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12 Articles in Volume 11, Issue #1
Simultaneous Use of Stimulants 
and Opioids
Therapy for Management of Childbirth Perineal Tears and Post-Partum Pain
Measuring Clinical Outcomes of Chronic Pain Patients
Real-Time Functional Magnetic Resonance Imaging in Pain Management
A Non-Surgical Treatment for Carpal Tunnel Syndrome
Fibromyalgia, Chronic Widespread Pain, and the Fallacy of Pain from Nowhere
Sonoanatomy and Injection Technique of the Iliolumbar Ligament
Back Surgery That Does Not Relieve Pain
The Immune System and Headache
Diversity in Pharmacologic Treatment of Pain
Memantine for Migraine and Tension-Type Headache Prophylaxis
Pain Management in Inflammatory Arthritis

Diversity in Pharmacologic Treatment of Pain

An essay on the neuroscientific, ethical and policy issues surrounding pharmacologic pain care in light of certain controlled substances that, while efficacious in certain patients, may be problematic in practice.

Pharmacologic Pain Care— From Epistemology to Ethics

Pharmacologic management of chronic pain remains problematic in that it often evokes questions and issues at the practical intersection of biomedical science, ethics and law. In the first domain, the recognition that chronic pain and its modulation are subserved by heterogeneous substrates and mechanisms that involve a variety of neurochemical systems is essential to any consideration of what agents would be viable to target one or more of the elements on the nociceptive neuraxis. This information enables a more thorough recognition of how certain neuroanatomic and neurochemical elements contribute to pain, and how they can be engaged to affect change(s) in nocicpetion and/or analgesia. This provides a basis for determining what agents in the contemporary pharmacopeia might be viable and valuable to produce desired levels of pain relief. In other words, such information affords insight to the first two critical questions, and discerning steps, of the clinical encounter, namely, the determination of what is wrong with a particular patient and what can be done to remedy their predicament. 1-3 Given the complexity of chronic pain, it is axiomatic that its pharmacologic management requires a diversity of agents —both to address individual differences inherent to the neurochemical profile of each patient’s pain and to engage pain- and treatment-related changes in an individual patients’ neurochemistry that occur over time. As I have often stated, our current knowledge of pain dictates against overly simplistic, “cookie cutter” orientations to practical pain management. 1,2,4 To be sure, this is becoming evermore relevant in light of calls for—and a trend towards—personalized medicine. Any realistic assumption of such a personalized approach to pain care would need to consider individual genotypic and phenotypic variations in nociceptive and anti-nociceptive systems at least as a starting point and/or basis for the development and implementation of appropriate pharmacotherapeutic regimens. 5

Personalized Pain Medicine

In many ways, a personalized pain medicine could be seen as most directly serving the primacy of each patient’s best interests in that it is grounded to the uniquity of the individual and thereby avoids “one size fits all” approaches to care. Certainly, knowledge of specific neurobiological bases of a given patient’s pain is critical but it is equally (if not in some cases more) important to consider and appreciate how psycho-social factors influence—and are affected by—the experience and expression of physiological variables. Simply put, humans are bio-psychosocial beings and pain is manifest in, and impacted by, each of these dimensions. This view is not esoteric. Rather, such an epistemological orientation to the person in pain and the effects of pain upon the lived body and life world of each person provides a foundation for the ethical responsibilities that arise from, and are entailed by, this position. 6,7 A more complete depiction of each patient’s bio-psychosocial individuality would:

  1. allow greater specificity in selecting what therapeutic interventions could be viable;
  2. facilitate resolution of equipoise in clinical decision-making, and thereby
  3. fortify prudential formulation of a care plan that is consistent with each patients’ (medical) needs, life values and goals, as well as the expert insights and therapeutic goals of the clinician. 8

This illustrates the relation of knowledge to ethically sound clinical practice—at least in principle. But, to quote an old adage: There is much to divert the egg between the chicken and the pan…

The Medical and Socio-Legal Realities of Pharmacologic Pain Care

Neuroscientific data that identifies that—and how—opioid, glutaminergic, GABA-ergic and monoaminergic systems are involved to varying degrees in the modulation of certain types of pain is undeniably critical to devising a pharmacotherapeutic regimen. Still, such data can be seen as “theoretical” or “conceptual,” and determination of the actual extent that these systems are engaged remains inferential for various reasons:

  1. measurements of central neurochemistry are impractical and/or overly invasive (i.e., requiring assessment of cerebrospinal fluid via lumbar puncture);
  2. are expensive and thus are characteristically used only in the research setting (e.g., use of radiolabeled ligands to determine differential activity/sensitivity of various CNS substrates); and/or
  3. not yet available at the level of accuracy or reliability necessary for broad clinical use. 9-11

In light of this, the use of any pharmacololgic agent is based upon empirical outcomes and existing levels of evidence gained in clinical trials and practice. In this latter regard, professional guidelines are formulated that suggest particular utility and parameters (e.g., dose, schedule, contraindications, etc.). Ultimately, however, policies and laws afford the most over-arching regulation to dictate and/or direct clinical provision and use of pharmacotherapeutics. However, a somewhat less overt level of control is effected through indirect regulation imposed by economic and market forces such as the availability of insurance, insurance-coverage dictates of the types and extant of use of particular agents and the portfolio of various hospitals’ pharmacopeia. 12 These elements are frequently non-aligned and, in many cases, may actually be dissonant and create situations in which the provision of necessary care cannot be achieved because of economics, policy, and/or law. To reiterate, chronic pain is frequently a complex entity that involves multiple anatomic and neurochemical mechanisms. But, such complexity does not refute the benefit of parsimony when executing clinical therapeutics. The right use of limited, but potent, pharmacotherapeutics will often provide the simplest means to achieve the best results in alleviating pain and restoring function. But here we may encounter an antinomy. What if the simplest solution fosters further complications? In other words, what if the right treatment—that also affords the most potential good—also incurs considerable difficulty, burden, and perhaps harm? For example, the prima facie use of opioid analgesics can be considered to provide meaningful benefit to patients with particular types of pain. Yet, even under ideal circumstances, we cannot deny the potential medical, ethical, economic, and legal issues that may arise in and from the use of such agents. Moreover, prima facie considerations very often pale in the glare of the multi-dimensional factors that constitute the realities of pain, pain patients, and their existential circumstances. Often, these are influenced by dispositions within the medical and socio-legal milieu that are based, at least in part, upon the ways that pain and its manifestations are defined and characterized. Despite an underlying incentive for overarching moral regard, such dispositions commonly affect public, medical and legal attitudes as well as conduct toward pain and the pain patient. Any authentic consideration of pain and its care must acknowledge these realities.

Is Ockham’s Razor Double-Edged?

In this issue of Practical Pain Management , Dr. Forest Tennant addresses the potential viability of stimulant agents in the pharmacololgic management of chronic pain. 13 As Dr. Tennant notes, like any class of drugs, stimulants are not universally applicable in the treatment of chronic pain and are clearly not indicated for use against certain types of pain (for example, sympathetically-maintained pain, and/or complex regional pain syndrome). Yet, there is a growing body of evidence to support the utility of stimulants:

1) as adjunctive analgesics (i.e., to potentiate noradrenergic mechanisms of centrifugal analgesia and/or engage forebrain dopaminergic substrates operative in perceptual/cognitive aspects of pain modulation 14,15 ), and

2) to counterbalance the sedative and cognitive-blunting effects of opioids.

    While describing the historical and practical use of stimulants in pain therapeutics, Dr. Tennant also raises a number of yet unanswered questions concerning dose, pharmacologic complications, and possibility of tolerance. To this last point, he adds concerns about the potential for abuse and recommends a cautionary stance and approach when, and if, stimulants are considered. Indubitably, these are important questions and implicit to Dr. Tennant’s argument is the need for responsible action—on the part of physicians, patients, and administrative bodies that direct and dictate the provision and conduct of care. Mechanistically, stimulant drugs engage monoaminergic mechanisms that are inherently plastic. 16 Pharmacologically-mediated changes in sympathetic function and central substrates of reinforcement and reward are certainly possible 17 and therefore must be considered as an effect of even moderate-term stimulant use. Dr. Tennant rightfully states that careful monitoring and dose regulation are important to prevent and/or subvert the potential tolerance and (physiological and psychological) dependence that may result. But, it would be naive to presume that each and every patient is wholly compliant with the prescriptions. Proscriptions provided by his/her physician and such non-compliance would incur particular risks for stimulant misuse, tolerance and dependence. Thus, I agree with Dr. Tennant’s advocacy that stimulants should only be prescribed to those pain patients that are well-known to the clinician and, even then, should be employed with restraint as part of a prudent pharmacotherapeutic regimen—either singularly or in combination with opioids and/or other (non-opioid) analgesics. The use of a stimulant may actually enable the analgesic regimen to be simplified by allowing somewhat higher doses of opioid to be utilized where needed, or an opioid rotation to be employed, without burden of adverse (cognitive) effects upon initiation of the new drug. 18 The case studies provided illustrate these possibilities to good effect. However, another unanswered question looms large—and has perhaps greater potential to affect the practical provision and conduct of pain management—namely, whether the use of stimulants in the pharmacologic management of pain is supportable and sustainable given the regnant medico-legal climate. Current guidelines and codifications of care do not uniformly endorse the use of stimulants as adjuncts to analgesic pharmacotherapy. Thus, despite existing evidence in the literature to support the use of stimulants, ambiguities regarding the value and benefit of such approaches, when coupled to variations in clinical guidelines, can create situations in which the validity of stimulant use is questioned. Moreover, these ambiguities may incur additional (medical and legal) issues and problems as a result of potential misconceptions and misdiagnoses of substance abuse and “addiction” as the DSM-IV is phased out and replaced with the new DSM-V in 2012. 19 For example, how would a pain patient, who is using both opioids and a stimulant, be regarded and treated if he/she was to seek (a) emergency care (e.g., for breakthrough pain), or (b) treatment by a provider other than their usual pain physician? This may be especially problematic, given:

    1) the absence of uniform and clear-cut guidelines advocating the use of stimulants in pain control, and

    2) shifting diagnostic criteria for substance abuse and addiction during and after the transition from DSM-IV to DSM-V?

      Obviously, there is a high likelihood and probability of stigmatization with such labels often incurring durable effects—both upon the nature of current and subsequent care, and the patient’s construct of self, illness, and worth. Furthermore, the problem is not limited to the patient. Stimulants are controlled substances and the lack of guidelines and policies to support their use in pain patients (particularly those who are already receiving other scheduled compounds such as opioids) can render physicians increasingly vulnerable to professional sanction and/or legal prosecution. As we have reported, even though the actual number of Drug Enforcement Agency (DEA) actions against licensed physicians over the past 10 years has been very low, the attitude and ambiance fostered by the DEA has prompted claims that the war on drugs has become a battleground in which the ultimate casualties are both law-abiding physicians and inadequately-treated pain patients. 20,21

      A Path Forward

      I concur with Dr. Tennant that stimulants can play a useful role in management of chronic pain and believe that this position is defensible on scientific, clinical and ethical grounds (vide supra). However, its feasibility and tenability are threatened by the lack of guidelines and policies to sustain it in practice. To illustrate the effect(s) of such conflicting imperatives, one need only consider the Gordian tangle of scientific evidence, guidelines, policies, law(s) and social stigma surrounding—and impeding—the medical use of cannabis for pain. Perhaps then, the truly critical unanswered question is not if, or why, stimulants can be successfully employed in the pharmacologic management of chronic pain but how guidelines, policies, and laws must be modified and/or developed to support the prudent use of these agents in the provision of ethically sound pain care. It is undeniable that any attempt in this direction must be built upon, informed, and sustained by fact(s), as well as the need for additional research that addresses the biomedical, ethical, economic, and legal aspects of this topic. Yet, such research will require financial support and here we encounter something of the “chicken and the egg” dilemma. Guidelines and polices to direct subsidy for such research must be in place to permit studies that inform clinical, economic and legal guidelines and policies. This can easily become an exercise in circular reasoning and futility. However, I do not believe that it is irresolvable. The absurd circularity of this situation can be remedied by:

      1) using available fiscal resources to expand the corpus of research in these areas;

      2) active lobbying to develop new avenues of financial support for studies to demonstrate the viability and ethically rational use of stimulants (as well as other classes of drugs, and novel techniques and technologies) in controlling certain types of chronic pain; and

      3) using extant information as a basis for revising current guidelines, policies and laws to better enable both research and the use of its outcomes in practice.

        Such efforts are usually regarded as the province of professional organizations and this is certainly accurate. However, there is equal responsibility for individual pain physicians to contribute to organizational efforts to reform and rewrite practice guidelines, engage in policy forums, and conduct and participate in clinical studies that expand the existing base of knowledge. Clearly, this will entail and obtain change and, while irrefutably necessary and important, the process can be arduous, time-consuming and slow. But, to quote Epictetus: “…nothing great comes into being all at once…do everything both cautiously and confidently at the same time.” 22

        Last updated on: March 7, 2011
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