INTERVIEW
A clinical pharmacologist’s journey in pain research and treatment Paul Rolan* speaks to Roshaine Gunawardana, Commissioning Editor: Paul Rolan graduated in Medicine
(MBBS) from the University of Adelaide, Australia, in 1979 and trained in internal medicine and clinical pharmacology. In 1987, he went to the UK to work at the Wellcome Research Laboratories where he was responsible for the exploratory development of a range of compounds, some of which became marketed (atovaquone, zolmitriptan). He was awarded an MD degree from the University of Adelaide in 1995 for novel conceptual work on the use of biomarkers in exploratory development for work performed while at Wellcome. In 1984, he was appointed Medical Director of Medeval (now part of ICON Clinical Research), a clinical pharmacology contract research organization spun out of the University of Manchester, UK. At Medeval the emphasis was on quantitative pharmacodynamics, especially in neuroscience, and increasingly focused on pain. In Manchester, his clinical practice was in management of complex headache cases and this is continued in his practice back in Australia following his return in 2005. At the University of Adelaide he continues to focus on translational research in pain especially focusing on potential immunologically directed biomarkers and therapies for pain and headache. He is a cofounder of the Pain and Anaesthesia Research Clinic at the University of Adelaide and is a member of the Australian National Medicines Policy Committee. He has been principal investigator in over 700 clinical pharmacology studies including 70 first-in-man studies. Your training began in medicine and clinical pharmacology. What led to your specific interests in aspects of pain medicine? QQ
I had become interested in pain medicine in my undergraduate years as it seemed to me to require all the skills of a good physician in developing a good relationship with the patient, professional teamwork and a thorough understanding of clinical pharmacology. However, I became particularly interested in headache – my current area of practice – when I was working in the pharmaceutical industry (The Wellcome Foundation, UK) and when I was given the responsibility for the translational development of a novel antimigraine compound. I realized how little we understood about the biology of this condition
News & Views News Journal Watch Ask the Experts Interview
and how interesting it was. Subsequently, when I moved to Manchester, I set up a headache clinic within a department of neurology as it appeared that many of the neurologists there and elsewhere were not particularly interested in pain. Returning to Adelaide, I joined a multidisciplinary pain management unit where skills in clinical pharmacology were thought to be helpful in trying to develop a rationally based treatment plan for complex patients for whom the evidence base was often lacking. Following on from the previous question, as a medically qualified clinical pharmacologist working in pain management, how is your perspective of the field of pain management different? QQ
part of
*School of Medical Sciences, University of Adelaide, South Australia, Australia; [email protected]
10.2217/PMT.12.12 © 2012 Future Medicine Ltd
Pain Manage. (2012) 2(3), 205–207
ISSN 1758-1869
205
NEWS & VIEWS INTERVIEW First, as a physician there is an emphasis on diagnosis. I have encountered several patients who had been within the pain management ‘system’ where the underlying diagnosis had not been elucidated and where specific therapy for the underlying disease had not been started. This had happened with some patients with cluster headache who markedly improved on specific therapy rather than through a general pain management approach. Second, with regards to drug therapy, there have been disappointingly few new classes of therapy in recent years and nothing that appears to be disease modifying. For the patients who are not well served by existing treatments, and for whom the existing evidence base is lacking, expertise in off-label prescribing, formulary application, relationships with the hospital drug committee, individual ‘N-of-1’ trials and clinical research complement existing skills in the unit. One of your specialties is in translational evaluation of novel therapies for pain. What specifically does this role entail? QQ
There are two aspects to this. First, new treatment approaches are developed from our own academic research and careful small studies in selected patients are necessary to demonstrate proof of principle. Second, pharmaceutical companies may develop potential new treatments and similarly they need to try to demonstrate proof of principle safely but as quickly as possible. In both of these situations, a clinical investigator who can translate the preclinical findings into a safe and efficient exploratory clinical program and who can recruit and manage such a program is needed. There is a diminishing role for traditional healthy volunteer studies, and translational studies directly in patients either stratified or guided by biomarkers has particular appeal. My experience in the pharmaceutical industry, having put over 70 new molecules into man, with a strong emphasis on neuropharmacology, helps me to fulfil such a role. Many areas of research involve searching for biomarkers as potential targets for disease treatment. Could you please explain some of your research into biomarkers of neuropathic pain? QQ
Currently, we diagnose and treat pain by clinical phenotype and, unfortunately, this often means several cycles of ineffective therapy before we find a suitable one for an individual patient.
206
Pain Manage. (2012) 2(3)
At present, we are lacking mechanism-based biomarkers that can help diagnose and guide treatment decisions for individual patients. The situation is fairly similar to cancer in the past where we used to make a diagnosis such as ‘breast cancer’. However, in cancer, the treatment is currently increasingly guided by molecular diagnosis. Clearly the major reason why pain has lagged behind in this area is that the important system, the CNS, is very difficult to access. This has left imaging to be the only practical biomarker for pain. However, given the increasing evidence of the immunological system in pain, we have been exploring whether useful information can be obtained from the easily accessible tissue – blood. This has already paid off. In animals, we have identified a gene signature of neuropathic pain and we are now proposing to validate this in humans. In humans we have seen evidence of a marked increase in immunological activity in the peripheral blood of pain patients and we are working to assess the specificity of this finding compared with other clinical conditions. You were recently invited to speak on ‘clinical challenges in assessing new drugs for pain’ at the Annual Scientific Congress of The Royal Australasian College of Surgeons in Adelaide. Could you briefly outline some of your findings? QQ
At that meeting, my presentation focused on two themes. The first was to describe the use of experimental pain models in humans to detect analgesic action and to determine dose–response relationships in preparation for later clinical trials. I also described our work in the search for biomarkers as described above. Your research also includes new therapies for headaches. In your opinion, have there been major advances in this field recently? What are the challenges still facing clinicians and researchers in the area of headache research? QQ
Progress has been relatively steady in headache research in the early 1990s when the clinical and commercial success of sumatriptan led to a marked increase in both academic and pharmaceutical company research into headache. Apart from the triptans, the other major development in the last decade or so has been the finding that certain (but not all) anticonvulsants can be highly effective in migraine prevention.
future science group
INTERVIEW Unfortunately, there are few disease-modifying strategies in patients who often need to stay on therapy for the medium to long term. We are currently trialing immunologically directed therapies as potential disease-modifying therapies in the area of medication overuse headache, as we believe this may have a glial mechanism that is amenable to specific therapy. You have experience as a senior consultant at the pain management unit at the Royal Adelaide Hospital, Australia. Can you identify common difficulties clinicians may experience on a day-to-day basis when assessing pain patients? QQ
The major problem, and one that I am fairly sure is likely to be reflected worldwide, is that there is a mismatch between the demand and supply of pain management skills. Pain is a huge clinical problem worldwide and in developed countries is generally one of the top five conditions consuming chronic health resources. In addition, unlike many chronic diseases that largely affect the elderly, chronic pain is generally a problem of middle-aged, and hence potentially working, patients and so the economic impact is very high. Multidisciplinary pain management units have been successful in that they allow both adequate time to thoroughly assess the patient and to develop the rapport for an understanding to help the patient be part of their pain management. However, such units are expensive, require senior skilled staff and, despite the community problems of increasing opioid use, there is often little expansion of services and even contraction. Unfortunately, pain does not have a strong voice nationally and hence both clinical and research resources in this area are grossly below the proportionate burden on society.
future science group
NEWS & VIEWS
The Pain and Anaesthesia Research Clinic was set up by you and your colleague Guy Ludbrook. What were your main reasons behind creating this establishment? QQ
Increasingly, successful research teams are made by combining skills from related but different areas. My expertise in drug development and Guy’s expertise in anesthesia research made a good fit to develop a combined academic and commercial translational clinical research unit. Our hospital does not have a general clinical research unit and the drugs that we give for pain and anesthesia often have a narrow therapeutic index. Studies using drugs in this area need high-intensity and quality medical and nursing care. Hence, it was necessary for us to establish this unit to be able to undertake clinical research to both the safety and operational standards expected. What do you hope to see achieved in the next 5–10 years in the field of pain management? QQ
To have biomarkers to help design and select
therapy for patients and to monitor response to treatment; To have disease-modifying therapies; To have enough resources to treat those in need. Financial & competing interests disclosure P Rolan has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert te stimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
www.futuremedicine.com
207
A clinical pharmacologist’s journey in pain research and treatment Paul Rolan* speaks to Roshaine Gunawardana, Commissioning Editor: Paul Rolan graduated in Medicine
(MBBS) from the University of Adelaide, Australia, in 1979 and trained in internal medicine and clinical pharmacology. In 1987, he went to the UK to work at the Wellcome Research Laboratories where he was responsible for the exploratory development of a range of compounds, some of which became marketed (atovaquone, zolmitriptan). He was awarded an MD degree from the University of Adelaide in 1995 for novel conceptual work on the use of biomarkers in exploratory development for work performed while at Wellcome. In 1984, he was appointed Medical Director of Medeval (now part of ICON Clinical Research), a clinical pharmacology contract research organization spun out of the University of Manchester, UK. At Medeval the emphasis was on quantitative pharmacodynamics, especially in neuroscience, and increasingly focused on pain. In Manchester, his clinical practice was in management of complex headache cases and this is continued in his practice back in Australia following his return in 2005. At the University of Adelaide he continues to focus on translational research in pain especially focusing on potential immunologically directed biomarkers and therapies for pain and headache. He is a cofounder of the Pain and Anaesthesia Research Clinic at the University of Adelaide and is a member of the Australian National Medicines Policy Committee. He has been principal investigator in over 700 clinical pharmacology studies including 70 first-in-man studies. Your training began in medicine and clinical pharmacology. What led to your specific interests in aspects of pain medicine? QQ
I had become interested in pain medicine in my undergraduate years as it seemed to me to require all the skills of a good physician in developing a good relationship with the patient, professional teamwork and a thorough understanding of clinical pharmacology. However, I became particularly interested in headache – my current area of practice – when I was working in the pharmaceutical industry (The Wellcome Foundation, UK) and when I was given the responsibility for the translational development of a novel antimigraine compound. I realized how little we understood about the biology of this condition
News & Views News Journal Watch Ask the Experts Interview
and how interesting it was. Subsequently, when I moved to Manchester, I set up a headache clinic within a department of neurology as it appeared that many of the neurologists there and elsewhere were not particularly interested in pain. Returning to Adelaide, I joined a multidisciplinary pain management unit where skills in clinical pharmacology were thought to be helpful in trying to develop a rationally based treatment plan for complex patients for whom the evidence base was often lacking. Following on from the previous question, as a medically qualified clinical pharmacologist working in pain management, how is your perspective of the field of pain management different? QQ
part of
*School of Medical Sciences, University of Adelaide, South Australia, Australia; [email protected]
10.2217/PMT.12.12 © 2012 Future Medicine Ltd
Pain Manage. (2012) 2(3), 205–207
ISSN 1758-1869
205
NEWS & VIEWS INTERVIEW First, as a physician there is an emphasis on diagnosis. I have encountered several patients who had been within the pain management ‘system’ where the underlying diagnosis had not been elucidated and where specific therapy for the underlying disease had not been started. This had happened with some patients with cluster headache who markedly improved on specific therapy rather than through a general pain management approach. Second, with regards to drug therapy, there have been disappointingly few new classes of therapy in recent years and nothing that appears to be disease modifying. For the patients who are not well served by existing treatments, and for whom the existing evidence base is lacking, expertise in off-label prescribing, formulary application, relationships with the hospital drug committee, individual ‘N-of-1’ trials and clinical research complement existing skills in the unit. One of your specialties is in translational evaluation of novel therapies for pain. What specifically does this role entail? QQ
There are two aspects to this. First, new treatment approaches are developed from our own academic research and careful small studies in selected patients are necessary to demonstrate proof of principle. Second, pharmaceutical companies may develop potential new treatments and similarly they need to try to demonstrate proof of principle safely but as quickly as possible. In both of these situations, a clinical investigator who can translate the preclinical findings into a safe and efficient exploratory clinical program and who can recruit and manage such a program is needed. There is a diminishing role for traditional healthy volunteer studies, and translational studies directly in patients either stratified or guided by biomarkers has particular appeal. My experience in the pharmaceutical industry, having put over 70 new molecules into man, with a strong emphasis on neuropharmacology, helps me to fulfil such a role. Many areas of research involve searching for biomarkers as potential targets for disease treatment. Could you please explain some of your research into biomarkers of neuropathic pain? QQ
Currently, we diagnose and treat pain by clinical phenotype and, unfortunately, this often means several cycles of ineffective therapy before we find a suitable one for an individual patient.
206
Pain Manage. (2012) 2(3)
At present, we are lacking mechanism-based biomarkers that can help diagnose and guide treatment decisions for individual patients. The situation is fairly similar to cancer in the past where we used to make a diagnosis such as ‘breast cancer’. However, in cancer, the treatment is currently increasingly guided by molecular diagnosis. Clearly the major reason why pain has lagged behind in this area is that the important system, the CNS, is very difficult to access. This has left imaging to be the only practical biomarker for pain. However, given the increasing evidence of the immunological system in pain, we have been exploring whether useful information can be obtained from the easily accessible tissue – blood. This has already paid off. In animals, we have identified a gene signature of neuropathic pain and we are now proposing to validate this in humans. In humans we have seen evidence of a marked increase in immunological activity in the peripheral blood of pain patients and we are working to assess the specificity of this finding compared with other clinical conditions. You were recently invited to speak on ‘clinical challenges in assessing new drugs for pain’ at the Annual Scientific Congress of The Royal Australasian College of Surgeons in Adelaide. Could you briefly outline some of your findings? QQ
At that meeting, my presentation focused on two themes. The first was to describe the use of experimental pain models in humans to detect analgesic action and to determine dose–response relationships in preparation for later clinical trials. I also described our work in the search for biomarkers as described above. Your research also includes new therapies for headaches. In your opinion, have there been major advances in this field recently? What are the challenges still facing clinicians and researchers in the area of headache research? QQ
Progress has been relatively steady in headache research in the early 1990s when the clinical and commercial success of sumatriptan led to a marked increase in both academic and pharmaceutical company research into headache. Apart from the triptans, the other major development in the last decade or so has been the finding that certain (but not all) anticonvulsants can be highly effective in migraine prevention.
future science group
INTERVIEW Unfortunately, there are few disease-modifying strategies in patients who often need to stay on therapy for the medium to long term. We are currently trialing immunologically directed therapies as potential disease-modifying therapies in the area of medication overuse headache, as we believe this may have a glial mechanism that is amenable to specific therapy. You have experience as a senior consultant at the pain management unit at the Royal Adelaide Hospital, Australia. Can you identify common difficulties clinicians may experience on a day-to-day basis when assessing pain patients? QQ
The major problem, and one that I am fairly sure is likely to be reflected worldwide, is that there is a mismatch between the demand and supply of pain management skills. Pain is a huge clinical problem worldwide and in developed countries is generally one of the top five conditions consuming chronic health resources. In addition, unlike many chronic diseases that largely affect the elderly, chronic pain is generally a problem of middle-aged, and hence potentially working, patients and so the economic impact is very high. Multidisciplinary pain management units have been successful in that they allow both adequate time to thoroughly assess the patient and to develop the rapport for an understanding to help the patient be part of their pain management. However, such units are expensive, require senior skilled staff and, despite the community problems of increasing opioid use, there is often little expansion of services and even contraction. Unfortunately, pain does not have a strong voice nationally and hence both clinical and research resources in this area are grossly below the proportionate burden on society.
future science group
NEWS & VIEWS
The Pain and Anaesthesia Research Clinic was set up by you and your colleague Guy Ludbrook. What were your main reasons behind creating this establishment? QQ
Increasingly, successful research teams are made by combining skills from related but different areas. My expertise in drug development and Guy’s expertise in anesthesia research made a good fit to develop a combined academic and commercial translational clinical research unit. Our hospital does not have a general clinical research unit and the drugs that we give for pain and anesthesia often have a narrow therapeutic index. Studies using drugs in this area need high-intensity and quality medical and nursing care. Hence, it was necessary for us to establish this unit to be able to undertake clinical research to both the safety and operational standards expected. What do you hope to see achieved in the next 5–10 years in the field of pain management? QQ
To have biomarkers to help design and select
therapy for patients and to monitor response to treatment; To have disease-modifying therapies; To have enough resources to treat those in need. Financial & competing interests disclosure P Rolan has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert te stimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
www.futuremedicine.com
207
