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Cited by 105Pain Mechanisms and TreatmentsPain Management and TreatmentMusculoskeletal pain and rehabilitation

Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome?

Attal, Nadine, Bouhassira, Didier, Baron, Ralf, Dostrovsky, Jonathan, Dworkin, Robert H., Finnerup, Nanna, Gourlay, Geoffrey, Haanpaa, Maija +4 more·2011·European Journal of Pain
DOI 10.1016/j.ejpain.2011.03.005
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Abstract

Neuropathic pain (NP) encompasses a large variety of conditions associated with a lesion or disease of the peripheral or central somatosensory system and remains particularly difficult to treat. Recent meta-analyses have indicated that on the average, about one third more patients with NP respond to active drugs compared to placebo treatment, and in many trials no superiority of the test compound above placebo was demonstrated (Finnerup et al., 2010). Although several reasons may be proposed to account for such findings, including a large placebo response or the fact that the current drugs do not act on the relevant pathophysiological targets, it is also possible that trials failed to identify responder populations because they did not take into account the heterogeneity of NP symptoms and signs that are presumably linked to distinct mechanisms (e.g., spontaneous pain such as burning, the most prominent symptom of NP, but also paroxysmal pains such as electric shocks, or evoked pains to mechanical/thermal stimuli). This could also be one reason for the recent negative results of drug trials in conditions considered as refractory, such as HIV neuropathies or lumbar radiculopathy (Attal et al., 2010). These observations have led to suggest as early as in 1990 that a preferable therapeutic approach to NP might be based on the specific mechanisms underlying the specific NP pain being treated rather than on the aetiological conditions, leading to targeted treatments of these mechanisms (e.g. Attal et al., 2008; Finnerup and Jensen, 2006; Max, 1990; Rowbotham, 2005; Woolf et al., 1998; Woolf, 2004). However such a rational approach is attractive but does not yet seem to be attainable, mainly because of the difficulties of translating in the clinic the pathophysiological mechanisms identified in animal studies (Bouhassira and Attal, 2004; Finnerup and Jensen, 2006; Hansson, 2003). Thus, a realistic and efficient therapeutic approach to overcome these obstacles should focus mainly on clinically observable manifestations of pathophysiology, i.e. on a comprehensive symptomatic assessment of patients with NP. Importantly it has been shown that specific pain symptoms or their combinations may provide with relevant information about underlying mechanisms (e.g. Hatem et al., 2010; Truini et al., 2010). The assessment of symptoms and signs can be best achieved with validated questionnaires such as the Neuropathic Pain Scale (NPS) or the Neuropathic Pain Symptom Inventory (NPSI) as regards symptoms, and with an extension of the clinical examination such as quantitative sensory testing (QST) for sensory signs (Refs. in Haanpaa et al., 2011). The advantage of a symptom based classification of NP has recently been outlined by three large scale clinical studies. One study performed in 482 patients with peripheral or central neuropathic conditions using the NPSI questionnaire failed to identify significant associations between symptoms or dimensions and aetiologies (Attal et al., 2008), suggesting the relevance to group aetiologically distinct conditions for therapeutic trials (Hansson and Dickenson, 2005). The two other studies confirmed the heterogeneity of sensory profiles (symptoms and signs) in patients within the same aetiological condition, which might indicate the involvement of distinct mechanisms. Thus, based on the PainDetect questionnaire, Baron and colleagues identified five different clusters of patients corresponding to various symptom combinations in 2100 patients with postherpetic neuralgia or painful diabetic polyneuropathy (Baron et al., 2009). All clusters occurred in relevant numbers in both diagnoses but their frequencies differed between postherpetic neuralgia and diabetic NP. Using quantitative sensory testing (QST) in 1236 NP patients, Maier and colleagues also found that QST profiles (i.e., loss of mechanoreception, thermoreception or nociception, gain in nociception) were heterogeneous accross the spectrum of NP conditions (Maier et al., 2010). Phenotypic profiling in clinical trials has mainly contributed to date to characterize the effects of treatments on sensory signs and symptoms of NP. Extensive sensory profiling using QST has been achieved mainly with intravenous tests of the sodium channel blocker lidocaine, opiates or the NMDA antagonist ketamine, which are not recommended as first line in clinical use (Attal et al., 2010). These studies found efficacy of these drugs on dynamic mechanical allodynia and less consistent effects on pinprick hyperalgesia, cold allodynia or temporal summation (e.g. Gottrup et al., 2006). In contrast, most trials using first line medications (e.g., tricyclic antidepressants, pregabalin, topical lidocaine) only assessed dynamic mechanical allodynia (Finnerup and Jensen, 2006). Although they found a significant alleviation of this sensory sign, it is not established whether this effect is specific or not in the lack of full sensory profiling. Thus there is evidence f

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Authors
Attal, N., Bouhassira, D., Baron, R., Dostrovsky, J., Dworkin, R. H., Finnerup, N., Gourlay, G., Haanpaa, M., Raja, S., Rice, A. S. C., Simpson, D., & Treede, R.
Affiliations
  • Inserm (FR)
  • University Hospital Schleswig-Holstein (DE)
  • University of Toronto (CA)
  • University of Rochester Medicine (US)
  • Aarhus University Hospital (DK)
  • Flinders Medical Centre (AU)
  • Johns Hopkins University (US)
  • Imperial College London (GB)
  • Icahn School of Medicine at Mount Sinai (US)
  • Heidelberg University (DE)
Corresponding author
Attal, Nadine
ORCID
Venue
European Journal of Pain
Publisher
Wiley
Published
2011-05
Volume
15
Issue
5
Pages
441-443
ISSN
  • 1090-3801 (ISSN-L)
  • 1532-2149
DOI
10.1016/j.ejpain.2011.03.005
OpenAlex
W2151210321
Cited by
105
References
28
Citations by year
2026: 3 · 2025: 3 · 2023: 3 · 2022: 4 · 2021: 10 · 2020: 10 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 7 · 2015: 12 · 2014: 8 · 2013: 16 · 2012: 12
FWCI
8.08
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 257 d)
Locations
  • European Journal of Pain (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
  • Health Sciences › Medicine › Pharmacology › Musculoskeletal pain and rehabilitation
Keywords
symptom profiles, symptom assessment, clinical trials, responder identification, placebo response, burn pain, paroxysmal pain, evoked pain, targeted therapy, symptom questionnaire, pain mechanisms, drug development, HIV neuropathy, lumbar radiculopathy, treatment outcome measures, patient-reported outcomes
MeSH terms
Clinical Trials as Topic, Humans, Neuralgia, Treatment Outcome

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