- Email: [email protected]
35 QUANTITATIVE SENSORY TESTING IN RESEARCH
S14
Invited Presentations / Workshop – Assessment And Diagnosis 2 / European Journal of Pain 11(S1) (2007) S1–S57
strategies that are being employed to develop cannabinoids with minimal CNS adverse effects, such as targeting CB2 receptors on peripheral immune and glial cells and targeting CB1 receptors on primary afferent neurones. Flemming Bach will review the clinical evidence base for the analgesic efficacy and adverse effects associated with cannabinoids in neuropathic pain. In particular, he will discuss some recent randomized controlled trials which have examined the analgesic efficacy of cannabinoids in neuropathic pain conditions, including multiple sclerosis. Finally, Stephen Lawrie will describe the methodologies which have been employed to acquire the epidemiological data which suggest an association of cannabis use with psychosis. He will then discuss in depth the strength of this evidence and its implications for the development of cannabinoids as therapeutics. The workshop will conclude with audience discussion and debate. doi:10.1016/j.ejpain.2007.03.046
33 CANNABIS CONCERNS AND CAUTIONS S. Lawrie Reader in Psychiatry, University of Edinburgh, Scotland, UK Psychiatrists are not renowned for reactionary views but see so many patients with psychoses apparently caused and/or exacerbated by the consumption of cannabis that the alternative interpretation of self-medication seems implausible. That clinical experience is increasingly supported by evidence from epidemiological surveys and prospective studies of subjects at high risk. Several recent large surveys suggest that cannabis causes psychotic symptoms and schizophrenia, and several systematic reviews and meta-analyses of these studies strongly suggest an overall 3-fold risk elevation and that the association is not artefactual. Our own study of young subjects at high risk of schizophrenia found a clear association between cannabis use and psychotic symptoms, with an apparent dose–response effect. There are also high quality reviews indicating that personality characteristics such as negative affect, emotionality, and unconventionality are at most weak predictors of subsequent cannabis abuse, and that the prescription of cannabinoids for chemotherapy induced nausea elevates the risk of hallucinations and delusions 6–9 times. Nevertheless, the baseline level of risk is low and there are effective antipsychotic drugs that can be used in such circumstances. The association between cannabis and psychosis does not therefore constitute a medical argument for criminalisation. doi:10.1016/j.ejpain.2007.03.047
Workshop – Assessment And Diagnosis 2: QST IN RESEARCH AND CLINICAL TRIALS
34 Workshop Summary: QUANTITATIVE SENSORY TESTING IN RESEARCH AND CLINICAL TRIALS R. Baron Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital, Kiel, Germany The increased knowledge of the pain-generating mechanisms and their translation into symptoms and signs may allow a dissection of the mechanisms that operate in neuropathic pain. If a systematic clinical examination of the neuropathic pain patient and a precise phenotypic characterization is combined with a selection of drugs acting at those particular mechanisms, it should ultimately be possible to design optimal treatments for the individual patient. Such research can only be performed in large cohorts of patients, ideally on a Research Network level. The workshop will present an overview of this technique, describe its strength and limitation. Major question that will be addressed include: (1) Is QST adequately validated to be used as a reimbursable diagnostic tool in the management of neuropathic pain? (2) Can we use QST to understand pathophysiological mechanisms in neuropathic pain? (3) Can we improve treatment outcome if we define QST results as primary outcomes in clinical trials? doi:10.1016/j.ejpain.2007.03.048
35 QUANTITATIVE RESEARCH R. Baron
SENSORY
TESTING
IN
Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital, Kiel, Germany The nationwide multi-center German Research Network of Neuropathic Pain (GNNP) was founded to improve the diagnosis, understanding and management of neuropathic pain. The heart of this Network is a large data-base that includes epidemiological, clinical and history data. To translate the hypothetical concept of the mechanism-based classification theme into the clinical framework the GNNP has implemented a standardized QST protocol with 13 parameters including thermal as
Invited Presentations / Workshop – Epidemiology And Health Care Systems 2 / European Journal of Pain 11(S1) (2007) S1–S57
well as mechanical testing procedures. To evaluate and compare somatosensory profiles of patients (plus or minus signs) an age- and gender-matched normative data-base of 180 healthy human subjects has been established. Furthermore, more than 1500 patients with a variety of different neuropathic pain states have been examined with these test procedures in a standardized fashion. In etiologies as postherpetic neuralgia at least two different somatosensory patterns could be analyzed (sensitization type with cutaneous hypersensitivity in combination with little sensory loss, degeneration type with spontaneous pain and severe sensory loss). Other specific patterns in particular combined with cold hypersensitivity were detected in polyneuropathies and in patients with CRPS. Somatosensory patterns that are specific for human surrogate models of pain in which the underlying mechanisms are relatively well understood were searched in the data-base to identify patients with this particular pattern assuming that the underlying mechanisms are similar. As an example, the pattern that is characteristic for the menthol surrogate model (cold allodynia, pinprick hyperalgesia) was detected in patients with oxaliplatin induced acute painful neuropathy. The results of such multi-center network trials will ultimately substantiate the mechanism-based treatment concept in neuropathic pain. Reference Rolke, R., Baron, R., et al. (2006). Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain, 123, 231–243. doi:10.1016/j.ejpain.2007.03.049
36 QUANTITATIVE SENSATION TESTING RESEARCH AND CLINICAL PRACTICE P.J. Dyck
IN
Department of Neurology, Mayo Clinic, Rochester, MN, USA Background. The AMA CPT Committee has provided coding for quantitative sensation testing (QST) of touch pressure, vibration, cooling, warming, and heat-pain and as done per limb, face or axial region. This is a first step towards recognition of QSTs as reimbursable evaluation techniques in the USA. Regulatory committees have concerns that QST be properly defined, validated, and used with reference to adequate controls. Standard procedures are being defined by the Quantitative Sensation Testing Society (www.qst-s.org) including description, quantitation, and reproducibility of stimuli. Stimuli should range over a broad range of magnitudes and should increase exponentially; algorithms should be
S15
pre-determined, efficient and accurate; and reports should relate to reference values and disease implications. The special uses of quantitative sensation testing will be described and illustrated: diagnostic purposes; therapeutic trials; detection of hyperalgesia; and recognition of foot hyposensitivity and increased vulnerability to injury. Conclusion. The neurologic community in the USA has a 3–4 year window in which to demonstrate the utility of QST approaches in diagnosis and management of metabolic, neurologic, and surgical disorders. Since psychophysical approaches have found a major place in hearing and vision studies, the time has come to use standard, calibrated, and appropriate approaches for the adequate study of human disorders of sensation. doi:10.1016/j.ejpain.2007.03.050
37 QST IN CLINICAL TRIALS – POTENTIALS AND CHALLENGES M. Backonja Department of Neurology, University of Wisconsin, Madison, WI, USA QST has been used in laboratory human research for more than a century, while application in human clinical practice and research, including clinical trials has been much more difficult to implement. The primary reason for that is the lack of widely accepted and implemented standards and procedures. Newly published databases and validation of procedures offer new methods that would require further efforts for standardization as well as for training and certification of examiners. The main effort in the development of QST methodology has been in the study of thresholds and to lesser degree analysis of suprathreshold stimuli, however complexity of neuropathic pain requires incorporation of negative sensory phenomena and study of special maps of positive and negative sensory phenomena. Limited experience with use of QST in clinical trials gives us a glimpse of what QST can offer. The ongoing challenge will be translation of information of QST findings into pain mechanisms. doi:10.1016/j.ejpain.2007.03.051
Workshop – Epidemiology And Health Care Systems 2: NEUPSIG GUIDELINES ON CLASSIFICATION, ASSESSMENT AND TREATMENT
38 Workshop Summary: NEUPSIG GUIDELINES ON CLASSIFICATION, ASSESSMENT AND TREATMENT OF NEUROPATHIC PAIN R.-D. Treede
Invited Presentations / Workshop – Assessment And Diagnosis 2 / European Journal of Pain 11(S1) (2007) S1–S57
strategies that are being employed to develop cannabinoids with minimal CNS adverse effects, such as targeting CB2 receptors on peripheral immune and glial cells and targeting CB1 receptors on primary afferent neurones. Flemming Bach will review the clinical evidence base for the analgesic efficacy and adverse effects associated with cannabinoids in neuropathic pain. In particular, he will discuss some recent randomized controlled trials which have examined the analgesic efficacy of cannabinoids in neuropathic pain conditions, including multiple sclerosis. Finally, Stephen Lawrie will describe the methodologies which have been employed to acquire the epidemiological data which suggest an association of cannabis use with psychosis. He will then discuss in depth the strength of this evidence and its implications for the development of cannabinoids as therapeutics. The workshop will conclude with audience discussion and debate. doi:10.1016/j.ejpain.2007.03.046
33 CANNABIS CONCERNS AND CAUTIONS S. Lawrie Reader in Psychiatry, University of Edinburgh, Scotland, UK Psychiatrists are not renowned for reactionary views but see so many patients with psychoses apparently caused and/or exacerbated by the consumption of cannabis that the alternative interpretation of self-medication seems implausible. That clinical experience is increasingly supported by evidence from epidemiological surveys and prospective studies of subjects at high risk. Several recent large surveys suggest that cannabis causes psychotic symptoms and schizophrenia, and several systematic reviews and meta-analyses of these studies strongly suggest an overall 3-fold risk elevation and that the association is not artefactual. Our own study of young subjects at high risk of schizophrenia found a clear association between cannabis use and psychotic symptoms, with an apparent dose–response effect. There are also high quality reviews indicating that personality characteristics such as negative affect, emotionality, and unconventionality are at most weak predictors of subsequent cannabis abuse, and that the prescription of cannabinoids for chemotherapy induced nausea elevates the risk of hallucinations and delusions 6–9 times. Nevertheless, the baseline level of risk is low and there are effective antipsychotic drugs that can be used in such circumstances. The association between cannabis and psychosis does not therefore constitute a medical argument for criminalisation. doi:10.1016/j.ejpain.2007.03.047
Workshop – Assessment And Diagnosis 2: QST IN RESEARCH AND CLINICAL TRIALS
34 Workshop Summary: QUANTITATIVE SENSORY TESTING IN RESEARCH AND CLINICAL TRIALS R. Baron Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital, Kiel, Germany The increased knowledge of the pain-generating mechanisms and their translation into symptoms and signs may allow a dissection of the mechanisms that operate in neuropathic pain. If a systematic clinical examination of the neuropathic pain patient and a precise phenotypic characterization is combined with a selection of drugs acting at those particular mechanisms, it should ultimately be possible to design optimal treatments for the individual patient. Such research can only be performed in large cohorts of patients, ideally on a Research Network level. The workshop will present an overview of this technique, describe its strength and limitation. Major question that will be addressed include: (1) Is QST adequately validated to be used as a reimbursable diagnostic tool in the management of neuropathic pain? (2) Can we use QST to understand pathophysiological mechanisms in neuropathic pain? (3) Can we improve treatment outcome if we define QST results as primary outcomes in clinical trials? doi:10.1016/j.ejpain.2007.03.048
35 QUANTITATIVE RESEARCH R. Baron
SENSORY
TESTING
IN
Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital, Kiel, Germany The nationwide multi-center German Research Network of Neuropathic Pain (GNNP) was founded to improve the diagnosis, understanding and management of neuropathic pain. The heart of this Network is a large data-base that includes epidemiological, clinical and history data. To translate the hypothetical concept of the mechanism-based classification theme into the clinical framework the GNNP has implemented a standardized QST protocol with 13 parameters including thermal as
Invited Presentations / Workshop – Epidemiology And Health Care Systems 2 / European Journal of Pain 11(S1) (2007) S1–S57
well as mechanical testing procedures. To evaluate and compare somatosensory profiles of patients (plus or minus signs) an age- and gender-matched normative data-base of 180 healthy human subjects has been established. Furthermore, more than 1500 patients with a variety of different neuropathic pain states have been examined with these test procedures in a standardized fashion. In etiologies as postherpetic neuralgia at least two different somatosensory patterns could be analyzed (sensitization type with cutaneous hypersensitivity in combination with little sensory loss, degeneration type with spontaneous pain and severe sensory loss). Other specific patterns in particular combined with cold hypersensitivity were detected in polyneuropathies and in patients with CRPS. Somatosensory patterns that are specific for human surrogate models of pain in which the underlying mechanisms are relatively well understood were searched in the data-base to identify patients with this particular pattern assuming that the underlying mechanisms are similar. As an example, the pattern that is characteristic for the menthol surrogate model (cold allodynia, pinprick hyperalgesia) was detected in patients with oxaliplatin induced acute painful neuropathy. The results of such multi-center network trials will ultimately substantiate the mechanism-based treatment concept in neuropathic pain. Reference Rolke, R., Baron, R., et al. (2006). Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain, 123, 231–243. doi:10.1016/j.ejpain.2007.03.049
36 QUANTITATIVE SENSATION TESTING RESEARCH AND CLINICAL PRACTICE P.J. Dyck
IN
Department of Neurology, Mayo Clinic, Rochester, MN, USA Background. The AMA CPT Committee has provided coding for quantitative sensation testing (QST) of touch pressure, vibration, cooling, warming, and heat-pain and as done per limb, face or axial region. This is a first step towards recognition of QSTs as reimbursable evaluation techniques in the USA. Regulatory committees have concerns that QST be properly defined, validated, and used with reference to adequate controls. Standard procedures are being defined by the Quantitative Sensation Testing Society (www.qst-s.org) including description, quantitation, and reproducibility of stimuli. Stimuli should range over a broad range of magnitudes and should increase exponentially; algorithms should be
S15
pre-determined, efficient and accurate; and reports should relate to reference values and disease implications. The special uses of quantitative sensation testing will be described and illustrated: diagnostic purposes; therapeutic trials; detection of hyperalgesia; and recognition of foot hyposensitivity and increased vulnerability to injury. Conclusion. The neurologic community in the USA has a 3–4 year window in which to demonstrate the utility of QST approaches in diagnosis and management of metabolic, neurologic, and surgical disorders. Since psychophysical approaches have found a major place in hearing and vision studies, the time has come to use standard, calibrated, and appropriate approaches for the adequate study of human disorders of sensation. doi:10.1016/j.ejpain.2007.03.050
37 QST IN CLINICAL TRIALS – POTENTIALS AND CHALLENGES M. Backonja Department of Neurology, University of Wisconsin, Madison, WI, USA QST has been used in laboratory human research for more than a century, while application in human clinical practice and research, including clinical trials has been much more difficult to implement. The primary reason for that is the lack of widely accepted and implemented standards and procedures. Newly published databases and validation of procedures offer new methods that would require further efforts for standardization as well as for training and certification of examiners. The main effort in the development of QST methodology has been in the study of thresholds and to lesser degree analysis of suprathreshold stimuli, however complexity of neuropathic pain requires incorporation of negative sensory phenomena and study of special maps of positive and negative sensory phenomena. Limited experience with use of QST in clinical trials gives us a glimpse of what QST can offer. The ongoing challenge will be translation of information of QST findings into pain mechanisms. doi:10.1016/j.ejpain.2007.03.051
Workshop – Epidemiology And Health Care Systems 2: NEUPSIG GUIDELINES ON CLASSIFICATION, ASSESSMENT AND TREATMENT
38 Workshop Summary: NEUPSIG GUIDELINES ON CLASSIFICATION, ASSESSMENT AND TREATMENT OF NEUROPATHIC PAIN R.-D. Treede