Chronic pain is difficult to treat. The analgesic effects elicited by existing drugs are often not satisfactory and patients show differing responses to the available therapies. For both these reasons, there is a need to develop more-effective treatment strategies and pain medications. Heterogeneity in the response to analgesics could be explained by the presence of different underlying pain-generating mechanisms in patients with the same disease. Furthermore, the same pain-generating mechanisms could occur in different conditions, and, in an individual patient, several mechanisms might be present all at once. Scholz et al.1 have developed a novel assessment system for chronic pain to distinguish between different subtypes of pain, and, possibly, distinct underlying pain-generating mechanisms.
Inflammatory pain can be distinguished clinically from neuropathic pain. In the former category, the nociceptive pathways are intact and activated by inflammatory mediators, whereas neuropathic pain develops after a lesion to the nervous system itself. Chronic inflammatory and neuropathic pain are both associated with a cascade of functional, molecular, biochemical and anatomical changes in the PNS and CNS. These changes are not uniform and depend on multiple factors, such as dimensions of the lesion and the contribution of different nerve fibers, as well as immunological, genetic and environmental factors. Consequently, several different pathophysiological mechanisms have been identified—mainly from animal studies—that lead to the symptom of pain.2 From these studies, a mechanism-based classification of pain was suggested.3 Such classifications have implications for the development and application of treatment approaches, in terms of defining pharmacological targets and identifying patients who are likely to benefit from the various available therapies.
To implement a mechanism-based classification of pain, such underlying pain-generating processes need to be reliably detected in patients. A thorough clinical investigation can reveal positive and negative symptoms and signs that potentially allow differentiation between subtypes of pain. Quantitative sensory testing (QST) is a precise way to identify somatosensory disturbances. The German Research Network on Neuropathic Pain, for example, has developed a standardized and comprehensive QST protocol, which consists of seven tests that measure 13 parameters of thermal and mechanical pain perception.4 QST data from more than 1,200 patients with neuropathic pain have so far been collected, and several relevant phenotypic subgroups can be described. Interestingly, these distinct subgroups occur across etiologies. This approach is currently reserved for research purposes or use in early phase II trials—QST is too time intensive and expensive to be used on a day-to-day basis in the clinic—so a need exists to develop alternative assessment tools that could be used in later phases of clinical trials and in routine clinical work.
Scholz and colleagues1 have attempted to meet this need by developing a practical, standardized assessment of pain-related symptoms and signs to differentiate distinct pain phenotypes. The investigators prospectively assessed the symptoms and signs of 130 patients with peripheral neuropathic pain—caused by diabetic polyneuropathy, postherpetic neuralgia or radicular low back pain—and 57 patients with non-neuropathic low back pain, by means of a structured interview and a standardized bedside examination. The interview consisted of 16 questions that explored pain localization, evoked pains, pain quality and further sensory qualities, such as dysesthesia and numbness. The physical examination included 23 bedside tests that provided information about trophic and autonomic signs, evoked pains and sensory deficits. From the results of the interview and bedside examination, Scholz and colleagues were able to determine six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain.
The physical examination was essential for the distinction of pain subtypes, with the response to pinprick being the most sensitive and most specific single test for distinguishing between neuropathic and non-neuropathic pain. Among patients with neuropathic pain, a positive result in the straight-leg-raising test was highly specific for radicular low back pain, whereas a decreased response to vibration was very sensitive and specific for detecting diabetic neuropathy and distinguishing this condition from postherpetic neuralgia. The responses to cold temperature and trophic changes were also essential for identifying pain subtypes. From their initial analysis to find out the best discriminatory procedures for identifying pain subtypes, Scholz and colleagues proposed an assessment tool comprising six interview questions and ten physical tests, which they named ‘Standardized Evaluation of Pain’ (StEP).
In the second part of the study, StEP was applied to an independent group of 137 patients with chronic low back pain for validation. For each patient, a diagnosis of neuropathic or non-neuropathic (axial) low back pain was made by an interdisciplinary team of clinical experts. Another group of investigators, who were blind to the diagnoses, applied StEP to the patients. Through use of this assessment, the investigators were able to identify patients with radicular pain with 92% sensitivity and 97% specificity. This was superior to the Douleur Neuropathique en 4 Questions—an established screening tool for neuropathic pain that consists of seven interview questions and three physical tests5—which was applied in parallel to StEP.
On the basis of the data reported by Scholz et al., we conclude that StEP will have an important role in future multicenter treatment trials. Until now, inclusion criteria for studies investigating new analgesic agents have relied almost exclusively on the nature of the underlying disease. Furthermore, study end points designed to determine treatment efficacy have relied mainly on overall pain intensity. With StEP, a validated bedside test is available whereby neuropathic pain can be distinguished from non-neuropathic pain, and information can also be gained to identify subtypes of pain, independently from disease etiology. This assessment technique should enable much more sophisticated study designs and data analyses, by identifying subgroups of patients with pain that can be correlated with their response to analgesic treatment. Such improvements should also lead to a better understanding of underlying pain mechanisms and drug action.
StEP could also be a useful supplementary technique for diagnosing pain in the clinic. Differentiating between neuropathic and non-neuropathic pain can be clinically challenging, and is of the utmost importance, because the two conditions require different treatment strategies. As with other screening tools, such as the patient-oriented questionnaire painDETECT6—which has both a sensitivity and specificity of 80% for detecting neuropathic pain components in patients with low back pain—StEP cannot and is not meant to replace a thorough clinical examination of patients with pain. As stated by Scholz et al.,1 further studies are needed to determine the accuracy of StEP in distinguishing neuropathic pain from non-neuropathic pain in conditions other than low back pain.
In conclusion, the study from Scholz and colleagues1 demonstrated a very promising bedside tool for pain assessment that differentiates pain phenotypes independently from disease etiology. The validation of this assessment for low back pain strongly supports the concept of a mechanism-based classification of pain and is a move towards developing better targeted analgesic therapies.
References
Inflammatory pain can be distinguished clinically from neuropathic pain. In the former category, the nociceptive pathways are intact and activated by inflammatory mediators, whereas neuropathic pain develops after a lesion to the nervous system itself. Chronic inflammatory and neuropathic pain are both associated with a cascade of functional, molecular, biochemical and anatomical changes in the PNS and CNS. These changes are not uniform and depend on multiple factors, such as dimensions of the lesion and the contribution of different nerve fibers, as well as immunological, genetic and environmental factors. Consequently, several different pathophysiological mechanisms have been identified—mainly from animal studies—that lead to the symptom of pain.2 From these studies, a mechanism-based classification of pain was suggested.3 Such classifications have implications for the development and application of treatment approaches, in terms of defining pharmacological targets and identifying patients who are likely to benefit from the various available therapies.
To implement a mechanism-based classification of pain, such underlying pain-generating processes need to be reliably detected in patients. A thorough clinical investigation can reveal positive and negative symptoms and signs that potentially allow differentiation between subtypes of pain. Quantitative sensory testing (QST) is a precise way to identify somatosensory disturbances. The German Research Network on Neuropathic Pain, for example, has developed a standardized and comprehensive QST protocol, which consists of seven tests that measure 13 parameters of thermal and mechanical pain perception.4 QST data from more than 1,200 patients with neuropathic pain have so far been collected, and several relevant phenotypic subgroups can be described. Interestingly, these distinct subgroups occur across etiologies. This approach is currently reserved for research purposes or use in early phase II trials—QST is too time intensive and expensive to be used on a day-to-day basis in the clinic—so a need exists to develop alternative assessment tools that could be used in later phases of clinical trials and in routine clinical work.
Scholz and colleagues1 have attempted to meet this need by developing a practical, standardized assessment of pain-related symptoms and signs to differentiate distinct pain phenotypes. The investigators prospectively assessed the symptoms and signs of 130 patients with peripheral neuropathic pain—caused by diabetic polyneuropathy, postherpetic neuralgia or radicular low back pain—and 57 patients with non-neuropathic low back pain, by means of a structured interview and a standardized bedside examination. The interview consisted of 16 questions that explored pain localization, evoked pains, pain quality and further sensory qualities, such as dysesthesia and numbness. The physical examination included 23 bedside tests that provided information about trophic and autonomic signs, evoked pains and sensory deficits. From the results of the interview and bedside examination, Scholz and colleagues were able to determine six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain.
The physical examination was essential for the distinction of pain subtypes, with the response to pinprick being the most sensitive and most specific single test for distinguishing between neuropathic and non-neuropathic pain. Among patients with neuropathic pain, a positive result in the straight-leg-raising test was highly specific for radicular low back pain, whereas a decreased response to vibration was very sensitive and specific for detecting diabetic neuropathy and distinguishing this condition from postherpetic neuralgia. The responses to cold temperature and trophic changes were also essential for identifying pain subtypes. From their initial analysis to find out the best discriminatory procedures for identifying pain subtypes, Scholz and colleagues proposed an assessment tool comprising six interview questions and ten physical tests, which they named ‘Standardized Evaluation of Pain’ (StEP).
In the second part of the study, StEP was applied to an independent group of 137 patients with chronic low back pain for validation. For each patient, a diagnosis of neuropathic or non-neuropathic (axial) low back pain was made by an interdisciplinary team of clinical experts. Another group of investigators, who were blind to the diagnoses, applied StEP to the patients. Through use of this assessment, the investigators were able to identify patients with radicular pain with 92% sensitivity and 97% specificity. This was superior to the Douleur Neuropathique en 4 Questions—an established screening tool for neuropathic pain that consists of seven interview questions and three physical tests5—which was applied in parallel to StEP.
On the basis of the data reported by Scholz et al., we conclude that StEP will have an important role in future multicenter treatment trials. Until now, inclusion criteria for studies investigating new analgesic agents have relied almost exclusively on the nature of the underlying disease. Furthermore, study end points designed to determine treatment efficacy have relied mainly on overall pain intensity. With StEP, a validated bedside test is available whereby neuropathic pain can be distinguished from non-neuropathic pain, and information can also be gained to identify subtypes of pain, independently from disease etiology. This assessment technique should enable much more sophisticated study designs and data analyses, by identifying subgroups of patients with pain that can be correlated with their response to analgesic treatment. Such improvements should also lead to a better understanding of underlying pain mechanisms and drug action.
StEP could also be a useful supplementary technique for diagnosing pain in the clinic. Differentiating between neuropathic and non-neuropathic pain can be clinically challenging, and is of the utmost importance, because the two conditions require different treatment strategies. As with other screening tools, such as the patient-oriented questionnaire painDETECT6—which has both a sensitivity and specificity of 80% for detecting neuropathic pain components in patients with low back pain—StEP cannot and is not meant to replace a thorough clinical examination of patients with pain. As stated by Scholz et al.,1 further studies are needed to determine the accuracy of StEP in distinguishing neuropathic pain from non-neuropathic pain in conditions other than low back pain.
In conclusion, the study from Scholz and colleagues1 demonstrated a very promising bedside tool for pain assessment that differentiates pain phenotypes independently from disease etiology. The validation of this assessment for low back pain strongly supports the concept of a mechanism-based classification of pain and is a move towards developing better targeted analgesic therapies.
References
- Scholz, J. et al. A novel tool for the assessment of pain: validation in low back pain. PLoS Med. 6, e1000047 (2009).
- Baron, R. Mechanisms of disease: neuropathic pain—a clinical perspective. Nat. Clin. Pract. Neurol. 2, 95–106 (2006).
- Woolf, C. J. et al. Towards a mechanism-based classification of pain? Pain 77, 227–229 (1998).
- Rolke, R. et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 123, 231–243 (2006).
- Bouhassira, D. et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 114, 29–36 (2005).
- Freynhagen, R., Baron, R., Gockel, U. & Tölle, T. R. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr. Med. Res. Opin. 22, 1911–1920 (2006).
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