role in pain medicine. This might seem fairly settled since the analgesic properties of opium have been known for at least 3,000 years. Not so!
The scene was set by eminent US pain specialist Jane Ballantyne, president of Physicians for Responsible Opioid Prescribing and adviser to the US Centers for Disease Control and Prevention (CDC). She described how over the last 25 years sales of prescription opioids have soared, as have emergency admissions and deaths.
In the US, some one in five patients with chronic non-cancer pain (CNCP) are prescribed opioids; since 1999, sales of prescription opioids have quadrupled; between 1999 and 2014, over 165,000 people died from overdose related to prescription opioids; more than 14,000 died this way in 2014, at least half of all opioid overdose deaths; nearly two million Americans abused or were dependent on prescription opioids in 2014, a quarter of those taking prescription opioids; over 1,000 people are treated in emergency departments for misusing prescription opioids every day. Eighty per cent of opioid prescriptions world wide are in the US, with just 5% of the population.
This is not because Americans are suffering more pain: it is the product of drug companies “educating” physicians and patients, together with a production line model of health care. How has it come to this and will the problem spread? Drug companies would no doubt like to increase their opioid sales. This is a gigantic problem without an obvious solution.
The new CDC Guidelines on Prescription Opioids may prevent the worsening of the situation but rolling back such a tide of addiction to legal drugs will not be easy. Poppy The opium poppy, Papaver somniferum, has been known at least since Neolithic times (perhaps even by Neanderthal people) and was widely cultivated and used in ancient Egypt, Sumer, Greece and so on. Morphine was isolated from opium in the 19th century and this allowed safer dosing, since the amount being dispensed could be accurately measured. Later, derivatives of morphine or compounds with similar actions, such as heroin, methadone, pethidine, oxycodone, hydrocodone and fentanyl, were developed.
These, the opioids, are mainly used for anaesthesia in operations (pethidine, fentanyl), for pain relief during childbirth (pethidine), and post-operative pain (often morphine). Morphine is supplied to US and British soldiers for use if injured on the field of battle. Opioids were also used as a cough suppressant (e.g. Codeine Linctus) and to treat diarrhoea (e.g. Collis Browne’s or Kaolin & Morphine).
Since the opioids efficiently suppress the acute pain of injury or operation, a wholly desirable outcome, one might wonder why they are so tightly controlled or even banned around the world. One reason is that the therapeutic dose is fairly close to the toxic dose: they suppress the breathing reflex and an overdose stops the victim breathing. As Paracelsus said, “The dose makes the poison,” and for heroin the Therapeutic Index (TI: the ratio of the toxic dose to the effective dose) is 25:1.
This is a problem for recreational heroin users who don’t know the purity of the drug they are taking. Another reason is that, if the patient takes opioids over a long period, they develop a tolerance to the drugs: the amount needed to achieve the desired effect slowly increases and can reach levels that would be instantly fatal to a new patient. The main reason for controlling or banning opioids is that they are very addictive.
This is less of a problem for those taking them, as they should, for short periods to deal with acute pain or to deal with pain associated with some terminal cancers. But, for those taking them for chronic pain or to experience the euphoric effect found with larger non-therapeutic doses, dependence or addiction can result, as well as side effects such as constipation, breathing problems in sleep, heart problems, suppressed immune systems, more bone fractures (perhaps because of dizziness and slower reactions), and disruption of hormone systems (including sex hormones).
There is also paradoxically, increased sensitivity to pain in a significant proportion of chronic opioid users.
For most of the three or more millennia that opium has been known, it has been legal in most of the world, if rather frowned upon when used recreationally. Indeed, the British authorities allowed opium sale in India and imposed it by force in China in the Opium Wars. Sales of laudanum (tincture of opium and alcohol) in Britain were legal though regulated from 1868. Gradually, particularly in the first half of the 20th century, opium and its derivatives became illegal unless prescribed by a doctor.
Following the International Opium Convention in 1912, drug control was incorporated into the Treaty of Versailles in 1919, and the League of Nations signatories agreed to prohibit trade in narcotics except for medical uses. Laws have become stricter and the “war on drugs” has escalated so that many countries now impose stiff penalties, up to execution, for possession and sale of opioids.
Except in terms of job creation, this war has not succeeded. Like other wars, this one has caused collateral damage with the legitimate medical use of opiates, especially in palliative care of cancer patients, being restricted unnecessarily. The WCP Special Session on Opioids heard from an Indian pain specialist that in half of the world opioids were not available to alleviate unbearable suffering. In her own country, opioids were theoretically available but legal restrictions made doctors afraid to prescribe them for fear of falling foul of the criminal law. It was in the USA, however, that the situation was the most bizarre.
Alongside serious jail terms for mere possession of opioids, the drug companies had successfully argued from about 1980 that opioid prescriptions should be allowed for patients with chronic (long-term) non-cancer pain. It was argued that this would not result in dependence problems since only a small percentage of patients had hitherto become addicted to prescription opioids. This went against medical advice that they be used only for acute pain or for cancer pain, especially in those with a terminal diagnosis.
The epidemic started in 1995 when the US Food and Drug Administration (FDA) approved the opioid painkiller OxyContin (oxycodone). Its manufacturer, Purdue Pharma, sold $45 million’s worth of OxyContin in 1996, $1.1 billion in 2000, $3.1 billion in 2010, some 30% of the painkiller market. It achieved this by aggressive advertising and targeting doctors already prescribing a lot of painkillers.
The result has been a large number of people addicted to OxyContin and as many deaths as occur with illegal use of opioids. The opioid-paracetamol mixture Vicodin (containing hydrocodone) is involved in opioid dependence but also in deaths from paracetamol overdose. This is at present almost entirely a US problem, with 80% of the world’s opioid consumption, legal and illegal, taking place in the USA.
Most of the users are poor whites in areas like the Appalachians: hence its nickname “hillbilly heroin.” The historic pattern of under-treatment of pain in Afro-Americans due to racist assumptions has ironically largely spared them from the opioid epidemic. A related problem is deaths from heroin overdose, which have nearly tripled in 12 years, exceeding 10,500 in 2014. The number of addicts has doubled in that time, with the vast majority of new users being people who had previously misused prescription opioids. What to do?
In a “shutting the stable door” move, the CDC have issued a new guideline for prescribing opioids for chronic pain, emphasising non-opioid treatments, low dosages, and following up patients to check that opioids are having the desired effect or to help them taper off the drugs. This sounds a very labour-intensive policy and one wonders how this would work in the US health system. Other private health systems will be prone to the problems of prescription opioids, but so too many public health systems: already it is reported that prescription opioid use has increased four-fold in 10 years in Australia while Canada, Germany, Austria, Switzerland, Belgium, Netherlands and Denmark are starting to catch up the USA.
Other European countries and New Zealand also seem to be increasing prescription opioid use. With USA, these countries account for 96% of prescription opioid use world-wide with just 15% of the population. We should remember, however, that this is also a problem for the 85% who may need access to prescription opioids but can’t get them.
How opioids work
Endogenous opioids (e.g. endorphin and enkephalin) have been found in all animals where they have been looked for, such as the very simple flatworms, as well as nematode worms, annelids, molluscs, crustaceans and insects, and all vertebrates.
One major purpose may be to suppress pain etc. when priority is escape but endogenous opiates are involved in many other systems, such as the gut, and in social behaviours and in reward systems in the brain. They work by binding to opioid receptors,* of which there are at least four types, found in different tissues and causing different effects. Morphine (and to a lesser extent codeine) is produced by the opium poppy as part of its defence mechanism against damage. Entirely fortuitously, morphine binds strongly to opioid receptors and activates them, resulting in relief of pain, euphoria (in the reward systems), inhibition of gut movement (resulting in constipation), suppression of the cough reflex, and depression of the breathing reflex (risking cessation of breathing). Codeine has no effect but is broken down by liver enzymes to produce morphine and other metabolites.
People lacking these enzymes get no benefit from codeine. Repeated use of morphine, or its derivatives such as heroin, reduces the body’s natural production of endogenous opioids, encouraging increased doses and resulting in withdrawal (abstinence) syndrome, an exaggeration of the opposite effects to those caused by morphine.
This makes the original problem worse, which is why opioids should only be used for short periods. Interestingly, there are some compounds, such as naloxone, which bind to opioid receptors even more strongly than morphine but do not activate them. These are opioid antagonists and can be used to reverse opioid poisoning since they rapidly displace opioids from the receptors and deactivate them. Some opioids do not activate all receptor types.
These partial agonists, such as Tramadol and buprenorphine, have been suggested as safer alternatives, with the latter being used to treat opioid dependence. When I was on a placement with Reckitt’s in the late 1970s, we were told that healthy volunteers taking buprenorphine for long periods had withdrawal symptoms when the drug was stopped but that they preferred these to the side effects from taking the drug.** Nevertheless, buprenorphine is abused by some people, as is Tramadol.
*Hans Kosterlitz developed the first bioassay for the opioids (allegedly after a dream!). This consisted of a length of guinea-pig intestine whose electrically-stimulated contractions were inhibited by certain concentrations of morphine. Other potential opioids could be checked against this to assess their potency. Kosterlitz and his colleagues predicted the existence of a naturally-occurring opioid in mammals and this was confirmed when some mashed-up pig brain was added to the saline solution bathing the intestine and its contractions were duly inhibited.
Kosterlitz was a refugee from Nazi Germany who settled in Aberdeen; his son Michael, now based in USA, has just jointly won the 2016 Nobel Prize in Physics: both are marvellous advertisements for the benefits of migration. Michael has said that he is considering renouncing British citizenship if Brexit goes ahead.
**We were also told by a senior scientist that there were no serious health effects from long-term use of (prescription) opioids, apart from addiction. We now know that there are health effects and that long-term use of opioids does not solve the problem for which they are prescribed. It is still better to legally supply addicts than to criminalise them, but the task of weaning them from their drugs is going to be a difficult one.