Researchers have published in PNAS promising results from a snail venom analogue used in the treatment of pain. This is exciting for a number of reasons, even if the current compounds under study do not pan out.

Pain is a difficult clinical problem. There are limited options for treating chronic pain and we can quickly run out of options if patients cannot tolerate certain classes of drugs. What we really need are entirely new classes of pain medication, and that is what this new approach promises.

There are essentially two neurological components to pain: there is the physical sensation, and then there is the emotional component. It is interesting to ask the question, why does pain hurt? There is nothing about the sensation itself that is inherently painful. Any sensation is just nerve cells firing and carrying signals to areas of the brain that interpret those signals. Pain hurts because pain pathways specifically connect to the emotional centers in the brain to create a negative experience.

For further background, clinically it is helpful to distinguish different types of pain. There is nociceptive pain, which is the nervous system appropriately sensing damage and generating protective painful sensations. There is also neuropathic pain, which is the nervous system malfunctioning and producing inappropriate pain that is not protective. We further divide pain into acute and chronic. Finally, we consider the context of the patient, such as whether or not they are terminal.

Opioids act mainly on central receptors that naturally block the perception of pain. These receptors block not only the pain but the emotional component of the pain. In fact the opposite emotional response can occur, euphoria. That is a strong component of why opioids are addictive. Opioids also suppress the respiratory centers, which is why overdoses are so deadly.

In addition to being addictive, opioids also display tolerance, meaning that they work less well over time. This is because they downregulate the receptors to which they bind, so there are less of them available. In fact this shifts the balance in the brain, so that at baseline chronic opioid users are dysphoric and hypersensitive to pain and they need to use opiates just to feel somewhat normal.  All of this is why chronic opiate use is so problematic in treating chronic pain – it makes the underlying pain worse and harder to treat.

NSAIDS (non-steroidal anti-inflammatory drugs) are another class of pain killers. These are the aspirin-like drugs, and are good first line pain treatments (available over the counter). Their advantage is that they are also anti-inflammatory, which is a common component of acute problems that cause pain. They have a ceiling effect, meaning that there is a maximum dose beyond which there is no further pain relief. Opioids by contrast have no ceiling, so you can always get more pain relief with a higher dose. The limiting factor for opioids is that at some point you will stop breathing.

Acetaminophen is another OTC pain reliever, although not anti-inflammatory. There is also tramodol which is centrally acting but non-opiate. It is less addictive and has less tolerance, but still has some of these negative features.

None of these pain drugs are very useful in chronic neuropathic pain. For that condition we need to use other drugs entirely, including anti-seizure drugs and anti-depressants, that suppress neuropathic pain production or conduction. These are variably effective.

At present there is no perfect pain medication. There is no medication that can entirely relieve pain in a sustainable way without serious side effects limiting their use. Many patients cannot tolerate entire classes of pain drugs. Allergies can eliminate many drugs. If a patient has kidney problems or gastric ulcers they may not tolerate NSAIDS. Opiates are not appropriate for many patients. We can therefore quickly run out of good options.

New Drug Development

The action of drugs are primarily determined by their targets. What receptors do they bind to, what enzymes to they inhibit, what channels do they block, etc.? Drug companies love to find new potential targets because this could mean an entirely new class of drugs with novel properties.

There are basically two types of new drug development – developing better drugs that use existing targets, and developing drugs with new targets. The former is highly useful, finding drugs that have fewer side effects, more bioavailability, less toxicity, more of an effect, or a longer half-life. It is good to have options, and having many drugs in a single class with different properties is very useful. Also, if a patient is allergic to one drug in a class they may not be allergic to others.

When a drug company finds a new drug target that is much more exciting, however, as it opens up new possibilities. Researchers have been looking for new pain targets for years in order to create new pain drug classes. This is what is potentially exciting about this new study.

“In this study, the researchers found that a compound isolated from snail’s venom, Rg1A, acts on a pain pathway distinct from that targeted by opioid drugs. Using rodent models, the scientists showed that a9a10 nicotinic acetylcholine receptors (nAChR) functions as a pain pathway receptor and that RgIA4 is an effective compound to block this receptor. The pathway adds to a small number of nonopioid-based pathways that could be further developed to treat chronic pain.”

RgIA4 was previously know from basic research, but this study takes the research further, testing it in animal models. They first developed 20 analogs to the snail venom that targeted the nAChR receptors. The analog that had the most activity was tested in a rodent model of pain. They significantly blocked pain perception in the rodents, and the effect lasted for up to 72 hours, even though the drug was out of the rodent’s system after four hours.

The nAChR receptor is a pain pathway receptor, meaning that it transmits pain signals. RgIA4 binds to and blocks those receptors, therefore blocking pain transmission. It’s interesting that the effect lasts beyond the presence of the RgIA4. Researchers need to figure out the mechanism of this prolonged effect.

This is exciting, but still a long way off from a drug product with FDA approval. There will be further animal testing, then the full course of human testing. At any step of the way a toxicity or harmful side effect can emerge.

There are two types of unwanted effects of a drug to consider. The first is inherent to the target, meaning, in this case, that the nAChR receptor may have other functions, and blocking these could have unwanted effects. Evolution is messy, and receptors are often coopted for different purposes. It would be convenient if every receptor was unique, had one function, and did not cross-react with other receptors. Then we could target just one receptor which would have just one function. But that is not the situation that evolution created.

This creates inherent limits to the specificity of pharmacology. It remains to be seen if other effects will emerge when we test RgIA4 antagonists in humans.

There are also effects that are not related to the primary target. A drug may have unrelated toxicity. These can sometimes be dealt with by making analogs that still activate the primary target, but lack the incidental toxicity.

Conclusion

Many researcher are working on finding new pain targets and then developing viable pharmaceuticals that work through those targets. As a clinician who treats pain as part of my practice, I anxiously await any such developments. We really need more options for pain treatment.

Most people will experience serious pain at some point in their life, and many people suffer from chronic pain. It’s difficult to overstate how useful new pain treatment options can be.

Any potential new pain target is therefore very exciting. My excitement, however, is tempered by the fact that we are early in the arc of research and development. Most compounds at this early stage do not make it all the way through to FDA approval. A new pain reliever can still be many years away, and may not manifest at all.

There are other potential new pain targets being researched as well. We can’t know how any one compound will work out until we do the research, but it seems likely something will emerge from all the research, so I am mostly hopeful.