Highlights of the Comparative Economic Analysis
A comprehensive decision analytical model comparing FDA-approved fibromyalgia (FM) treatments with off-label amitriptyline has revealed critical insights into value-based care. The study highlights three primary findings:
- Duloxetine 120 mg emerged as the most cost-effective strategy across both health care payer and societal perspectives, offering the best balance of quality-adjusted life-year (QALY) gains and cost.
- Pregabalin 450 mg proved economically favorable relative to amitriptyline only when societal costs, such as productivity losses, were included in the model.
- Amitriptyline, despite its age and off-label status, remains a more efficient value choice than milnacipran or lower doses of duloxetine and pregabalin, which were largely dominated in the economic model.
Introduction: The Economic and Clinical Burden of Fibromyalgia
Fibromyalgia is a complex, chronic pain syndrome characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, and cognitive dysfunction. Affecting approximately 2% to 4% of the adult population, it imposes a significant burden not only on the individual’s quality of life but also on the healthcare system and the broader economy. In the United States, the economic impact is driven by high direct medical costs and substantial indirect costs related to disability and lost work productivity.
While the FDA has approved pregabalin, duloxetine, and milnacipran for FM management, clinical guidelines—including those from the European Alliance of Associations for Rheumatology (EULAR)—continue to recommend the low-cost tricyclic antidepressant amitriptyline as a first-line option. However, direct economic comparisons between these agents have been scarce, often complicated by heterogeneous outcome measures. This study, recently published in JAMA Network Open, addresses this gap by utilizing a lifetime Markov model to determine which pharmacologic strategy provides the best value.
Methodological Framework: The Markov Cohort State Transition Model
The researchers employed a decision analytical model to simulate the lifetime clinical and economic outcomes of a cohort of adults (mean age 48.4 years, 94.4% women) with moderate to severe FM. The model transitioned patients through various health states based on treatment response, side effects, and disease progression.
The study compared several exposures:
- Amitriptyline (25–100 mg)
- Pregabalin (150, 300, 450, and 600 mg)
- Duloxetine (60 and 120 mg)
- Milnacipran (100 and 200 mg)
The primary endpoints were quality-adjusted life-years (QALYs) and lifetime costs. The analysis was conducted from two perspectives: the US health care payer perspective (focusing on direct medical costs) and the societal perspective (incorporating indirect costs like lost productivity). Willingness-to-pay (WTP) thresholds were set at $50,000, $100,000, and $150,000 per QALY to assess cost-effectiveness.
Detailed Results: Payer vs. Societal Perspectives
The results of the simulation provide a nuanced view of how different drugs perform economically depending on who is bearing the cost.
US Health Care Payer Perspective
From the perspective of an insurance payer, duloxetine 120 mg was highly cost-effective. Compared to amitriptyline, it produced more QALYs at an incremental cost-effectiveness ratio (ICER) of just $1,536 per QALY. This is well below the standard $50,000 WTP threshold, suggesting that the clinical benefits of high-dose duloxetine significantly justify its cost. In contrast, pregabalin 450 mg was dominated by duloxetine 120 mg in this perspective, meaning it was less effective and/or less cost-efficient than the duloxetine strategy.
Societal Perspective and Indirect Costs
When the analysis shifted to a societal perspective—accounting for the fact that better-managed FM allows patients to remain in the workforce—the economic profile of modern agents improved further. Both duloxetine 120 mg and pregabalin 450 mg were found to be “cost-saving” relative to amitriptyline. This means the higher initial drug costs were more than offset by the reduction in indirect costs associated with FM disability.
At a WTP threshold of $100,000, the incremental net monetary benefit (iNMB) for duloxetine 120 mg was $40,375 (payer) and $70,063 (societal). For pregabalin 450 mg, the iNMB was $21,211 (payer) and $40,190 (societal).
The Dose-Response Dynamics in Economic Value
A striking finding of the study was the poor economic performance of milnacipran and lower doses of duloxetine (60 mg) and pregabalin (150–300 mg). In most scenarios, amitriptyline was both more effective and less costly than these options. This suggests that if clinicians choose to use FDA-approved modern agents, they should aim for the higher therapeutic doses (such as duloxetine 120 mg or pregabalin 450 mg) to achieve the clinical efficacy necessary to outweigh the costs. Lower doses may not provide enough symptom relief to translate into meaningful economic or quality-of-life gains over the much cheaper amitriptyline.
Expert Commentary and Clinical Implications
The findings underscore the importance of looking beyond the pharmacy price tag. While amitriptyline is remarkably inexpensive, its side-effect profile (including sedation and anticholinergic effects) can limit its utility in moderate to severe cases. The data suggests that for patients who can tolerate it, duloxetine 120 mg provides a superior value proposition by significantly improving quality of life.
However, the study also highlights that milnacipran, in this model, did not demonstrate a favorable value profile compared to its competitors. For health policy experts and payers, these results may inform formulary designs that prioritize high-dose duloxetine or pregabalin for patients who fail initial low-cost therapies.
Limitations of the study include its reliance on published data for model inputs rather than a direct head-to-head clinical trial, and the inherent uncertainty in modeling lifetime transitions for a condition as variable as FM. Furthermore, individual patient tolerance varies significantly, and economic models cannot account for the personalized “trial and error” often required in pain management.
Conclusion: Moving Toward Value-Based Pain Management
This decision analytical model provides a robust framework for selecting pharmacotherapy in fibromyalgia based on value. Duloxetine 120 mg stands out as the preferred strategy for moderate to severe cases. Amitriptyline remains a high-value option for those who cannot access or tolerate newer agents, while milnacipran and lower-dose modern therapies appear less economically justifiable. Clinicians should consider these economic realities alongside clinical presentation to optimize both patient outcomes and healthcare resource utilization.
References
Downen SS, Farag HM, Davies A, Okeke CM, Ben-Umeh KC, Yunusa I, Eguale T. Cost-Effectiveness of Pregabalin, Duloxetine, and Milnacipran vs Amitriptyline for Moderate to Severe Fibromyalgia. JAMA Netw Open. 2026 Feb 2;9(2):e2557536. doi: 10.1001/jamanetworkopen.2025.57536. PMID: 41632472.