-PainCare-

Pogatzki-Zahn, Esther M et al. “Developing consensus on core outcome domains for assessing effectiveness in perioperative pain management: results of the PROMPT/IMI-PainCare Delphi Meeting” Pain vol. 162,11 (2021): 2717-2736. https://doi.org/10.1097/j.pain.0000000000002254
 
Many patients experience severe pain after surgery, and sometimes this pain even becomes chronic. If pain is not treated well immediately after surgery, patients suffer, their recovery from the operation can be impaired and they often need strong painkillers, like for example opioids. This is what makes pain management after surgery so important.

To implement better pain treatments, we need to improve our understanding of what makes a treatment successful.  Currently, how we measure the success of treatments for pain varies significantly. Is a treatment considered successful if it changes the intensity of pain, pain interference, has low harms, or anything else? Until there is agreement on the most important things to measure, it is very difficult to say if a pain treatment is successful.
 
The aim of this study was to identify the treatment goals of pain management after surgery and to find out how to best assess these goals. An invited panel of international health-care representatives and experts in their field (like surgeons, anaesthesiologists, pain specialists, nurses, physiotherapists, psychologists etc) as well as patient representatives discussed these questions. .  All members of the panel met face-to-face and were engaged in group discussions and brainstorming. Important was that the visions of all participants were expressed, discussed and taken into consideration. At the end, all participants voted on a final list of those aspects (“domains”) important for assessing the success of treatments for pain after surgery. 
 
The panel voted on the final list of domains to be measured. The panel decided that five aspects should be addressed: 1. Physical function/ability, 2. Level of pain at rest, 3. Level of pain during activity, 4. Harms of treatment, and 5. Patient confidence (“self-efficacy”) in managing their pain after surgery. The last, and somehow unexpected aspect, was brought up by nurses and patients and points to a new direction in acute pain assessment. The next step will be to identify the best suited measures relevant for assessing these pain-related domains after surgery.

Sachau, Juliane et al. “Patient Reported Outcome Measures in Chronic Neuropathic Pain Clinical Trials - A Systematic Literature Review” The Journal of Pain vol. 24,1 (2023): 38-54. https://doi.org/10.1016/j.jpain.2022.09.003

For a nerve pain drug to be considered helpful, it needs to have an effect on domains seen as important by the patient living with the pain condition. These are called patient reported outcome measures. One is pain severity. Others include physical functioning (e.g. movement), emotional functioning (e.g. mood), side effects of the treatment, and patient satisfaction. These various domains should be measured in all clinical trials – where scientists are investigating the effect of a drug on a patient with nerve pain. We reviewed all nerve pain clinical trials which examined the effect of a drug on long term nerve pain to see what domains they measure, and how they compare across trials. While there has been an improvement in the number of high-quality trials measuring a range of these measures since 2011, there is still large variation between trials, and major room for improvement. Ensuring future clinical trials consistently measure a range of patient reported measures is crucial to better understanding the effect of drugs on patients living with nerve pain.

Gierthmühlen, Janne et al. “Association of sensory phenotype with quality of life, functionality, and emotional well-being in patients suffering from neuropathic pain” Pain vol. 163,7 (2022): 1378-1387. https://doi.org/10.1097/j.pain.0000000000002501

Patients with neuropathic pain - pain, numbness, tingling, swelling, or muscle weakness caused due to nerve injury or disorder – present in a different ways with a range of characteristics. Patients often present in 3 different ways:

1. Sense loss (e.g. numbness, muscle weakness),
2. Increased sensitivity to physical things (e.g exaggerated pain in response to movement or pin-prick), or
3. Increased sensitivity to temperature (e.g. exaggerated pain in response to heat and/or cold).

These three characteristics may indicate different underlying causes, that may benefit from individualised treatments. In this study of 433 patients with various neuropathic pain conditions, we examined differences in mental health, physical function, and quality of life between patients with one of the three pain characteristics mentioned above. The study found no differences in disability, pain intensity, depression, anxiety between patients categorized into one of the three pain characteristics. Patients with the sense loss had higher pain interference, lower quality of life, and more problems with movement, activities of daily living and self-care compared to patients with increased sensitivity to temperature. Patients with sense loss had a higher tendency to ruminate and think negatively about their pain condition compared to patients with increased sensitivity to physical things and temperature.

In summary, certain pain characteristics – in this case sensory loss (e.g numbness) – have a large effect on patient suffering compared to other neuropathic pain presentations. Patients with sensory loss may benefit from more individualised tailored treatment to help their condition.

Harkouk, Hakim et al. “Paravertebral block for the prevention of chronic postsurgical pain after breast cancer surgery” Regional anesthesia and pain medicine vol. 46,3 (2021): 251-257. https://doi.org/10.1136/rapm-2020-102040

Patients who undergo breast cancer surgery often report long lasting pain after their surgery. A paravertebral block (an injection of pain medicine in between the spinal bones where the spinal nerve come out) may prevent this pain, but we are uncertain about the evidence. In this study, we compiled and reviewed all the available trials that have examined the effect of a paravertebral block on preventing long lasting pain after breast cancer surgery. This is important to do as it informs us if this treatment is helpful or not. Twelve trials were compiled, and their methods and results were reviewed. Based on these trials, a paravertebral injection does not seem to prevent long term pain after breast cancer surgery. Larger and higher quality studies are required to reach more definitive conclusions.

Quesada, Charles et al. “Human surrogate models of central sensitization: A critical review and practical guide” European journal of pain (London, England) vol. 25,7 (2021): 1389-1428. https://doi.org/10.1002/ejp.1768

Current medicines for chronic pain are not very effective. Neuropathic pain – pain relating to diseases of the warning system of the body (“nociceptive system”)– is particularly difficult to manage. Neuropathic pain often involves increased sensitivity to stimulation of the skin: increased pain to stimuli that should be just barely painful (hyperalgesia) and pain in response to stimuli that are normally not painful (allodynia). Animal experiments have shown that this increased sensitivity is often due to signal amplification in the central nervous system (spinal cord and brain) that is called “central sensitization”. But findings from animal experiments are difficult to translate to humans. Mimicking increased sensitivity of the central nervous system (hyperalgesia and allodynia) in humans, through experiments on healthy volunteers, may aid our understanding of this pain and help to identify new targets for medicines.
 
The aim of this study was to gather and review all currently available research studies that have attempted to induce increased sensitivity of the central nervous system in humans, through a real or simulated tissue injury. Success rate, accuracy, feasibility of the methods used, as well as drug response, were analysed.
 
Analysis of 269 studies involving 15 different methods of inducing central sensitization revealed that four methods were reliable in inducing hyperalgesia: application or injection of capsaicin (chemical compound from chilli peppers), heat injury, repetitive electrical stimulation, and ultraviolet B rays (sunburn). As a limitation, these methods were poor at inducing allodynia. The capsaicin, heat injury and electrical stimulation models consistently responded to medicines that are effective for neuropathic pain management and not to medicines that are clinically ineffective. Thus, these models reflect some aspects of neuropathic pain in healthy volunteers; the methods used are easy to use in the clinic and may inform the development of better treatments for chronic pain.

Di Lionardo, A et al. “Modulation of the N13 component of the somatosensory evoked potentials in an experimental model of central sensitization in humans” Scientific reports vol. 11,1 20838. 21 Oct. 2021, https://doi.org/10.1038/s41598-021-00313-7

Increased pain sensitivity (hyperalgesia) occurs for a short period of time at and around minor and major acute injuries (e.g. cuts, burns). It is also an important feature of many chronic pain conditions. After a tissue injury, various chemicals in the body (e.g. ones responsible for inflammation) produce increased sensitivity in neurons around the area of the injury. This is seen as an important survival mechanism as it can help prevent us from doing more injury. This protective response produces an increase in the amount of inputs (e.g. messages about threat/danger) sent to the spinal cord. This increase in inputs can lead to the production of increased sensitivity in uninjured areas, which if maintained can contribute to long term pain states - long after the initial injury has healed. This happens in central nervous system sensitization which is defined as an increase in the excitability or responsiveness of neurons. How to reliably identify and measure central sensitization in patients is still an matter of uncertainty, and is critical to research for scientists to better target this state in patients.We studied a small electrical signal that is believed to be generated by nerve cells in the spinal cord; many stimulus repetitions need to be recorded and averaged to visualize this signal that is called “N13” (negativity 13 ms after electrical stimulation of the ulnar nerve). The N13 component of somatosensory evoked potentials (N13 SEP) is recorded in front–back direction from the lower neck (Cv6) after upper limb stimulation is mediated by non-nociceptive Aβ fibres. This component , generated at the cervical dorsal horn, probably reflects the segmental postsynaptic response of dorsal horn neurons in the lower cervical grey matter, and might therefore constitute a neurophysiological measure sensitive to the excitability changes of dorsal horn neurons during central sensitization.

Different experimental pain models have been devised to produce central sensitization in humans, among them topical application of capsaicin that leads to intensive activation of C and Aδ nociceptive nerve fibres, producing burning pain.

In this neurophysiological study in healthy humans, it has been investigated if and how capsaicin-induced central sensitization modulates the dorsal horn N13 SEPs and whether pregabalin, a first-line treatment for neuropathic pain targeting voltage-gated calcium channels expressed in the dorsal horn and the brain, is able to modulate capsaicin-induced N13 SEP sensitization. The study demonstrated in healthy participants that central sensitization induced by topical capsaicin was associated with an increase in the amplitude of the dorsal horn N13 SEP. Furthermore, it showed that pregabalin, a drug with proven efficacy on dorsal horn neurons, prevented the N13 SEP modulation associated with capsaicin-induced central sensitization. These findings suggest that N13 SEP reflects changes in dorsal horn excitability and might represent a biomarker of central sensitization in humans.