… neque porro quisquam est, qui dolorem ipsum, quia dolor sit amet consectetur adipisci velit …
(… nor is there anyone who wants pain itself, because pain is undesirable …)
—Marcus Tullius Cicero, On the Ends of Good and Evil
There are a few distinct classes of painkiller drugs, but all others pale before opioids.
Unlike COX-2 inhibitors, cannabinoids, and NMDA antagonists, opioids provide comprehensive relief almost every time. They are so universally useful for treating pain that morphine-resistant pain is sometimes called “paradoxical pain”. Opium and its derivatives have been at the forefront of analgesia for thousands of years, and for acute pain it isn’t much of an exaggeration to say they are the be-all and end-all. If lesser drugs don’t do the trick, accept no substitutes.
Chronic pain is different. In the short run opioids are excellent, but prolonged use has the twin drawbacks of induced tolerance and respiratory depression. The longer opioids are used, the less the brain responds to them. The more opioids are taken to counteract the reduced efficacy, the greater the risk of death.
Doctors are well aware of this dilemma, and there are a constellation of chronic pain management techniques out there to help slow the decline. In the realm of pharmacology, the best strategy seems to be analgesic adjuvants: drugs like SSRIs or anticonvulsants with a mild painkilling effect that are inadequate on their own, but can supplement hydrocodone just fine.
Unfortunately, this is a problem that escalates. About one in twenty chronic pain cases evolves into an addiction to drugs like heroin or fentanyl. Hundreds of people die of drug overdoses every day. It’s a serious problem, and one that deserves a closer look. Why are opioid drugs so lethal?
Opioid receptors are found in a lot of places. The receptors in the central grey matter of the brain produce an analgesic effect, the receptors in the gastrointestinal tract reduce gut motility, and the receptors in the brainstem cause respiratory depression. All three of those effects are modulated by tolerance – heroin addicts need more heroin to get high than the average person can take without passing out, but they’re also more resistant to constipation and respiratory depression. In a perfect world everything would cancel out, but tolerances are idiosyncratic. Heavy opioid users develop resistance to all three effects, making respiratory depression uncommon in long-term opioid users, but statistics suggest that addicts aren’t always careful about dosage.
We have drugs for respiratory failure, of course. Naloxone, available as a kit at your local pharmacy with no prescription necessary, is a non-selective opioid antagonist. One dose of naloxone will shut off the effects of all other opioids for at least half an hour, and it’s extremely effective at preventing death. The problem with naloxone is that it not only blocks respiratory depression, but also the analgesic effect. Opioid users hate that. It’s better than dying, but even addicts without chronic pain would rather not suffer through withdrawal symptoms. Using naloxone prophylactically is a non-starter.
Other drugs with related modes of action, like naltrexone, have a similar problem. We need to look deeper.
Viable Research Options
Pharmaceutical companies chase after the holy grail of a less addictive analgesic, and every time they claim success, history serves them with yet another defeat. Bayer marketed heroin as a less addictive substitute for morphine; almost a century later, Purdue Pharma marketed their formulation of oxycodone as a less addictive alternative to the scores of opioids that came before it. If the physicians who read these claims seem a little too credulous, well, there are a lot of people with cancer and poorly-healed injuries. Opioids won’t make the pain go away forever, but after a few years they’ll still help you get out of bed in the morning.
A better narcotic would act as a safe analgesic, not a less addictive one. Any good analgesic is going to be addictive – drugs are habit-forming because they feel good, and the pain relief certainly doesn’t hurt – and it seems unlikely that opioids with good analgesic action but no effect on the respiratory system will be developed any time soon. There are multiple classes of opioid receptors, and there are a variety of drugs that target subsets of those receptors, but it seems like the same types of opioid receptors are involved with analgesia and respiratory control, which would make selectively targeting only one region of the brain extremely difficult.
I propose adding analeptic drugs directly to prescription painkillers to stimulate breathing in overdose victims while they’re unconscious. Intravenous doxapram is known to be effective for counteracting respiratory depression, mostly for post-anaesthesia cases but also sometimes in opioid overdoses where naloxone isn’t an option, but there’s a surprising lack of research on whether compounding it directly into opioids is a good idea.
It is almost certainly not a good idea, for the record. Doxapram specifically is way too cute to work, although the mental image of codeine coming packaged with a strong CNS stimulant is entertaining. Doxapram works by tricking the carotid body (a biological blood gas sensor) into reporting higher blood CO2 concentration to the brain, which then responds by breathing harder, so among other problems this method stops working if the overdose is lethal. Caffeine and other methylxanthine analeptics have the same problem.
Other drugs look promising but are still in the early stages of research. GAL-021, another drug that acts on the carotid body, seems to be the closest to reaching clinical trials. Two other research drugs, an ampakine called CX-717 and a 5-HT4 agonist called BIMU8, work by directly stimulating the respiratory center. None of this research is very far along, and it’s mostly conducted with the hope of creating new analeptics for emergency use on people who aren’t responsive to naloxone, but there’s no reason in principle one of these drugs couldn’t be added as an adjuvant directly to fentanyl.
Even a hypothetical combination drug that completely negated the respiratory depression effect still wouldn’t be perfectly safe. The other cause of death in opioid overdose, aspirating vomit while unconscious and suffocating, would still be an issue. But, given the amount of money poured into analgesic research every year with very little to show for it, this seems like an inexpensive and potentially very worthwhile avenue to explore.