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Pain and Quantitative Sensory Testing in Clinical Trials: Why it Matters for CNS Drug Development

 

Pain is one of the most common and complex human experiences, and yet one of the most difficult to measure. Within clinical trials, especially in the development of therapies targeting the central nervous system (CNS), assessing pain accurately is crucial. Pain not only affects patient quality of life but can also emerge as an adverse effect of novel treatments. Incorporating structured pain assessment into early-phase studies can improve drug development outcomes, refine dosing, and ultimately protect patients (Butul 2025). 

Understanding Pain in Clinical Research 

 

Pain is typically classified by duration, acute (short-term) or chronic (long-term), and by mechanism: 

  • Nociceptive pain from tissue damage
  • Neuropathic pain from nerve damage
  • Neuroplastic pain from altered processing within the nervous system 

In drug development, pain may present as either a target symptom (e.g., in analgesic trials) or as an adverse reaction to new compounds. Monitoring pain levels throughout a study allows sponsors to identify unexpected or severe adverse events early (Weaver et al. 2021). This is especially important in CNS research, where the complexity of neurological pathways can make safety signals difficult to interpret. 

The Rise of Quantitative Sensory Testing (QST) 

 

One of the most powerful methods for systematically assessing pain is Quantitative Sensory Testing (QST). QST evaluates sensory thresholds and tolerance to standardised thermal and mechanical stimuli. Unlike conventional electrophysiology, which focuses on large, myelinated fibres, QST provides a comprehensive view of the entire somatosensory system, including small fibres often implicated in chronic pain syndromes. 

QST can be broadly divided into two categories: 

  • Static QST, which measures thresholds to detect hypo- or hyperalgesia
  • Dynamic QST, which probes central pain processing mechanisms, such as temporal summation and conditioned pain modulation 

A highly standardised approach, such as the German Research Network on Neuropathic Pain (DFNS) protocol (Rolke et al. 2006), has become a benchmark in both research and clinical settings. The DFNS has developed a standardised QST “battery” of 7 tests measuring 13 parameters to assess the functioning of somatosensory fibres responsible for pain, temperature, and touch. 

Applications of QST in CNS Drug Development 

 

In clinical trials, QST offers several advantages: 

  • Objective pain profiling: By measuring thresholds and responses across modalities (thermal, pressure, tactile), QST can capture subtle changes in sensory function that subjective reports may miss. For example, in multiple sclerosis (MS), QST can detect early sensory deficits linked to small fibre dysfunction, helping evaluate whether a treatment prevents worsening pain (Srotova et al. 2021).  

  • Dose-response optimisation: Monitoring pain responses at different dose levels helps sponsors define effective and tolerable ranges. This is especially useful in Parkinson’s disease, where non-motor symptoms such as pain can worsen with dopaminergic therapy (Fründt et al. 2019).

  • Biomarker identification: QST phenotyping provides mechanistic insights into how a drug interacts with the nervous system, supporting biomarker discovery. In fibromyalgia, for instance, QST can reveal altered central pain processing (e.g., temporal summation), which may serve as a surrogate endpoint in clinical studies (da Silva et al. 2013). 

  • Patient stratification: Phenotyping can identify subgroups more likely to respond to specific treatments. In migraine research, QST helps distinguish patients with heightened thermal or mechanical sensitivity, guiding tailored therapies (van Driel et al. 2024). 

For drugs specifically targeting pain, QST is particularly valuable in demonstrating efficacy. For compounds not aimed at pain relief, QST can act as an early warning system for pain-related side effects, such as the neuropathic pain sometimes observed in chemotherapy-induced peripheral neuropathy (CIPN) or in CNS disorders like Alzheimer’s disease, where sensory changes can complicate disease progression (Jensen-Dahm et al. 2014). 

Clinical and Practical Considerations 

 

QST is not yet routine in clinical practice, partly because it requires trained personnel and careful interpretation. Nevertheless, its potential and applications are increasing in their appeal and necessity for increasing clinical trial success. 

Both the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and the Neuropathic Pain Special Interest Group (NeuPSIG) recommend and are actively investigating novel ways of applying QST for sensory profiling in clinical trials (Backonja et al. 2013, Edwards and Schreiber 2023). 

Widely used modalities include: 

  • Von Frey filament testing for tactile sensitivity (useful in diabetic neuropathy and peripheral nerve disorders). 

  • Thermal cutaneous stimulation to assess heat and cold perception thresholds (applied in MS and small fibre neuropathies). 

  • Pressure pain testing to evaluate deep tissue sensitivity (often relevant in fibromyalgia and migraine research). 

These techniques (alongside many others) when applied in standardised protocols, can identify small fibre neuropathies, monitor sensory deficits, and track treatment effects over time. 

Why Pain Prevention in Clinical Trials Matters 

 

Beyond efficacy, pain monitoring has an ethical dimension. Clinical trial participants should not endure unnecessary or preventable suffering. By integrating QST into early-phase CNS studies, sponsors can: 

  • Detect pain-related adverse events before they escalate. 

  • Adjust protocols or dosing strategies to improve patient safety.

  • Demonstrate commitment to patient welfare, strengthening trust in research. 

In an era where CNS drug development faces immense scientific and financial challenges, QST offers a practical, mechanistic, and patient-cantered tool. By uniting computational models, clinical practice, and pain profiling, the future of neuroscience trials may become more predictive, efficient, and humane (Cruz et al 2014). 

We utilise cutting-edge technology to deliver controlled thermal stimulation as part of our comprehensive QST protocols. Our services are designed to meet the rigorous demands of clinical investigations, offering unmatched precision, efficiency, and versatility in pain assessments.

If you are interested in incorporating QST into one of your early drug development clinical trials. Please reach out to us, we would be excited to assist in your drugs success. 

 

References: 

  1. Backonja, M.M., Attal, N. and Baron, R., 2013. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain, 154(9), pp.1807–1819. https://doi.org/10.1016/j.pain.2013.05.047 

  1. Butul, M., 2025. Experimental human and clinical pain models – a mapping review of standardised methods for clinical evaluation of analgesic drugs. International Journal of Pharmaceutical Research, 17, pp.9–18. https://doi.org/10.31838/ijpr/2025.17.02.002 

  1. Cruz-Almeida, Y. and Fillingim, R.B., 2014. Can quantitative sensory testing move us closer to mechanism-based pain management? Pain Medicine, 15(1), pp.61–72. https://doi.org/10.1111/pme.12230 

  1. da Silva, L.A., Kazyiama, H.H.S., Teixeira, M.J. et al., 2013. Quantitative sensory testing in fibromyalgia and hemisensory syndrome: comparison with controls. Rheumatology International, 33, pp.2009–2017. https://doi.org/10.1007/s00296-013-2675-6 

  1. Edwards, R.R. and Schreiber, K.L., 2023. Optimizing and accelerating the development of precision pain treatments for chronic pain: IMMPACT review and recommendations. The Journal of Pain, 24(2), pp.204–225. https://doi.org/10.1016/j.jpain.2022.08.010 

  1. Fründt, O., Grashorn, W., Buhmann, C. et al., 2019. Quantitative sensory testing (QST) in drug-naïve patients with Parkinson’s disease. Journal of Parkinson’s Disease, 9(2), pp.369–378. https://doi.org/10.3233/JPD-181513 

  1. Gilron, I., Carr, D.B. and Desjardins, P.J., 2018. Current methods and challenges for acute pain clinical trials. Pain Reports, 4(3), e647. https://doi.org/10.1097/PR9.0000000000000647 

  1. Jensen-Dahm, C., Werner, M.U., Dahl, J.B., Jensen, T.S., Ballegaard, M., Hejl, A.-M. and Waldemar, G., 2014. Quantitative sensory testing and pain tolerance in patients with mild to moderate Alzheimer disease compared to healthy control subjects. Pain, 155(8), pp.1439–1445. 

  1. Rolke, R., Baron, R. and Maier, C., 2006. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain, 123(3), pp.231–243. https://doi.org/10.1016/j.pain.2006.01.041 

  1. Srotova, I., Kocica, J., Vollert, J., Kolcava, J., Hulova, M., Jarkovsky, J., Dusek, L., Bednarik, J. and Vlckova, E., 2021. Sensory and pain modulation profiles of ongoing central neuropathic extremity pain in multiple sclerosis. European Journal of Pain, 25(3), pp.573–594. 

  1. Truini, A., Aleksovska, K. and Anderson, C.C., 2023. Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment. European Journal of Neurology, 30(8), pp.2177–2196. https://doi.org/10.1111/ene.15831 

  1. van Driel, M.E.C., Huygen, F.J.P.M. and Rijsdijk, M., 2024. Quantitative sensory testing: a practical guide and clinical applications. BJA Education, 24(9), pp.326–334. https://doi.org/10.1016/j.bjae.2024.05.004 

  1. van Welie, F.C., Dahan, A., van Velzen, M. et al., 2024. Pain profiling in migraine: a systematic review of quantitative sensory testing (QST), conditioned pain modulation (CPM), and corneal confocal microscopy (CCM). Journal of Headache and Pain, 25, p.224. https://doi.org/10.1186/s10194-024-01932-x 

  1. Weaver, K.R., Griffioen, M.A., Klinedinst, N.J., Galik, E., Duarte, A.C., Colloca, L., Resnick, B., Dorsey, S.G. and Renn, C.L., 2022. Quantitative sensory testing across chronic pain conditions and use in special populations. Frontiers in Pain Research, 2, Article 779068. https://doi.org/10.3389/fpain.2021.779068