Gabapentin May Be Appropriate for Off-Label Uses

Gabapentin May Be Appropriate for Off-Label Uses In this issue, Alicia Mack, PharmD, discusses the clinical literature of the “off-label” uses of gabapentin (Neurontin) to prepare managed care practitioners for the appropriate uses of gabapentin. In the review, Mack examines several off-label uses of gabapentin, leading her to the conclusion that patients should only receive gabapentin when they have failed standard treatment options and when efficacy has been demonstrated in a randomized controlled trial. The methods by which gabapentin has become a drug with more than a billion dollars in annual sales in the United States are being examined in the federal court system. Regardless of the outcomes of the federal investigation of marketing practices, the use of gabapentin for off-label indications far surpasses its FDAapproved indications. Gabapentin may have become a “catchall” medication for practitioners because its exact mechanism of action remains unknown and because it can be prescribed to patients with hepatic and/or renal insufficiencies. Furthermore, data ranging from case studies to randomized double-blind, placebo-controlled studies suggest that gabapentin may have positive effects on patients with a variety of disease states. Randomized double-blind studies are the gold standard when researchers are trying to compare medication regimens. However, the studies must be critically evaluated to ensure that the results can be applied to a specific patient population. Mack cites a study by Morello that was a randomized double-blind study comparing the efficacy of gabapentin to amitriptyline on diabetic peripheral neuropathy pain. The results state that there is no statistically significant difference between the 2 medications. However, the study was conducted in the Veterans Affairs (VA) San Diego Healthcare System. The demographics of the study—24 men and 1 woman—do not accurately depict the American population of diabetics, which is more than 50% female. The study was well designed and the results are accurate, but they may not be generalized to patient populations outside the VA system. A similar study performed by Dallocchio et al. states that gabapentin significantly reduced pain scores, improved paresthesia scores, and had a better safety profile when compared with amitriptyline. The study was an open-label design, but the authors lessened possible biases by randomizing the patients to treatment arms. In addition, the patient population was also more representative of the American diabetic population (11 males, 14 females). Even though the study lacked blinding, the results may be considered as more applicable based upon the generalizability of the results. Moreover, all published data must be assessed to determine their applicability to specific patient cases. The evidence-based practice of medicine allows therapies to evolve in search of the optimal treatment. A recent example utilizes metformin as adjunctive therapy in adolescents with type 1 diabetes. Another article by Gomez states that metformin adjunctive therapy may improve glycemic control in type 1 diabetic patients. If several articles are published about metformin use in type 1 diabetes, a meta-analysis can be performed to determine treatment effectiveness. A meta-analysis, such as the one performed by Backonja and Glanzman for gabapentin, provides an immense amount of data on the treatment of painful diabetic neuropathy, postherpetic neuralgia, and other neuropathic pain syndromes. Metaanalyses of well-designed studies provide greater generalizability when compared with smaller well-designed, randomized controlled trials, due to greater statistical power. Therefore, a practitioner can confidently apply the data to treat a more diverse patient population. Off-label uses may become clinically acceptable without having an FDA-approved indication. Speculation arises concerning consistency of gabapentin offlabel use due to a lack of manufacturer prescribing guidelines. A retrospective study in a managed Medicaid population (N=105) by Hamer et al. demonstrated that 95% of patients received gabapentin for off-label uses. Results indicated that 59% of patients receiving gabapentin continued treatment with the initial prescriber; 47% of patients received gabapentin 3 times daily, the usual dosing frequency; 40% of patients had no documented follow-up related to gabapentin; and 65% of patients discontinued therapy by the end of the study period. Additionally, the average dose received was predominately at the lower end of published dosage ranges. Based on the review, Hamer concluded that patients did not appear to receive benefit from gabapentin. Consequently, are the results due to gabapentin ineffectiveness, improper titration and follow-up, poor patient compliance, an atypical population, or a combination thereof? Health professionals choosing to practice evidence-based medicine must adhere to the published literature in regard to dosing, titration, and follow-up to accurately medicate their patient population. The medical community has helped to make gabapentin a blockbuster drug, in part through prescribing for off-label uses. Gabapentin is used to treat some patients with unexplainable pathophysiologies; in patients with multiple, complex disease states; and in patients who have demonstrated intolerance to other therapies. John Barbuto, MD, a practicing neurologist, observed in a previous issue of the Journal that logic drives the use of gabapentin because of its (a) few major side effects (and lower risk of malpractice lawsuits); (b) few drug interactions, a consideration more important for this patient population that has a relatively high incidence of affective disorders and chronic pain and tends to be taking multiple drugs; (c) favorable tolerance for these patients with affective disorders and chronic pain who are more prone to complain of side effects; and (d) relative ease of use (e.g., less need for follow-up laboratory monitoring). In many cases, practitioners are unable to pinpoint the mechanism causing relief; critics refer to this as the placebo effect and demand randomized controlled trials to justify the cost of gabapentin. Is it financially responsible to conduct a randomized controlled study to demonstrate results beyond a rea-

In this issue, Alicia Mack, PharmD, discusses the clinical literature of the "off-label" uses of gabapentin (Neurontin) to prepare managed care practitioners for the appropriate uses of gabapentin. 1 In the review, Mack examines several off-label uses of gabapentin, leading her to the conclusion that patients should only receive gabapentin when they have failed standard treatment options and when efficacy has been demonstrated in a randomized controlled trial. 1 The methods by which gabapentin has become a drug with more than a billion dollars in annual sales in the United States are being examined in the federal court system. 2 Regardless of the outcomes of the federal investigation of marketing practices, the use of gabapentin for off-label indications far surpasses its FDAapproved indications. 3 Gabapentin may have become a "catchall" medication for practitioners because its exact mechanism of action remains unknown and because it can be prescribed to patients with hepatic and/or renal insufficiencies. 4 Furthermore, data ranging from case studies to randomized double-blind, placebo-controlled studies suggest that gabapentin may have positive effects on patients with a variety of disease states.
Randomized double-blind studies are the gold standard when researchers are trying to compare medication regimens. However, the studies must be critically evaluated to ensure that the results can be applied to a specific patient population.
Mack cites a study by Morello 5 that was a randomized double-blind study comparing the efficacy of gabapentin to amitriptyline on diabetic peripheral neuropathy pain. The results state that there is no statistically significant difference between the 2 medications. However, the study was conducted in the Veterans Affairs (VA) San Diego Healthcare System. 5 The demographics of the study-24 men and 1 woman-do not accurately depict the American population of diabetics, which is more than 50% female. 6 The study was well designed and the results are accurate, but they may not be generalized to patient populations outside the VA system. A similar study performed by Dallocchio et al. states that gabapentin significantly reduced pain scores, improved paresthesia scores, and had a better safety profile when compared with amitriptyline. 7 The study was an open-label design, but the authors lessened possible biases by randomizing the patients to treatment arms. 7 In addition, the patient population was also more representative of the American diabetic population (11 males, 14 females). Even though the study lacked blinding, the results may be considered as more applicable based upon the generalizability of the results. Moreover, all published data must be assessed to determine their applicability to specific patient cases.
The evidence-based practice of medicine allows therapies to evolve in search of the optimal treatment. A recent example utilizes metformin as adjunctive therapy in adolescents with type 1 diabetes. 8 Another article by Gomez 9 states that metformin adjunctive therapy may improve glycemic control in type 1 diabetic patients. If several articles are published about metformin use in type 1 diabetes, a meta-analysis can be performed to determine treatment effectiveness.
A meta-analysis, such as the one performed by Backonja and Glanzman 10 for gabapentin, provides an immense amount of data on the treatment of painful diabetic neuropathy, postherpetic neuralgia, and other neuropathic pain syndromes. Metaanalyses of well-designed studies provide greater generalizability when compared with smaller well-designed, randomized controlled trials, due to greater statistical power. Therefore, a practitioner can confidently apply the data to treat a more diverse patient population. Off-label uses may become clinically acceptable without having an FDA-approved indication.
Speculation arises concerning consistency of gabapentin offlabel use due to a lack of manufacturer prescribing guidelines. A retrospective study in a managed Medicaid population (N=105) by Hamer et al. demonstrated that 95% of patients received gabapentin for off-label uses. 11 Results indicated that 59% of patients receiving gabapentin continued treatment with the initial prescriber; 47% of patients received gabapentin 3 times daily, the usual dosing frequency; 40% of patients had no documented follow-up related to gabapentin; and 65% of patients discontinued therapy by the end of the study period. 11 Additionally, the average dose received was predominately at the lower end of published dosage ranges. 11 Based on the review, Hamer concluded that patients did not appear to receive benefit from gabapentin. 11 Consequently, are the results due to gabapentin ineffectiveness, improper titration and follow-up, poor patient compliance, an atypical population, or a combination thereof? Health professionals choosing to practice evidence-based medicine must adhere to the published literature in regard to dosing, titration, and follow-up to accurately medicate their patient population.
The medical community has helped to make gabapentin a blockbuster drug, in part through prescribing for off-label uses. Gabapentin is used to treat some patients with unexplainable pathophysiologies; in patients with multiple, complex disease states; and in patients who have demonstrated intolerance to other therapies. John Barbuto, MD, a practicing neurologist, observed in a previous issue of the Journal that logic drives the use of gabapentin because of its (a) few major side effects (and lower risk of malpractice lawsuits); (b) few drug interactions, a consideration more important for this patient population that has a relatively high incidence of affective disorders and chronic pain and tends to be taking multiple drugs; (c) favorable tolerance for these patients with affective disorders and chronic pain who are more prone to complain of side effects; and (d) relative ease of use (e.g., less need for follow-up laboratory monitoring). 12 In many cases, practitioners are unable to pinpoint the mechanism causing relief; critics refer to this as the placebo effect and demand randomized controlled trials to justify the cost of gabapentin. Is it financially responsible to conduct a randomized controlled study to demonstrate results beyond a reawww.amcp.org Vol. 9, No. 6 November/December 2003 JMCP Journal of Managed Care Pharmacy 569 sonable doubt when conclusions from a meta-analysis of all published data suggest clinical effectiveness and certain patients seem to respond favorably to gabapentin?
Limiting the use of gabapentin to an alternative status for only times when the patient is intolerant of the standard treatment option(s) or only when it has been studied in randomized controlled trials would be practicing "black and white" medicine in an environment that is actually various shades of gray. Practicing evidence-based medicine requires the health care professional to critically evaluate the literature, consider all possible therapeutic options, select therapy that will adequately treat the patient, and properly follow the patient in order to minimize the cost to the health care system.

Shawn Davis PharmD Candidate, 2004 The Ohio State University College of Pharmacy
Columbus, Ohio E-mail: davis.1685@osu.edu

II Use of Drugs for Off-Label Indications: Living in the Same World
Learning is acquired by reading books; but the much more necessary learning, the knowledge of the world, is only to be acquired by reading man, and studying all the various editions of them.
-Philip Dormer Stanhope, statesman and writer  In this issue Alicia Mack, PharmD, 1 discusses a proposal that gabapentin use be restricted to its label indications. 1 While her argument is based on perspectives of documented science, it may miss the point. Medical care is based on serving patients. The demands of this are a far cry from rigorous science. In the real world, the perspectives of Mack are, in my opinion, impractical.
Scientifically, it would be ideal if medical care proceeded as a rigorous science. Yet, it doesn't. Ultimately, medical care is about patient satisfaction. Patients do not go to the doctor to be provided rigorous science. Patients go to the doctor to meet their medical desires. There is only a partial correlation between these and the interests of science. If you were to attempt to provide medical care based on rigorous science (and I, more or less, have tried this), you would find that what you receive is patient dissatisfaction, even hostility. The average patient is only interested in rigorous science when this happens to be consistent with beliefs and desires.
What is the proof for this? The proof is plentiful indeed. Let' s start with some very simple perspectives: smoking, obesity, narcotic addiction. Is there evidence that smoking is bad for health? Do people continue to smoke? Do a lot of people continue to smoke? Or, is there evidence that obesity is bad for health? Do people continue to overeat? Do a lot of people continue to overeat? Or, is there evidence that drug addiction is bad for health? Do a lot of people abuse drugs? What do we learn from these observations? What are these people doing? Are they looking for the answers of rigorous science, or something else?
Now, let' s consider more subtle proof. There are countries of the world that have life expectancies equal to ours but that also have far lower health care costs. Widely available statistics (from the U.S. Census Bureau' s International Data Base, for instance) reveal that the United States is certainly not heading the list of life expectancy. By some measures, we're down around rank 20. Yet, our health care costs are not only the highest in the world in terms of percent GNP but also are about double the costs for some other countries whose life expectancies are similar (or greater) than ours, such as England and Japan. 2 Why is this proof for the tenet above? Science would dictate that all of our cost is not necessary. Yet, people of America do seek and consume health care to a greater extent than anywhere in the world. So, is this meeting the needs revealed by science, or is this consumption driven by something else? Information on heath care costs across the world are widely available. If we are so interested in reducing costs, why do we not, as scientists, look at outcomes across the world? Part of the reason is simply that medical care is only part-