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Practical applications of alpha blockade
Commentary
Practical Applications of Alpha Blockade J. E. Charlton
or those who cannot be bothered to read either the article or the commentary, the answer to the question posed in the title is y e s m p r o b a b l y m a n d you may have to change your clinical practice. For those who want to know a little bit more, this paper is yet another in a string of excellent papers from this distinguished group of authors. However, having said that, this latest work, as the authors freely admit, merely points both clinician and researcher in a particular direction. There has been evidence for a role for the alpha1 adrenoreceptor in the genesis of certain painful conditions for some time. Campbell and his colleagues quote this anecdotal evidence as support for their own contentions. The problem has been that no strong body of evidence exists to support the clinical use of alpha-adrenergic blocking agents such as phenoxybenzamine, phentolamine, or prazocin for treatment purposes. Of course, this has never stopped clinicians from trying them out in a speculative manner. Random use in occasional patients who fall into the category of "failed-to-respond-to-the-usual-things-let's-try-alpha-blockers-next" has led to a certain amount of skepticism about their value. This focus article permits the clinical use of these agents to be viewed in perspective, and suggests some guarded optimism about the future management of sympathetically maintained pain. The International Association for the Study of Pain has tried hard to introduce the concept of common terminology and definitions to improve our communication concerning pain. One of the most difficult areas has been concern over use of the terms "reflex sympathetic dystrophy" or '.'sympathetically main-
F
From Royal Victoria Infirmary, Newcastleupon Tyne,GreatBritain. Reprint requests:J. E. Charlton, C()nsultantAnestetist,The Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, Great Britain. APS Journal 1(1):23-25, 1992
tained pain." Campbell's group has drawn attention to the misleading nature of the terminology in the past. For example, from the clinician's point of view, sympathetically maintained pain implies that if a sympathetic block relieves the pain, there must be pathology of the sympathetic nervous system. The logical extension of this conclusion is that clinical benefit can be obtained by damaging the sympathetic system on a long-term basis. I must state at this point that I have always had problems with the idea of destroying parts of the neuraxis on an indiscriminate basis; if something is damaged, it seems illogical to expect further damage to be helpful! It is my view that if invasive therapy is to be used, it can only be after the most rigorous efforts to seek successful management with noninvasive methods. It must be clear to anyone with the most remote interest in the management of pain that there are many clinical conditions with a similar presentation where sympathetic block is not the complete answer to the problem, nor, it would appear, is alpha-1 adrenergic blockade. Thus, it is better to use the widely recognized term "reflex sympathetic dystrophy" until putative mechanisms and treatments become clearer. Some idea of the difficulties faced by clinicians can be gained by reading the article by A r n ~ on the development of the intravenous phentolamine test. This study included many patients, all of whom appeared to fit the criteria for sympathetically maintained pain. In previous years all may have been treated by destruction of the sympathetic nervous system on an empirical basis. With the intravenous phentolamine test Arn~r was able to differentiate between patients who would and would not respond to a sympathetic block. In the current paper, Campbell and his colleagues enlarge on the contribution of this diagnostic procedure to:the extent that testing the effect of alpha-1 adrenergic blockade must now be 23
24
COMMENTARY/Charlton
regarded as mandatory in patients presenting with reflex sympathetic dystrophy. What happens after that? What number of patients will respond to alpha-1 adrenergic blockade? Clearly, we don't know. Finding that a percentage of patients have pain which is mediated through the alpha-1 adrenergic system is valuable, but becomes less so if this knowledge cannot be translated into a long-term clinical benefit. Papers by Ghostine et al. 6 and Abram and Lightfoot 2 have reported benefit from oral alpha-adrenergic blocking drugs. Ghostine and colleagues reported 40 patients with causalgia, all with documented neural injury, who were treated with oral phenoxybenzamine in doses varying from 40 to 120 mg/day in divided doses. All patients reported total resolution of pain. Abram and Lightfoot's case report was most interesting as it used intravenous phentolamine to predict a successful response to alpha-adrenergic blockade with prazocin. Abram has alluded to further experience with prazocin in other published work, noting that the use of intravenous phentolamine was a predictor of a favorable response. 1 No details are given, but he seems lukewarm in his enthusiasm for prazocin as a treatment, describing improvement as "moderate," a term that could include many definitions. Thus, treatment with oral alpha-adrenergic blocking drugs appears to have made no impact on clinical practice, despite public knowledge of the alleged benefit for some years. What is the explanation for this? The first conclusion One might make is that it doesn't work, despite the mare/times it has been tried. The likely explanation is that clinicians have lacked the time and the willpower needed to carry outproperly conducted clinical trials. The time is now right for change. The last World Pain Congress, in Adelaide, saw a consensus statement and general recommendations for diagnosis and clinical research in reflex sympathetic dystrophy. 8 It is significant that Campbell was one of the signatories of that statement. Failure to produce clinical progress that parallels that made in basic research is probably due to a lack of clear definitions and guidelines for those with access to the clinical material. This excuse can no longer be considered valid. The foundation of a special interest group for pain and the sympathetic nervous system within the International Association for the Study of Pain, the presence of sessions and workshops on sympathetic pain a.t American Pain Society and similar meetings, and articles such as this have given widespread publicity to'the need for structured clinical research.
In a timely editorial, J~.nig7 summarized what needs to be done with regard to reflex sympathetic dystrophy. First, criteria for diagnosis must be agreed on by all disciplines. Second, there is a need for a large mass of reliable quantitative data from patients about changes in somatosensory and somatomotor functions and the various tissue changes. These may permit identification of subgroups of patients within the reflex sympathetic dystrophy heading. Finally, experimental work and hypotheses such as that in the focus article may be used to identify mechanisms and improve diagnosis, thus closing the audit loop and permitting the audit cycle to start again. This paper by Campbell and colleagues asks several questions at its conclusion. Among these are one about the prevalence of sympathetically maintained pain and others concerning aspects of the mechanisms concerned. The assumption is that the use of alpha-adrenergic blockade with phentolamine will diagnose accurately all those patients whose pain is due to this mechanism. This may well be true, but what does the clinician do with those who don't respond and who have a similar clinical presentation as shown by Arn6r? 3 It is clear that although the burning pain and the touch-provoked sensitivity seen in these patients may be dependent on sympathetic activity, other aspects are not. These include heatprovoked sensitivity, numbness, and paroxysmal pain. 9 However, it must be said that if we don't even know the prevalence of this problem, it is obvious that a substantial amount remains to be done. New animal models are being developed to aid in the investigation of the role of neuronal mechanisms and that of the sympathetic nervous system. 4,5.1~ However, these models will not provide all the answers, and this sort of work is increasingly threatened by public opinion. Cliniciar~s need to recognize the need to support this sort Of research and bring their own observations of clinical material into the public forum. Only by this methodcan we support our colleagues in basic science. The focus article does two important things. First, it brings basic science and clinical practice together in a way that has clear implications for the benefit of patient care. Second, by posing more questions than it answers, it acts as a stimulus for all who are concerned with this group of painful conditions to act together in a cohesive and coherent manner. These facts make this an important contribution and ensure a rousing send-off to the APSJournal, to which I add my own good wishes!
COMMENTARY/Charlton
References 1. Abram SE: Pain of sympathetic origin, pp. 451-463. In Raj PP (ed): Practical management of pain. Year Book, Chicago, 1986 2. Abram SE, Lightfoot RW: Treatment of long-standing causalgia with prazocin. Reg Anesth 6:79-81, 1981 3. Arn6r S: Intravenous phentolamine test: diagnostic and prognostic use in reflex sympathetic dystrophy. Pain 46:17-22, 1991 4. Attal N, Jazat F, Kayser V, Guilbaud G: Further evidence for 'pain-related' behaviours in a model of unilateral peripheral mononeuropathy. Pain 41:235-251, 1990 5. Bennet GJ: Evidence from animal models on the pathogenesis of painful peripheral neuropathy: relevance for pharmacotherapy. In Basbaum AI, Besson J-M (eds): Towards a new pharmacotherapy for pain: Dahlen workshop reports. Wiley, Chichester, NY, 1991
25
6. Ghostine SY, Comair YG, Turner DM et al: Phenoxybenzamine in the treatment of causalgia. J Neurosurg 60:1263-1268, 1984 7. J&nig W: Experimental approach to reflex sympathetic dystrophy and related syndromes. Pain 46:241-245, 1991 8. J&nig W, Blumberg H, Boas RA, Campbell JN: The reflex sympathetic dystrophy syndrome: consensus statement and general recommendations for diagnosis and clinical research, pp. 373-376. In Bond MR, Chad~ ton JE, Woolf CR (eds): Pain research and clinical management. Proceedings of the Vlth World Congress on Pain. Elsevier, Amsterdam, 1991 9. Price DD, Bennet GJ, Raffii A: Psychophysical observations on patients with neuropathic pain relieved by a sympathetic block. Pain 36:273-288, 1989 10. Seltzer Z, Dubner R, Shir Y: A novel behavioural model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43:205-218.
Practical Applications of Alpha Blockade J. E. Charlton
or those who cannot be bothered to read either the article or the commentary, the answer to the question posed in the title is y e s m p r o b a b l y m a n d you may have to change your clinical practice. For those who want to know a little bit more, this paper is yet another in a string of excellent papers from this distinguished group of authors. However, having said that, this latest work, as the authors freely admit, merely points both clinician and researcher in a particular direction. There has been evidence for a role for the alpha1 adrenoreceptor in the genesis of certain painful conditions for some time. Campbell and his colleagues quote this anecdotal evidence as support for their own contentions. The problem has been that no strong body of evidence exists to support the clinical use of alpha-adrenergic blocking agents such as phenoxybenzamine, phentolamine, or prazocin for treatment purposes. Of course, this has never stopped clinicians from trying them out in a speculative manner. Random use in occasional patients who fall into the category of "failed-to-respond-to-the-usual-things-let's-try-alpha-blockers-next" has led to a certain amount of skepticism about their value. This focus article permits the clinical use of these agents to be viewed in perspective, and suggests some guarded optimism about the future management of sympathetically maintained pain. The International Association for the Study of Pain has tried hard to introduce the concept of common terminology and definitions to improve our communication concerning pain. One of the most difficult areas has been concern over use of the terms "reflex sympathetic dystrophy" or '.'sympathetically main-
F
From Royal Victoria Infirmary, Newcastleupon Tyne,GreatBritain. Reprint requests:J. E. Charlton, C()nsultantAnestetist,The Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, Great Britain. APS Journal 1(1):23-25, 1992
tained pain." Campbell's group has drawn attention to the misleading nature of the terminology in the past. For example, from the clinician's point of view, sympathetically maintained pain implies that if a sympathetic block relieves the pain, there must be pathology of the sympathetic nervous system. The logical extension of this conclusion is that clinical benefit can be obtained by damaging the sympathetic system on a long-term basis. I must state at this point that I have always had problems with the idea of destroying parts of the neuraxis on an indiscriminate basis; if something is damaged, it seems illogical to expect further damage to be helpful! It is my view that if invasive therapy is to be used, it can only be after the most rigorous efforts to seek successful management with noninvasive methods. It must be clear to anyone with the most remote interest in the management of pain that there are many clinical conditions with a similar presentation where sympathetic block is not the complete answer to the problem, nor, it would appear, is alpha-1 adrenergic blockade. Thus, it is better to use the widely recognized term "reflex sympathetic dystrophy" until putative mechanisms and treatments become clearer. Some idea of the difficulties faced by clinicians can be gained by reading the article by A r n ~ on the development of the intravenous phentolamine test. This study included many patients, all of whom appeared to fit the criteria for sympathetically maintained pain. In previous years all may have been treated by destruction of the sympathetic nervous system on an empirical basis. With the intravenous phentolamine test Arn~r was able to differentiate between patients who would and would not respond to a sympathetic block. In the current paper, Campbell and his colleagues enlarge on the contribution of this diagnostic procedure to:the extent that testing the effect of alpha-1 adrenergic blockade must now be 23
24
COMMENTARY/Charlton
regarded as mandatory in patients presenting with reflex sympathetic dystrophy. What happens after that? What number of patients will respond to alpha-1 adrenergic blockade? Clearly, we don't know. Finding that a percentage of patients have pain which is mediated through the alpha-1 adrenergic system is valuable, but becomes less so if this knowledge cannot be translated into a long-term clinical benefit. Papers by Ghostine et al. 6 and Abram and Lightfoot 2 have reported benefit from oral alpha-adrenergic blocking drugs. Ghostine and colleagues reported 40 patients with causalgia, all with documented neural injury, who were treated with oral phenoxybenzamine in doses varying from 40 to 120 mg/day in divided doses. All patients reported total resolution of pain. Abram and Lightfoot's case report was most interesting as it used intravenous phentolamine to predict a successful response to alpha-adrenergic blockade with prazocin. Abram has alluded to further experience with prazocin in other published work, noting that the use of intravenous phentolamine was a predictor of a favorable response. 1 No details are given, but he seems lukewarm in his enthusiasm for prazocin as a treatment, describing improvement as "moderate," a term that could include many definitions. Thus, treatment with oral alpha-adrenergic blocking drugs appears to have made no impact on clinical practice, despite public knowledge of the alleged benefit for some years. What is the explanation for this? The first conclusion One might make is that it doesn't work, despite the mare/times it has been tried. The likely explanation is that clinicians have lacked the time and the willpower needed to carry outproperly conducted clinical trials. The time is now right for change. The last World Pain Congress, in Adelaide, saw a consensus statement and general recommendations for diagnosis and clinical research in reflex sympathetic dystrophy. 8 It is significant that Campbell was one of the signatories of that statement. Failure to produce clinical progress that parallels that made in basic research is probably due to a lack of clear definitions and guidelines for those with access to the clinical material. This excuse can no longer be considered valid. The foundation of a special interest group for pain and the sympathetic nervous system within the International Association for the Study of Pain, the presence of sessions and workshops on sympathetic pain a.t American Pain Society and similar meetings, and articles such as this have given widespread publicity to'the need for structured clinical research.
In a timely editorial, J~.nig7 summarized what needs to be done with regard to reflex sympathetic dystrophy. First, criteria for diagnosis must be agreed on by all disciplines. Second, there is a need for a large mass of reliable quantitative data from patients about changes in somatosensory and somatomotor functions and the various tissue changes. These may permit identification of subgroups of patients within the reflex sympathetic dystrophy heading. Finally, experimental work and hypotheses such as that in the focus article may be used to identify mechanisms and improve diagnosis, thus closing the audit loop and permitting the audit cycle to start again. This paper by Campbell and colleagues asks several questions at its conclusion. Among these are one about the prevalence of sympathetically maintained pain and others concerning aspects of the mechanisms concerned. The assumption is that the use of alpha-adrenergic blockade with phentolamine will diagnose accurately all those patients whose pain is due to this mechanism. This may well be true, but what does the clinician do with those who don't respond and who have a similar clinical presentation as shown by Arn6r? 3 It is clear that although the burning pain and the touch-provoked sensitivity seen in these patients may be dependent on sympathetic activity, other aspects are not. These include heatprovoked sensitivity, numbness, and paroxysmal pain. 9 However, it must be said that if we don't even know the prevalence of this problem, it is obvious that a substantial amount remains to be done. New animal models are being developed to aid in the investigation of the role of neuronal mechanisms and that of the sympathetic nervous system. 4,5.1~ However, these models will not provide all the answers, and this sort of work is increasingly threatened by public opinion. Cliniciar~s need to recognize the need to support this sort Of research and bring their own observations of clinical material into the public forum. Only by this methodcan we support our colleagues in basic science. The focus article does two important things. First, it brings basic science and clinical practice together in a way that has clear implications for the benefit of patient care. Second, by posing more questions than it answers, it acts as a stimulus for all who are concerned with this group of painful conditions to act together in a cohesive and coherent manner. These facts make this an important contribution and ensure a rousing send-off to the APSJournal, to which I add my own good wishes!
COMMENTARY/Charlton
References 1. Abram SE: Pain of sympathetic origin, pp. 451-463. In Raj PP (ed): Practical management of pain. Year Book, Chicago, 1986 2. Abram SE, Lightfoot RW: Treatment of long-standing causalgia with prazocin. Reg Anesth 6:79-81, 1981 3. Arn6r S: Intravenous phentolamine test: diagnostic and prognostic use in reflex sympathetic dystrophy. Pain 46:17-22, 1991 4. Attal N, Jazat F, Kayser V, Guilbaud G: Further evidence for 'pain-related' behaviours in a model of unilateral peripheral mononeuropathy. Pain 41:235-251, 1990 5. Bennet GJ: Evidence from animal models on the pathogenesis of painful peripheral neuropathy: relevance for pharmacotherapy. In Basbaum AI, Besson J-M (eds): Towards a new pharmacotherapy for pain: Dahlen workshop reports. Wiley, Chichester, NY, 1991
25
6. Ghostine SY, Comair YG, Turner DM et al: Phenoxybenzamine in the treatment of causalgia. J Neurosurg 60:1263-1268, 1984 7. J&nig W: Experimental approach to reflex sympathetic dystrophy and related syndromes. Pain 46:241-245, 1991 8. J&nig W, Blumberg H, Boas RA, Campbell JN: The reflex sympathetic dystrophy syndrome: consensus statement and general recommendations for diagnosis and clinical research, pp. 373-376. In Bond MR, Chad~ ton JE, Woolf CR (eds): Pain research and clinical management. Proceedings of the Vlth World Congress on Pain. Elsevier, Amsterdam, 1991 9. Price DD, Bennet GJ, Raffii A: Psychophysical observations on patients with neuropathic pain relieved by a sympathetic block. Pain 36:273-288, 1989 10. Seltzer Z, Dubner R, Shir Y: A novel behavioural model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43:205-218.