Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations

Abstract

There is tremendous inter-patient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for “precision medicine”, or personalized pain therapeutics (i.e., empirically-based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain, and the success rates for putative analgesic drugs in Phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

Neuropathic pain

“…This is the only trial in which a pre-specified primary analysis demonstrated a difference in treatment versus placebo response in patient subgroups identified by phenotyping. These results are very promising, but require replication as well as use of phenotyping measures that would be suitable for larger confirmatory trials and use in clinical practice 188 . Phenotyping could also be used to test whether certain patients have a more robust response to non-pharmacological treatments, for example, invasive, psychological and complementary interventions 188 , as well as to identify which patients are most likely to respond to combinations of treatments.…”

“…These results are very promising, but require replication as well as use of phenotyping measures that would be suitable for larger confirmatory trials and use in clinical practice 188 . Phenotyping could also be used to test whether certain patients have a more robust response to non-pharmacological treatments, for example, invasive, psychological and complementary interventions 188 , as well as to identify which patients are most likely to respond to combinations of treatments. Indeed, given the importance of expectations and psychological and social factors — including adaptive coping and catastrophizing — in the development and maintenance of chronic neuropathic pain, it would not be surprising if phenotyping has a great part to play in demonstrating the efficacy of psychological interventions as it does for medications.…”

Quantitative sensory testing measures individual pain responses in emergency department patients

“…Individualized treatment requires methods to reliably compare individual perceptions of painful stimuli and individual responses to analgesia in the ED 12. Measurement of pain and response to pain treatment is difficult because of the chaotic ED setting.…”

Translational studies identify long-term impact of prior neonatal pain experience

“…[175] Similarly, in clinical analgesic trials for chronic pain, detailed phenotyping of patients may provide information related to factors that predict not only the risk of persistent pain, but also the response to treatment. [55] This is particularly relevant given emerging data that mechanisms and efficacy of potential interventions for neuropathic pain differ between males and females. [124] Core phenotyping domains recommended as part of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) include: pain qualities; psychosocial measures; sleep; and quantitative sensory testing, including conditioned pain modulation.…”

“…[124] Core phenotyping domains recommended as part of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) include: pain qualities; psychosocial measures; sleep; and quantitative sensory testing, including conditioned pain modulation. [55] However, as evidence increases for long-term effects following pain and stress in early life, should early life experience also form part of a comprehensive pain history and patient phenotyping?…”