Is opioid-induced hyperalgesia the hidden cause of the opioid epidemic?

The opioid epidemic in the United States has been making front-page news for a while. It consists of a dramatic increase in deaths caused by opioid overdoses starting in 2011. In 2015, annual deaths by opioid overdoses surpassed deaths from guns and traffic accidents. Drug overdose is now the main cause of deaths of Americans under 50. The number of deaths caused by opioids keeps increasing steadily, from 4,000 in 1999 to 16,000 in 2010 to 62,000 in 2016. Contrary to the usual racial stereotypes about drug abuse, the opioid epidemic affects all segments of the population without much difference according to race and gender. If anything, it seems to affect more working-class whites, particularly those living in rural areas. Interestingly, a study across the 50 states found that the opioid epidemic was significantly lower in states that had legalized marijuana.

The opioid epidemic is not caused by a sudden increase in the number of people that want to get high on heroin and other illegal opioids. There is a growing consensus that it originated in the over-prescription of opioid pain relievers in the 90s. In turn, this seems to stem from a growing awareness of the impact of chronic pain on the general population and a simultaneous push from pharmaceutical companies to increase the sale of new opioids. Drugs like OxyContin (oxycodone) were presented as “mild”, non-addictive opioids, but led to abuse. Apparently, many patients that got it prescribed by their doctors could not get off it. When the doctor finally refused to write more prescriptions the patients looked for the drug in the street, only to find that heroin was cheaper and had more pleasant effects. Unfortunately, drug dealers started to cut heroin with fentanyl, a synthetic opioid that is 50 to 100 times more potent than morphine and has a very fast action. Fentanyl is deadly: there is no time for the user to realize that he has overdosed, he goes quickly into respiratory arrest and dies.

The sad part of the story is that neuroscientists who work on chronic pain have known that something like this could happen for many years. They did their work, published their research… but it had little effect. Doctors were not paying attention. Neither did the pharmaceutical companies that were pushing the new deadly opioids. What did these scientists find that was so important? They found that if you give an opioid to an animal it reduces pain in the short term, as it is supposed to do, but in the long term it increases the pain. Even worse, if you combine the opioid with an injury that induces chronic pain, the pain-increasing effects of the opioid and the injury synergize with each other, producing even more pain. That increase in pain lasts for a long time. In fact, in rats and mice, it seems that it never goes away!

This increase in pain produced by opioid drugs was called opioid-induced hyperalgesia [3,6,9,11,12,14]. The basic finding is illustrated in the figure, which is from a paper published in 2007 by the group of Guy Simonnet from Bordeaux, France [10]. It was part of a series of papers on opioid-induced hyperalgesia published by this group [4,7,8,13]. The figure is actually easier to understand than it looks at first sight. The experiment was done in rats by measuring their responses to a mildly painful stimulus. The dotted line represents normal responses, points above it represent a decrease in pain (analgesia), and those below the line an increase in pain (hyperalgesia). The X-axis represents time in a variable scale of hours and days (D1, D4, etc. mean days 1, 4, etc. after the treatment). Panel ‘a’ just shows the effect of stress, which in normal rats is mildly analgesic. The stress was induced by putting the rats in a new cage under a strong light. Panel ‘b’ shows the effect of fentanyl, the powerful opioid I mentioned above. Fentanyl initially produced strong analgesia, but after 4–6 hours its effect falls precipitously and turns into hyperalgesia. But note the change in the time scale, that pain-inducing effect of fentanyl lasts a week! Also, note how fentanyl changes the effect of stress from analgesia to hyperalgesia. Panel ‘c’ shows the effect of an inflammatory compound, carrageenan (‘Car’), which when injected in the paw of the rat produces hyperalgesia lasting about a week. Finally, panel ‘d’ shows what happens when you combine fentanyl with carrageenan: the hyperalgesia is stronger and now last for almost 12 days. Also, stress induces more pain and for a longer period of time.

So, what does this means? Imagine a patient with a work injury or who has undergone surgery. This is equivalent to the injection of carrageenan to the rat: they both induce chronic pain. If you give that patient an opioid drug, you put him in a situation like that in panel ‘d’: the opioid relieves pain in the short term but increases chronic pain for the following week. That means that the patient will take more of the opioid to relieve the extra pain. However, every additional dose of opioid increases the underlying chronic pain. Not only that, there is another phenomenon called tolerance that makes the analgesic effect of opioids decrease when taken repeatedly. Unfortunately, there is not tolerance to opioid-induced hyperalgesia. So, after a few months, the supposed painkillers have made the chronic pain worse and the patient has to take more to stay pain-free. The doctor gets alarmed by this increased consumption, thinks the patient is turning into an addict and stops writing prescriptions. The patient goes looking for drugs in the street.

The mechanisms of opioid-induced hyperalgesia remain quite mysterious, but we are making quick progress in unraveling them. Opioid drugs produce most of their effects by binding to a receptor (a protein that sends signals inside the neurons) called the mu-opioid receptor. There are three other opioid receptors -the delta, kappa and nociceptin/orphanin receptors- but the analgesic, euphoric and hyperalgesic effects of opioids are mediated in large part by the mu opioid receptor. Opioid-induced hyperalgesia is caused because the mu opioid receptor has a bipolar behavior, like Dr. Jekyll and Mr. Hyde. If you give it just a little bit of drug it is the benign Dr. Jekyll, who takes away your pain. But give it too much drug, or too often, and it turns into the evil Mr. Hyde, who will cause you pain for a long time [1,2]. In terms of molecular mechanisms, the normal action of the mu opioid receptor is to block the calcium channels in the synapses that trigger neurotransmitter release. It also inhibits an enzyme called adenylyl cyclase that produces cyclic AMP (cAMP), a molecule that sends stimulatory signals inside the neuron. When these things happen in the synapses that pain-transmitting nerves make in the spinal cord, pain gets inhibited. However, when you give the mu opioid receptor too much drug, it turns into Mr. Hyde and instead of inhibiting adenylyl cyclase it stimulates it, causing it to produce large amounts of cAMP [5]. This changes the behavior of the pain-transmitting neurons for the long term, leading to hyperalgesia.

In view of all this, you may be asking yourself why do we keep giving opioids to people with chronic pain? The short answer is that we don’t have anything to replace them. Opioids are by far the strongest analgesics, so when a person comes to a doctor in excruciating pain, what is the doctor supposed to do? But, as the current epidemic of opioid death is showing, we cannot continue to ignore opioid-induced hyperalgesia.

References

1. Araldi, D, L F Ferrari, J D Levine. Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain. J Neurosci 35: 12502–12517 (2015)
2. Araldi, D, L F Ferrari, J D Levine. Hyperalgesic Priming (Type II) Induced by Repeated Opioid Exposure: Maintenance Mechanisms. Pain (2017)
3. Bannister, K. Opioid-induced hyperalgesia: where are we now? Current opinion in supportive and palliative care 9: 116–121 (2015)
4. Celerier, E, C Rivat, Y Jun, J P Laulin, A Larcher, P Reynier, G Simonnet. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology 92: 465–472 (2000)
5. Corder, G, S Doolen, R R Donahue, M K Winter, B L Jutras, Y He, X Hu, J S Wieskopf, J S Mogil, D R Storm, Z J Wang, K E McCarson, B K Taylor. Constitutive μ-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science 341: 1394–1399 (2013)
6. Fletcher, D, V Martinez. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth 112: 991–1004 (2014)
7. Laboureyras, E, F Aubrun, M Monsaingeon, J B Corcuff, J P Laulin, G Simonnet. Exogenous and endogenous opioid-induced pain hypersensitivity in different rat strains. Pain Res Manag 19: 191–197 (2014)
8. Le Roy, C, E Laboureyras, S Gavello-Baudy, J Chateauraynaud, J P Laulin, G Simonnet. Endogenous opioids released during non-nociceptive environmental stress induce latent pain sensitization via a NMDA-dependent process. Journal of Pain 12: 1069–1079 (2011)
9. Ramasubbu, C, A Gupta. Pharmacological treatment of opioid-induced hyperalgesia: a review of the evidence. J Pain Palliat Care Pharmacother 25: 219–230 (2011)
10. Rivat, C, E Laboureyras, J P Laulin, C Le Roy, P Richebe, G Simonnet. Non-nociceptive environmental stress induces hyperalgesia, not analgesia, in pain and opioid-experienced rats. Neuropsychopharmacology 32: 2217–2228 (2007)
11. Rivosecchi, R M, M J Rice, P L Smithburger, M S Buckley, J C Coons, S L Kane-Gill. An evidence based systematic review of remifentanil associated opioid-induced hyperalgesia. Expert Opin Drug Saf 13: 587–603 (2014)
12. Roeckel, L A, G M Le Coz, C Gaveriaux-Ruff, F Simonin. Opioid-induced hyperalgesia: Cellular and molecular mechanisms. Neuroscience 338: 160–182 (2016)
13. Simonnet, G, C Rivat. Opioid-induced hyperalgesia: abnormal or normal pain? Neuroreport 14: 1–7 (2003)
14. Yi, P, P Pryzbylkowski. Opioid Induced Hyperalgesia. Pain Med 16 Suppl 1: S32–36 (2015)

UCLA professor. Neuroscientist doing research on pain. Writes about science, philosophy, politics and kinky sex. https://sexsciencespirit.blogspot.com/

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