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  • Michele Curatolo

What have we achieved after 50 years of pain research?


Fifty years after the foundation of the International Association for the Study of Pain (IASP), the official journal of the society has published an overview of the achievement of pain research in the last 5 decades. Here I explain in simple language some of the advances that are discussed in the journal.

Opioids can be administered at the spine

Opioids were thought to work only in the brain. The discovery of opioid receptors in the spinal cord has prompted extensive research to determine whether administering opioids close to the spinal cord would produce pain relief without the side effects caused by their action on the brain. This research resulted in the routine use of spinal opioids, administered though catheters or injections, to treat severe pain after surgery. Spinal opioids are also used to treat cancer pain that does not respond to conventional therapies and, more restrictively and with important limitations, in chronic non-malignant pain.

After major surgery, patients recover faster and have less complications

Pain treatment has been embedded in multimodal programs that includes physical therapy, early mobilization, and early nutrition, among others. In the context of multimodal postoperative programs, improvement in pain treatment has been crucial in facilitating recovery after surgery, reducing complications, such as respiratory failure or cardiac events, and shortening hospital stay ("fast-track surgery").

Pain signals are augmented or reduced in the spinal cord and brain

For instance, when an arthritic knee joint sends painful signals to the central nervous system, that signal can be amplified or reduced by processes that occur in the spinal cord and the brain. Many studies in animals and humans, including brain imaging studies, have substantially contributed to our knowledge of pain processes in the central nervous system. Considering the example of knee pain, the amount and type of pain that we perceive is not only the result of what is happening in the joint. In certain cases, the changes that happen in the central nervous system play the major role: small injuries can cause substantial pain, and severe injury modest pain, depending on how spinal cord and brain elaborate the signal. Read more in this blog.

This notion has been essential to explain the ability of different treatments to reduce pain. Examples are anti-depressants, anti-convulsants, non-pharmacological treatments such as mindfulness or psychological treatments, and invasive treatments such as spinal cord stimulation. All these treatments act mainly by enhancing the ability of the central nervous system to reduce pain transmission.

We have a new medication class for migraine

This is because of the discovery and targeting of CGRP, a receptor that is involved in migraine. Antibodies against CGRP and medications that block that receptor have been developed, resulting in improved quality of life for many patients with migraine. This has been a successful translation of findings from animal studies to applications in humans.

However, many other attempts to develop therapeutics for humans after discovery in animals have been disappointing, in part because of differences in pain processes between species.

We now have better ways to study painful tissues of patients

The molecular profile of tissues and neurons that are involved in pain transmission can be studied in human tissues recovered from surgery using RNA-sequencing. Read here about our project using this method. Furthermore, the human cells that convey pain signals (nociceptors) can be created in a lab from accessible samples. For instance, cells derived from a blood draw of a patient can be transformed into nociceptors and studied in the lab (induced pluripotent stem cells - iPSC).

These methods are too new to produce results that can be already implemented to patients, but will hopefully allow the development of a new generation of effective therapeutics that target specifically human pain pathways. The target discovery on human tissues will be crucial to reduce the disappointing gap between the large amount of discoveries, mostly obtained from animal studies, and the availability of effective pain treatments (read more here).

Interventional treatments have emerged

Neuromodulation consists in placing electrodes close to nerves and delivering electrical stimuli to reduce the pain. Spinal cord stimulation has an increasing literature support. Although not mentioned by the paper that I am reviewing, nerve ablations have gained scientific support, particularly for the treatment of neck, low back, and knee osteoarthritis pain.

Psychological treatments are standard of care

Extensive research has provided methods to assess psychosocial function and treatments that have be proven to improve patients' quality of life. Improvement of psychosocial function is now a crucial component of multidisciplinary management of pain.

Access to such a specialized care has been a main barrier, as the high number of patients that may benefit is not matched by a corresponding number of health professionals specialized in delivering these treatments. However, more accessible treatments modalities, such as internet-delivered cognitive-behavioral therapy, have been validated and are becoming available to clinical care.

Molecular mechanisms of pain generation have been identified, resulting in Nobel Prize awards

Two discoveries that resulted in Nobel Prize in 2021 have allowed us to understand how stimuli applied to tissues trigger the impulses that ultimately result in a pain sensation. These discoveries pertain to the Piezo channels and TRPV receptors. The latter is the site of action of capsaicin, the constituent of red chili pepper, which is used in patients with neuropathic pain (read more here).

My main takes are:

  • We know much more than 50 years ago

  • We do not know enough

  • We can offer more treatments than 50 years ago

  • Nevertheless, modest progress in terms of benefits for patients has been made

Is that all? Pretty much ...

There have been other achievements that are not discussed in the article, but even if we would discuss more of them, the overall picture of the research achievements remains upsetting. This is reflected by the fact that pain remains a public health problem and the major determinant of disability.

There are many possible reasons why our ability to relieve pain is still very limited. One point I would like to mention is the very limited allocation of funds to pain research. Despite the enormous social and medical importance of pain, research resources allocated to this field pale when compared to other areas of medicine, such as cancer or cardiovascular diseases.

We may however witness a change. Prompted by the opioid crisis, the need to address pain by research has been addressed by the NIH with the HEAL Initiative. Extensive pain research is now funded and hopefully will bring tangible benefits for patients.

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