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ORIGINAL RESEARCH Gabapentin Use in a Managed Medicaid Population ANN M. HAMER, PharmD; DEAN G. HAXBY, PharmD, BENTSON H. MCFARLAND, MD, PhD; and KATHY KETCHUM, RPh, MPA:HA ABSTRACT OBJECTIVE: The use of gabapentin, an antiepileptic agent, in a primary care setting was evaluated to determine (a) the conditions being treated, (b) specialties of the prescribers, (c) dose ranges, and (d) the extent of documentation and follow-up. METHODS: A retrospective review of both claims data and patient charts was performed by a clinical pharmacist. Patients were identified from CareOregon and Oregon Medicaid fee-for-service drug claim databases. All patients were recipients of the Oregon Medicaid program known as the Oregon Health Plan (OHP) and were enrolled members of CareOregon, a contracted OHP managed care organization that primarily serves Medicaid recipients. All patients received care at one of four Oregon Health and Science University primary care clinics. RESULTS: Of the 105 patients studied, 95% received gabapentin for off-label diagnoses. Chronic pain and mental disorders were the diagnoses associated with the majority of prescriptions for gabapentin. Dose and dose intervals varied greatly. Very few patients (12%) had a documented efficacious response to gabapentin therapy. Of the patients started on gabapentin, 40% of patients had no documented follow-up. CONCLUSIONS: Almost all patients in this sample from the Medicaid managed population received gabapentin for off-label indications. Evidence from clinical trials does not support the use of gabapentin for many of the conditions treated with gabapentin in this study. Most patients did not appear to benefit from gabapentin therapy. KEYWORDS: Gabapentin, Medicaid, Drug Use Review, Off-Label Use J Man Care Pharm 2002:(8)4:266-71 G abapentin is an antiepileptic agent approved by the FDA in 1993 for the adjunctive therapy of partial seizures with or without secondary generalization. Despite being indicated only for the adjunctive treatment of seizures, utilization of gabapentin has increased markedly since its introduction. The National Institute for Health Care Management reported that gabapentin was the 17th-ranked drug in terms of expenditures in 2000 and the top-selling anticonvulsant. They also reported a 63.3% increase in annual sales from 1999 to 2000 and a 45.9% increase in prescription volume.1 These are among the largest increases reported for the top 50 drugs. Similar trends are noted in the Oregon Health Plan (OHP), Oregon’s Medicaid program. In 2001, gabapentin was listed in the top-10 drug products by total cost for the fee-for-service Oregon Medicaid program. The rise in the number of prescriptions and drug spending for gabapentin is not attributed solely to its use as an anticonvulsant. In fact, much has been published on the off-label use of gabapentin, particularly in psychiatric disorders and chronic pain syndromes. Many of these studies, however, are open-label or case studies and do not offer adequate evidence for the off-label use of gabapentin. A limited number of randomized controlled trials are available and have been summarized in Table 1. Currently, there is little published information available regarding how gabapentin is being used in clinical practice. Due to the widespread and growing use of this drug, it is important to assess utilization patterns. The objective of this study was to evaluate the use of gabapentin in a primary care setting to determine the following: (a) conditions being treated, (b) specialties of the prescribers, (c) dose ranges, and (d) extent of documentation of follow-up care, monitoring, and evidence of effectiveness. ■■ Methods Authors ANN M. HAMER, PharmD, is a Clinical Pharmacy Specialist, Oregon State University, College of Pharmacy, Oregon Health and Science University, Portland, Oregon; DEAN G. HAXBY, PharmD, is an Associate Professor of Pharmacy Practice and Director of Medicaid Programs, Oregon State University, College of Pharmacy, Oregon Health and Science University, Portland, Oregon; BENTSON H. MCFARLAND, MD, PhD, is Professor of Psychiatry, Public Health, and Preventive Medicine, Department of Psychiatry, Oregon Health and Science University, Portland, Oregon; KATHY KETCHUM, RPh, MPA, HA, is Coordinator of Medicaid Programs, Oregon State University, College of Pharmacy, Oregon Health and Science University, Portland, Oregon. AUTHOR CORRESPONDENCE: Dean Haxby, PharmD, Oregon State University, College of Pharmacy, GH 212, Oregon Health and Science University, Portland, OR 97201. Tel: (503) 494-5778; Fax: (503) 494-8797; E-mail: [email protected]. Copyright©2002 Academy of Managed Care Pharmacy. All rights reserved. 266 Journal of Managed Care Pharmacy JMCP July/August 2002 Study Design This study involved a retrospective review of both reimbursement claims data and patient medical charts. Subjects included in the study were identified from CareOregon and Oregon Medicaid feefor-service drug claim databases. CareOregon is a contracted OHP managed care organization that primarily serves Medicaid recipients. These databases capture basic demographic information as well as drug claim information from prescriptions dispensed at Oregon pharmacies. Chart review and data collection were conducted by a clinical pharmacist. A data-collection form was developed and tested on a sample population. Information gathered by the form included patient demographics, prescriber information, indications for gabapentin use, secondary diagnoses, duration of use, reasons for discontinuation, and follow-up information. Vol. 8, No. 4 www.amcp.org Gabapentin Use in a Managed Medicaid Population TABLE 1 Summary of Randomized Controlled Trials Using Gabapentin to Treat Off-Label Conditions STUDY Neuropathic Pain Backonja M, Beydoun A, et al. 7/96-3/97 RCT 8-week trial Morello CM, et al. 3/97-12/97 RCT, crossover 2-week, 6-week trials Gorson KC, et al. unknown date RCT, crossover 12-week trial Rowbotham M, et al. 8/96-7-97 RCT 8-week trial Bipolar Affective Disorder Frye M, Post RM, et al. RCT, crossover 3-week, 6-week monotherapy evaluations Pande AC, et al. RCT Spasticity/Tremor Gironell A, et al. RCT, crossover and placebo-controlled 26-day trial Ondo W, et al. RCT, crossover and placebo-controlled TREATMENT POPULATION RESULTS REFERENCE 3,600 mg/day (forced max) 67% achieved Uncontrolled diabetics (75% type 2) n=84 gabapentin n=81 placebo JAMA. 1998;280:1831-36 gabapentin= 900-1,800 mg/day amitriptyline: 25-75 mg/day Controlled diabetics n=19 veterans completing both tx arms of cross-over trial Diabetics; control not mentioned n=19 gabapentin n=21 placebo Gabapentin vs. placebo Difference in mean pain score at end point=-1.2 (P<.001). Difference in mean sleep interference score= -1.47 (P<.001). No statistically significant difference in pain intensity scores or in pain relief. Statistical improvement in only 1 of 4 end points; the MPQ (McGill Pain Questionnaire) with a mean reduction of 8.9 pts. compared to 2.2 pts. placebo (P=0.03). Decrease in average daily pain score=33% gabapentin, 7% placebo (P<0.001). J Neurol Neurosurg Psychiatry. 1999; 66:251-52 900 mg/day vs. placebo 3,600 mg/day (65% achieved max dose) vs. placebo Postherpetic neuralgia n=113 gabapentin n=112 placebo gabapentin= 3,987 ±856 mg/day lamotrigine=274 ±128 mg/day vs. placebo adjunctive use of gabapentin 900-3,600 mg/day Refractory BAD or unipolar mood disorder n=31 BAD, type I, current symptoms despite ongoing therapy gabapentin= Essential tremor 1,200 mg/day n=16 propranolol= 120 mg/day gabapentin= Essential tremor 1,800 mg/day or n=20 3,600 mg/day vs. placebo Cutter N, et al. RCT, crossover 26-day trial 2,700 mg/day vs. placebo Spasticity in MS n=21 (19M, 2F) Panic/Anxiety Pande AC, et al. RCT 14-week trial 900-3,600 mg/day vs. placebo Social phobia n=69 600-3,600 mg/day vs. placebo Panic disorder n=103 2,400 mg/day vs. placebo Migraine prophylaxis n=143 Pande AC, et al. RCT 8-week trial Migraine Prophylaxis Mathew NT, et al. RCT 16-week trial Arch Intern Med.1999; 159:1931-37 Ann Pharmacother. 2000; 34:802-07 Gabapentin monotherapy is equivalent to placebo. (P=0.70) Primary outcome measure was the Clinical Global Impressions Scale (CGI). Both decreased Young Mania Rating Scale, placebo significantly more than gabapentin (P<0.05). No significant difference between groups on HAM-D. J Clin Psychopharmacol. 2000;20:607-14. No significant differences found between active treatments on Tremor Clinical Rating Scale (P=0.20). Patient global assessments (P<0.05), observed tremor scores (P<0.005), water pouring scores (P<0.05), and ADL scores (P<0.005) significantly improved. Low dose equivalent to high dose. Comparing changes from gabapentin with changes from placebo, there were significant differences noted in spasm severity, interference with function, painful spasm, global assessment, Modified Ashworth Scale, and plantar stimulation response. There was no significant change in Digit Span, Digit Symbol, the adjective generation technique, or the EDSS. Arch Neurol. 1999; 56:475-80 Bipolar Disorders. 2000;2:249-55. (abstract only) Movement Disorders. 2000; 15:678-82. (abstract only) Arch Phys Med Rehabil. 2000; 81:164-69 A significant (P<0.05) reduction in sex was seen in active vs. placebo groups. Further studies are required to determine dose-response relationship. No overall drug/placebo difference was observed in scores on the Panic and Agoraphobia Scale. (P=0.606). J Clin Psychopharmacol. 1999;19:341-48 A significant number of patients receiving gabapentin showed at least a 50% reduction in migraine rate over placebo; 24 of 98 gabapentin patients discontinued prematurely due primarily to adverse effects. Headache. 2001;41: 119-28. www.amcp.org Vol. 8, No. 4 July/August 2002 JMCP J Clin Psychopharmacol. 2000;20:467-71. Journal of Managed Care Pharmacy 267 Gabapentin Use in a Managed Medicaid Population TABLE 2 Conditions Treated With Gabapentin in the Study Population INDICATION N=105 (%) Pain Neuropathies Back pain Unspecified chronic pain Fibromyalgia Headache/Migraine Neuralgias Other 75 (71) 31 (30) 10 (10) 8 (8) 6 (6) 4 (4) 3 (3) 13 (12) Bipolar affective disorder 11 (11) Epilepsy 5 (5) Restless leg 3 (3) Multiple sclerosis 3 (3) Anxiety 2 (2) Behavior disorders 2 (2) Other 4 (4) TABLE 3 ■■ Results Demographics A total of 105 patients met the eligibility criteria, and all were reviewed. Patients ranged in age from 22 to 83 years (mean 50.3 years; SD 12.9) and were predominantly female (73% versus 27% male); 81% were classified as Caucasian, 8.6% African American, 6.6% Hispanic, and 3.8% Asian. Prescriber Information Initial Prescriber Maintenance Prescriber Discipline N (%) N=105 N (%) N=105 Internal medicine 17 (16) 28 (26) Family practice 15 (14) 28 (26) Nurse practitioner 12 (11) 24 (23) Psychiatrist 18 (17) 7 (7) Neurologist 17 (16) 3 (3) Pain specialist 7 (7) 4 (4) Physician assistant 2 (2) 2 (2) Other 6 (6) 3 (3) 11 (11) 6 (6) Undetermined Study Population The study population was limited to those who were continuously eligible for the OHP and enrolled in CareOregon during the entire study period. A total of 4,638 patients were continuously eligible and enrolled in CareOregon during this period. To be included in the retrospective chart review, patients must have had at least one drug claim for gabapentin in the 33-month period 268 Journal of Managed Care Pharmacy JMCP July/August 2002 between January 1, 1998, and September 30, 2000. In addition, participants must have been patients at one of 4 Oregon Health and Science University primary care clinics (3 family medicine, 1 internal medicine). A pool of 29 physicians, 42 residents, 3 nurse practitioners, and 1 physician assistant attend patients at these clinics. Exclusion criteria included disenrollment from the OHP and inability to access the patient chart or electronic medical record. Patient confidentiality was maintained as data were collected, entered into an Access database, and verified by the clinical pharmacist. Descriptive statistics were used for analysis. The study was approved by the Oregon Health and Science University Institutional Review Board (Human Subjects Committee). Utilization Table 2 summarizes the indications for use of gabapentin within this study population. Ninety-five percent of patients were receiving gabapentin for an off-label indication. Various chronic pain conditions accounted for the majority of gabapentin use (71.4%). Mental health disorders accounted for 15% of the gabapentin use, with bipolar disorder being the most common. Seizure disorders only accounted for 5% of gabapentin use. Prescriber information is outlined in Table 3. Therapy was initiated by primary care providers 45% of the time compared to 46% started by specialists. While 59% of patients continued to have involvement by the initial prescriber, often there was a shift of care. Specialists appeared to be less involved with maintenance prescribing of gabapentin. Dosing of gabapentin was inconsistent. There was a wide range of prescribed doses both between and within each indication, as demonstrated in Table 4. Only 47% of patients received gabapentin 3 times daily, the usual dosing frequency. Other patients received the drug once daily (26%), twice daily (18%), or 4 times daily (9%). After the initiation of gabapentin therapy, 40% (n=42) of patients had no documented follow-up related to the drug. Only 12% (n=13) of the study patients had a documented efficacious response. Any positive statement, regardless of how subjective, was included as a response to the medication. A summary of these patients is presented in Table 5. The average dose for those patients where a positive response was documented was 1,770 mg (range=300 mg-4,800 mg). The average duration of therapy for these patients was 24.8 months, with 11 of the 13 patients remain- Vol. 8, No. 4 www.amcp.org Gabapentin Use in a Managed Medicaid Population TABLE 4 Dosing of Gabapentin By Indication Diagnosis For all indications Pain Bipolar affective disorder Epilepsy Restless leg Multiple sclerosis Anxiety Average Daily Dose (mg) Range (mg) 975 100–4,800 1,080 100–4,800 645 200–1,200 1,320 300–2,700 100 100 1,000 900–1,200 550 200–900 ing on therapy at the end of the study period. As expected, most patients were receiving ongoing treatment for either chronic neuropathic pain or epilepsy and were using at least one other medication for the same purpose. By the end of the study period, 68 patients (65%) had discontinued therapy. The average duration of therapy for patients who discontinued gabapentin was 4.2 months (range=1 day to 4 years). The most prominent documented reason for discontinuation was lack of efficacy (43%; n=29), followed by adverse effects (12%; n=8), nonadherence (10%; n=7), and symptom resolution (1%; n=1). In 34% (n=23) of patients, the reason for discontinuation was not documented. The total cost of drug therapy for all 105 patients during the study period was $1,198,613 ($11,415 per patient). An average of $1,123 was spent per patient on gabapentin alone, or about 10% of the total cost of drug therapy. Patients who were labeled as responders had a higher average gabapentin expenditure of $3,095 per patient. ■■ Discussion Little clinical trial data exist (Table 1) to support the use of gabapentin in many of the conditions being treated in this study. Due to a lack of clinical trial data, there are no dosing or therapeutic guidelines to direct the use of gabapentin. Information that does exist is primarily based on case reports and a few open-label trials. While such reports are valuable for directing further research, they are generally not sufficient as the basis of treatment decisions. In this study, gabapentin was largely used for a variety of pain syndromes. Clinical trials of gabapentin support its efficacy in selected neuropathic pain syndromes. Specifically, gabapentin is efficacious for the treatment of diabetic neuropathy and postherpetic neuralgia, especially when high doses are used.2,3 Data are lacking for other types of chronic pain conditions. To date, only one controlled trial has been published comparing gabapentin to tricyclic antidepressants in the treatment of diabetic neuropathy. Tricyclic antidepressants are generally considered first-line therapy, although toxicity in overdose is considered a disadvantage. Gabapentin and amitriptyline appear to be comparable in efficacy and tolerability for the treatment of diabetic neuropathy,4 but the effective dose of gabapentin has an average wholesale price of $191 per month compared to $7 per month for amitriptyline. There are two published randomized controlled trials that studied the use of gabapentin in migraine prophylaxis. In the first study, gabapentin failed to demonstrate efficacy greater than placebo.5 A second study reported efficacy with gabapentin for the prevention of migraine when compared to placebo.6 The American Academy of Neurology cites both of these studies in its published guidelines for the prophylaxis of migraines. The AAN guidelines maintain that there is limited evidence for the use of gabapentin in clinical practice.7 Studies of gabapentin in psychiatric disorders have ranged from anxiety and social phobia to affective disorders and drug dependence. Only two randomized trials have been published that evaluate the use of gabapentin monotherapy in bipolar disorder. Both failed to demonstrate efficacy superior to placebo.8,9 Similarly, Pande et al. evaluated the use of gabapentin in the treatment of panic disorder and failed to show a difference from placebo in the Panic and Agoraphobia Scale.10 For other psychiatric indications (e.g., anxiety, obsessive-compulsive disorder, drug and alcohol withdrawal), randomized controlled trials are lacking. This retrospective chart review found that gabapentin was being used almost exclusively for off-label indications in the population reviewed. Unfortunately, it appeared that relatively few patients benefited from treatment based on information documented in the medical record. Although gabapentin was being used for chronic conditions, only a small number of patients remained on therapy at the end of the study period. It is interesting to speculate as to why gabapentin was being used for such a wide variety of off-label indications. First, marketing may have played a role. The manufacturer of gabapentin has been accused of aggressively promoting the drug for off-label indications due to the limited market for seizure disorders.11 Second, patients with chronic pain and/or mood disorders can be difficult to manage. Gabapentin may be viewed as a treatment option that has relatively few serious side effects and drug interactions, reasonable tolerance, and is fairly easy to prescribe. Clinicians may be hoping for a positive response while minimizing the risk of harm. The pattern of gabapentin use documented in this study does not appear to represent the best use of health care resources. Health plans might want to consider options to promote more cost-effective use of gabapentin. Prior authorization is one option. Criteria could be developed to approve the use of gabapentin for off-label diagnoses where clinical trial data support its efficacy. Mandatory follow-up could also be considered to ensure an appropriate therapeutic response after 2 or 3 months of treatment, before long-term use is approved. Educational interventions such as academic detailing might also help promote the appropriate use of gabapentin. There are a couple of important limitations to interpreting this www.amcp.org Vol. 8, No. 4 July/August 2002 JMCP Journal of Managed Care Pharmacy 269 Gabapentin Use in a Managed Medicaid Population TABLE 5 Summary of Patients Who Responded Favorably to Gabapentin Therapy Maximum Daily Dose (mg) Duration of Therapy 2,700 20 months 300 Secondary Diagnoses Concurrent Therapy Charted Efficacious Response Depression, Fibromyalgia, Anxiety, Diabetes Vicodin, Relafen, Lodine “Neurontin is helpful but prefer Vicodin.” 12 months Celebrex, Acupuncture. “Gabapentin helps her feet and hands quite a lot.” 4,800 23 months Tylenol #3, Tegretol, Darvocet, Vicodin “Has made a substantial impact on pain.” Peripheral neuropathy 300 5 months Prednisone “Satisfied with the results of Neurontin.” Hyperesthesia 900 6 months APAP “Vague abdominal discomfort gone with Neurontin.” 1,200 24 months Depression, Substance Abuse, Anxiety Percocet “Noted some benefit from it.” 900 45 months Substance Abuse Unspecified neuropathic pain 3,200 30 months Diabetic neuropathy 1,800 36 months Amputation pain 1,800 Indication For Use Peripheral neuropathy Fibromyalgia Transverse myelitis HIV-related neuropathy Epilepsy Depression “Good initial clinical response.” IBU, MS Contin “Had some relief; has decreased the burning pain.” Diabetes Ultram, Tylenol #3, Nortriptyline “Apparently improved with Neurontin.” 23 months Depression Tylenol #3, Vicodin, Naprosyn “She has noted particular improvement in her generalized pain since starting Neurontin.” 300 9 months Diabetes Amitriptyline “Able to walk with much less foot pain.” Epilepsy 1,200 42 months Diabetes Depakote “Have apparently stopped most of the episodes with the slight increase in Neurontin.” Intercostal neuralgia 3,600 48 months Depression Vicodin, Imipramine, Catapres “Pain is 6/10, which is tolerable.” Diabetic neuropathy study. First, we studied a Medicaid population at one academic institution. These results may not generalize to other settings. Additional studies are needed to confirm our findings. Second, data were obtained only from the review of patient medical records and reimbursement claims data. We did not collect information directly from patients or providers. Thus, definitive conclusions regarding effectiveness of gabapentin for various conditions cannot be drawn from our data. There is a tremendous need for clinical trials to better define the role of gabapentin in a variety of conditions for which it is currently being prescribed. ■■ Conclusion This retrospective review demonstrated that gabapentin is prescribed for a wide variety of conditions. Almost all patients (95%) received gabapentin for off-label diagnoses. The use of gabapentin in many of these patients is not supported by evidence from ran270 Journal of Managed Care Pharmacy JMCP July/August 2002 domized clinical trials. Most patients did not appear to benefit from gabapentin therapy, and many patients did not appear to receive adequate follow-up once gabapentin was started. DISCLOSURES Funding for this research was provided by a service contract with Oregon Medical Assistance Program. It was obtained by author Dean G. Haxby. None of the authors involved with the creation of this project have financial interests or are affiliated with any company or product mentioned in the article. Author Ann M. Hamer served as principal investigator and author of the study. Study concept and design were contributed primarily by Hamer, Haxby, and authors Bentson H. McFarland and Kathy Ketchum. Analysis and interpretation of data were contributed primarily by Hamer, Haxby, and Ketchum. Drafting of the manuscript was primarily the work of Hamer and Haxby. Critical revision of the manuscript was primarily the work of Hamer, Haxby, McFarland, and Ketchum. Statistical expertise was contributed primarily by Hamer, Haxby, and Ketchum. Vol. 8, No. 4 www.amcp.org Gabapentin Use in a Managed Medicaid Population REFERENCES 6. Mathew NT, Rapoport A, Saper J, et al. Efficacy of gabapentin in migraine prophylaxis. Headache. 2001;41:119-28. 1. Department of Health and Human Services Office of Inspector General. Medicaid pharmacy actual acquisition cost of brand-name prescription drug products. A-06-00-00023, August 2001. Available at: http://www.hhs.gov/progorg/oas/reports/region6/60000023.htm. Accessed September 17, 2001. 7. American Academy of Neurology: U.S. Headache Consortium. Evidencebased guidelines for migraine headache in the primary care setting: pharmacological management for the prevention of migraine. Available at: http://www.aan.com. Accessed February 14, 2002. 2. Backonja M, et al. Gabapentin monotherapy for the symptomatic treatment of painful neuropathy. A multicenter, double-blind, placebo-controlled trial in patients with diabetes mellitus. JAMA.1998;280:1831-36. 8. Frye M, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharm. 2000;20:607-14. 3. Rowbatham M, et al. Gabapentin for the treatment of postherpetic neuralgia. A randomized controlled trial. JAMA. 1998;280:1837-42. 4. Morello CM, et al. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med. 1999;159:1931-37. 5. Wessely P, Baumgartner C, Klinger D, et al. Preliminary results of a doubleblind study with the new migraine prophylactic drug gabapentin. Cephalalgia. 1987;7(suppl 6):477-78. 9. Botts SR, Raskind J. Gabapentin and lamotrigine in bipolar disorder. Am J Health-Syst Pharm. 1999;56:1939-44. 10. Pande AC, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharm. 2000;20:467-71. 11. Petersen, M. Whistle-blower says marketers broke the rules to push a drug. New York Times. March 14, 2002;sect C:1. www.amcp.org Vol. 8, No. 4 July/August 2002 JMCP Journal of Managed Care Pharmacy 271