For more than a century, scientists have been searching for pain treatments that work well without the risks associated with opioid medicines, such as dependence and overdose. While some newer approaches have been developed – including treatments for migraine and severe pain – many have limitations in terms of how they are given, their side effects, or which types of pain they help with.
A recent review published in the journal PAIN examined current research on nociceptors – the specialised nerve cells that detect and transmit pain signals. The authors, based at the National Institutes of Health in the United States, investigated how understanding the molecular composition of these nerve cells could inform the development of new pain-relief strategies.
The review focused on a particular type of nociceptor that expresses a receptor known as TRPV1. This receptor is of special interest because it is also the target of capsaicin, the compound that gives chilli peppers their heat.
What Is TRPV1 and Why Does It Matter for Pain?
TRPV1 is a receptor found on pain-sensing nerve cells. It helps the body detect heat and inflammation, and it plays an important role in transmitting pain signals.
This receptor is also activated by capsaicin, the chemical that makes chilli peppers feel hot. When capsaicin activates TRPV1, it initially causes a burning sensation. However, this activation may eventually lead to a process called “defunctionalisation,” where the nerve endings become less responsive to pain over time.
According to the review, topical capsaicin patches are already used in clinical settings for certain peripheral neuropathic pain conditions, such as painful diabetic neuropathy. Other capsaicin-based treatments are being evaluated for post-surgical pain.
The review also discussed resiniferatoxin (RTX), a more potent compound derived from a North African plant that acts on the same TRPV1 receptor. Unlike capsaicin, which binds and unbinds repeatedly, RTX appears to bind more durably to TRPV1, which may result in faster and longer-lasting nerve inactivation. RTX is currently being investigated in clinical trials for conditions including cancer-related pain, neuropathic pain, and knee osteoarthritis pain.
Are There Different Types of Pain-Sensing Nerves?
One of the most notable findings highlighted in the review relates to research on human dorsal root ganglion (DRG) neurons – the nerve cells that carry pain signals from the body to the spinal cord.
Recent molecular studies suggest that TRPV1 pain-sensing nerve cells can be divided into at least two broad groups:
- TRPV1+OPRM1+ (“peptidergic”) nociceptors: These nerve cells express both the TRPV1 receptor and the mu-opioid receptor. The authors suggest they may be mainly responsible for sustained pain from tissue damage and inflammation. Because they have opioid receptors, they appear to respond to opioid-based treatments.
- TRPV1+OPRM1− (“nonpeptidergic”) nociceptors: These nerve cells express TRPV1 but do not express the mu-opioid receptor. They appear to respond to harmful stimuli such as heat and mechanical pressure, and may play a role in neuropathic pain. Because they lack opioid receptors, the authors hypothesise that opioid treatments may be less effective for the types of pain these nerves transmit.
If this distinction holds true, it could have important implications for how pain treatments are developed and targeted. The review suggests that pain could potentially be categorised as “opioid-responsive” and “opioid-resistant,” which may enable more precise treatment strategies in the future.
Why Have Some Non-Opioid Pain Treatments Not Worked as Expected?
The review examined why several promising non-opioid approaches have not succeeded in clinical trials, despite encouraging results in animal studies.
Alternative Opioid Agonists
Scientists previously hoped that targeting delta and kappa opioid receptors – rather than the mu-opioid receptor targeted by medicines like morphine – might provide pain relief with fewer side effects. However, the review notes that clinical trials of these agents produced limited results as painkillers.
The authors suggest this may be because delta and kappa opioid receptors are expressed at very low levels in human pain-sensing nerve cells. In other words, there may simply not be enough of these receptors to produce meaningful pain relief.
Interestingly, although kappa-targeting compounds did not appear to work well for pain, some have shown potential for treating itch (pruritus), leading to one such compound receiving regulatory approval for itch associated with kidney dialysis.
TRPA1 Pain Channel
Another receptor called TRPA1 was thought to be a promising target for pain treatment because of its role in detecting injury and inflammation. However, the review explains that TRPA1 is only found in about half of human TRPV1 nociceptors. This partial expression means that blocking TRPA1 alone may not be enough to meaningfully reduce pain.
The review notes that a drug designed to block TRPA1 (LY3526318) performed well in animal studies but did not outperform placebo in human trials for osteoarthritis, chronic low back pain, or diabetic nerve pain.
What New Non-Opioid Targets Are Being Explored?
The review highlighted several new targets that researchers are investigating for non-opioid pain relief, particularly voltage-gated sodium channels called Nav1.8 and Nav1.9. These channels are found specifically on nociceptors and are essential for transmitting pain signals from the body to the spinal cord.
According to the review:
- Nav1.8 appears to be more common in nerve cells linked to tissue-damage pain (nociceptive pain).
- Nav1.9 appears to be more common in nerve cells linked to nerve-injury pain (neuropathic pain).
One Nav1.8 inhibitor, known as suzetrigine, successfully passed two phase 3 clinical trials for acute post-surgical pain and has received regulatory approval in the United States for moderate to severe acute pain in adults. The review describes this as a significant development in non-opioid pain research.
However, the authors note that it remains unclear whether such treatments will be effective for the long-term management of chronic pain, particularly neuropathic pain. They also raise potential safety considerations that require further investigation.
The review suggests that targeting both Nav1.8 and Nav1.9 together – or developing treatments that act on multiple pain-related receptors – could be a more effective strategy, though this remains an area for future research.
What Could This Mean for People Living with Chronic Pain?
For the millions of people worldwide who live with chronic pain, research like this may offer reasons for cautious optimism. While the treatments discussed in this review are at various stages of development, the overall direction of the science suggests that:
- Researchers are making progress in understanding why some types of pain respond to certain treatments and others do not.
- The identification of different nociceptor populations could lead to more personalised approaches to pain management in the future.
- Non-opioid alternatives are a major focus of ongoing research, which may eventually expand the range of options available to patients and their clinicians.
If you are living with chronic pain and would like to explore what treatment options may be available to you, speaking with a specialist clinician can help you understand your choices.
What Are the Limitations of This Research?
When reading about this research, it is important to keep the following limitations in mind:
- This is a narrative review, not a clinical trial. It summarises and interprets existing research rather than generating new experimental data.
- Many of the molecular findings are based on laboratory and animal studies. Results from animal models do not always translate to humans, as the review itself emphasises.
- The proposed distinction between opioid-responsive and opioid-resistant nociceptor populations is a hypothesis. Further research is needed to confirm this in clinical settings.
- Several of the treatments discussed (such as RTX and Nav1.9 inhibitors) are still in early-stage clinical trials. Their safety and efficacy in humans have not yet been fully established.
- The authors note that factors beyond gene expression – such as protein interactions and post-translational modifications – can influence how treatments work in practice.
- The review was conducted by researchers at the National Institutes of Health (USA). Findings may not account for all population or regional differences.
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