The cost-effectiveness of pregabalin in the treatment of fibromyalgia: US perspective

Figures & data

Figure 1.  Model structure.

Table 1.  Comparators included in the model.

Pharmacologic agent	Dosage, mg	Administration
Pregabalin	150	BID
	225	BID
Duloxetine	60	QD
	60	BID
Milnacipran	50	BID
	100	BID
Gabapentin	600	TID
Tramadol	50	Variable up to 200 mg/day
Amitriptyline	50	QD

BID, twice a day; QD, once daily; TID, three times a day.

Table 2.  Studies of effectiveness of treatment for FM, including at least one active treatment compared with placebo.

Drug	Study	Follow-up, week	Drug dosage/treatment regimen	Study design	Inclusion criteria (pain score)*	Exclusion criteria (treatment-related)
Gabapentin	Arnold et al.30	12	Flexible-dose	Multi-center, double-blind, randomized controlled trial	Average pain score ≥4 (BPI average pain severity item at screening)
Pregabalin	Arnold et al.19	14	1-week placebo run-in, 2-week dose-escalation starting at 150 mg/day, 12-week fixed-dose	Multi-center, double-blind, randomized controlled trial	Average pain score ≥4 (11-point NRS during run-in); pain score ≥40 mm (VAS)	Patients with ≥30% decrease in pain VAS after placebo run-in phase (placebo responders)
	Mease et al.22	13	Started 150 mg/day, titrated to 225 mg/day by week 1	Multi-center, double-blind, randomized controlled trial	Average pain score ≥4 (11-point NRS, baseline); pain score ≥40 mm (VAS of SF-MPQ)
	Pauer et al.23	14	1-week placebo run-in, 2-week dose-escalation, 12-week fixed-dose		Pain score ≥40 mm (VAS, screening and baseline)	Patients with ≥30% decrease in pain VAS after placebo run-in phase (placebo responders)
Duloxetine	Arnold et al.28	12	1-week placebo lead-in, 12-week with forced titration 20 mg/day to 60 mg BID by week 2	Multi-center, double-blind, randomized controlled trial	Pain intensity score ≥4 (FIQ pain intensity item, screening and lead-in phase)	Failure to respond to at least two adequate regimens of two different classes of antidepressants for depression or FM
	Arnold et al.29	12	Duloxetine 60 mg QD or duloxetine 60 mg BID (forced titration from 60 mg QD for 3 days to 60 mg BID)	Multi-center, double-blind, randomized controlled trial	Average pain score ≥4 (BPI average pain severity item, randomization); female patients only
	Russell et al.43	15 & 28	Duloxetine 20 mg/day, 60 mg/day, or 120 mg/day. Duloxetine 20-mg/day group titrated to 60 mg/day after month 3	Multi-center, double-blind, randomized controlled trial; 1-week screening phase, 15-week randomized controlled trial (acute phase), 13-week maintenance. Patients completing 6 months of treatment were entered into the 28-week extension (not reported)	Average pain score ≥4 (BPI average pain severity item, screening)
Milnacipran	Gendreau et al.38	12	Drug study dose titrated up to 200 mg QD (group 1) or 100 mg BID (group 2)	Multi-center, double-blind, randomized controlled trial; 2-week screening phase followed by randomization, 3-week escalation phase, and 12-week maintenance	Pain score ≥10 on 20-point logarithmic pain scale (Gracely scale)
	Clauw et al.45	15	Drug study dose titrated up to 100 mg/day BID (group 1) or milnacipran 100 mg QD (group 2)	Multi-center, double-blind, randomized controlled trial; 3-week escalation phase and 12-week maintenance	Pain intensity score ≥4 (FIQ pain intensity item, screening and lead-in phase); pain score ≥40 mm (VAS, end of baseline)
	Mease et al.46	26	Drug study dose titrated up to 50 mg/day BID (group 1) or milnacipran 100 mg BID (group 2)	Multi-center, double-blind, randomized controlled trial; 3-week escalation phase and 24-week maintenance	Pain score ≥50 mm (VAS, end of baseline)
Tramadol	Bennett et al.33	12	Tramadol ≤300 mg and ≤2600 mg acetaminophen	Multi-center, double-blind, randomized controlled trial	Pain score ≥40 mm (VAS, screening and baseline)	Previous failure of tramadol therapy (four patients excluded)
	Russell et al.44	12	Tramadol ≤400 mg/day	Multi-center, double-blind, randomized controlled trial; 3-week tramadol open-label run-in phase; responders (self-assessed) entered double-blind study
Amitripty-line	Carette et al.35	26	Amitriptyline 50 mg/day	Double-blind, randomized controlled trial; 14-week escalation phase and 12-week maintenance	Pain score ≥4 (10-cm VAS); global assessment of FM score ≥4 (10-cm VAS)	Patients non-naïve to amitriptyline
	Carette et al.36	9	Amitriptyline 50 mg/day	Double-blind randomized controlled trial; 4-week escalation phase and 5-week maintenance	None	None
	Carette et al.37	8	Sustained-release amitriptyline 25 mg/day	Double-blind crossover trial	Pain score ≥4 (10-cm VAS); global assessment of FM score ≥4 (10-cm VAS)	None
	Ginsberg et al.39	8	Sustained-release amitriptyline 25 mg/day	Double-blind, randomized controlled trial	None	None
	Hannonen et al.41	12	Amitriptyline 12.5 mg QD	Double-blind, randomized controlled trial with 2-week single-blind placebo run-in period	Pain score ≥4 (10-cm VAS) on at least three among patient global assessment of general health, pain, sleep quality and quantity, and fatigue	None

*All studies had common inclusion criterion of a diagnosis of FM according to the American College of Rheumatology 1990 criteria.

BPI, Brief Pain Inventory; NRS, numeric rating scale; VAS, visual analog scale; SF-MPQ, short-form McGill Pain Questionnaire; BID, twice a day; FIQ, Fibromyalgia Impact Questionnaire; FM, fibromyalgia; QD, once daily.

Table 3.  Pooled relative risk of response compared with placebo, active treatments.

Drug name	RR of response compared with placebo (CI)	Significance test(s) of RR = 1	I^2 test of heterogeneity	Source
Pregabalin 150 mg BID (pain and PGIC)	2.00 (1.65–2.44)	N/A		Mease et al.22; Arnold et al.19; Pauer et al.23
Pregabalin 225 mg BID (pain and PGIC)	2.06 (1.68–2.50)	N/A
Pregabalin 150 mg BID (pain)	1.83 (1.52–2.12)	N/A
Pregabalin 225 mg BID (pain)	1.91 (1.58–2.21)	N/A
Amitriptyline 50 mg QD	2.18 (1.55–3.03)	z = 4.62	I^2= 57.6%	Ginsberg et al.39; Carette et al.35–37; Hannonen et al.41
		p = 0.000	df = 4
			p = 0.051
Duloxetine 60 mg QD	1.52 (1.24–1.85)	z = 4.03	I^2= 0.0%	Arnold et al.29; Russell et al.43
		p = 0.000	df = 1
			p = 0.404
Duloxetine 60 mg BID	1.55 (1.28–1.88)	z = 4.53	I^2= 0.0%	Arnold et al.28,29; Russell et al.43
		p = 0.000	df = 2
			p = 0.793
Tramadol 200 mg QD	1.85 (1.37–2.48)	z = 4.04	I^2= 0.0%	Russell et al., 200044; Bennett et al.33
		p = 0.000	df = 1
			p = 0.584
Gabapentin 600 mg TID	1.51 (1.00–2.28)	z = 1.96	N/A	Arnold et al.30
		p = 0.050
Milnacipran 50 mg BID	1.21 (1.09–1.35)	z = 3.68	I^2= 11.8%	Clauw et al.45; Gendreau et al.38; Mease et al.46
		p = 0.000	df = 2
			p = 0.322
Milnacipran 100 mg BID	1.22 (1.11–1.33)	z = 4.07	I^2= 0.0%	Clauw et al.45; Gendreau et al.38; Mease et al.46
		p = 0.000	df = 2
			p = 0.798

RR, relative risk; CI, confidence interval; I², variation in RR attributable to heterogeneity; BID, twice a day; PGIC, Patient Global Impression of Change; N/A, not available; QD, once daily; TID, three times a day.

Table 4.  Costs, annual resource use, and utility estimates for the model.

	Cost per day	Mean (SD)	Source
Drug costs
Drug name
Pregabalin 150 mg BID	$3.62		Centers for Medicare and Medicaid Services50
Pregabalin 225 mg BID	$3.63
Amitriptyline 50 mg QD	$0.12
Duloxetine 60 mg QD	$3.35
Duloxetine 60 mg BID	$6.69
Tramadol 200 mg QD	$0.46
Gabapentin 600 mg TID	$1.94
Milnacipran 50 mg BID	$2.99
Milnacipran 100 mg BID	$3.05
Other model costs
Direct healthcare costs
Intercept		$2667 ($876)	Goldenberg et al.52
Coefficient, FIQ (total score)		$83 ($16)
Indirect (productivity) costs
Intercept		$7780 ($1488)	Goldenberg et al.52
Coefficient, FIQ (FIQ work missed item, 0–10)		$4370 ($727)

BID, twice a day; QD, once daily; TID, three times a day; SD, standard deviation; FIQ, Fibromyalgia Impact Questionnaire.

Table 5.  Base-case results.

	Placebo	Pregabalin 150 mg BID	Pregabalin 225 mg BID
12-week model results
Total direct cost per treated patient	$1,883	$2,167	$2,004
Total indirect cost per treated patient	$5,890	$5,835	$4,903
Total costs per treated patient	$7,773	$8,002	$6,907
Total responder days	13.51	27.03	27.62
Incremental costs		$229	–$866
Incremental responders, d^a		13.51	14.11
ICER (responders)^b		$17	Cost saving
1-year model results
Total indirect cost per treated patient	$28,892	$27,784	$26,806
Total (direct and indirect) costs per treated patient	$38,358	$37,565	$36,418
Total responder days	59.58	119.16	121.78
Incremental total costs		–$793	–$1,940
Incremental responders, d^a		59.58	62.21
ICER (responders)^b		Cost saving	Cost saving

^aIncremental days in response.

^bCost-effectiveness analysis based on direct and indirect costs. BID, twice a day; ICER, incremental cost-effectiveness ratio.

Table 6.  Pregabalin vs comparators in patients with severe fibromyalgia and severe pain over 1 year.

Comparator	Total cost per treated patient	Total responder days	Incremental costs	Incremental responder days	ICER (responders)
Incremental analysis compared with pregabalin 150 mg BID (total costs per treated patient, $37,565; total responder days, 119.16)
Duloxetine 60 mg	$38,001	90.27	–$436	28.89	Cost saving
Duloxetine 120 mg	$38,476	92.51	–$911	26.64	Cost saving
Gabapentin 1800 mg	$37,788	90.03	–$223	29.13	Cost saving
Tramadol	$37,041	109.96	$524	9.20	$57
Amitriptyline	$36,464	129.76	$1101	–10.61	Dominated
Milnacipran 100 mg	$38,380	72.09	–$815	47.07	Cost saving
Milnacipran 200 mg	$38,197	66.38	–$632	52.78	Cost saving
Incremental analysis compared with pregabalin 225 mg BID (total cost per treated patient, $36,418; total responder days, 121.78)
Duloxetine 60 mg	$38,001	90.27	–$1583	31.52	Cost saving
Duloxetine 120 mg	$38,476	92.51	–$2058	29.27	Cost saving
Gabapentin 1800 mg	$37,788	90.03	–$1370	31.75	Cost saving
Tramadol	$37,041	109.96	–$623	11.83	Cost saving
Amitriptyline	$36,464	129.76	–$46	–7.98	$6
					Amitriptyline is cost-effective
Milnacipran 100 mg	$38,380	72.09	–$1962	49.69	Cost saving
Milnacipran 200 mg	$38,197	66.38	–$1779	55.41	Cost saving

ICER, incremental cost-effectiveness ratio; BID, twice a day.

Figure 2.  Incremental cost-effectiveness of pregabalin vs placebo in patient sub-groups. BID, twice a day.

Table 7.  Results of the one-way sensitivity analysis on key inputs: pregabalin 150 mg BID vs placebo at 1 year.

Description of sensitivity analysis	Incremental costs	Incremental responder days	ICER (responder days)
Decrease pregabalin response to lower CI	–$583	40.99	Cost saving
Increase pregabalin response to upper CI	–$1002	60.33	Cost saving
Increase long-term loss of response	–$798	50.81	Cost saving
Decrease long-term loss of response	–$787	50.51	Cost saving
Increase long-term dropout	–$810	51.32	Cost saving
Decrease long-term dropout	–$776	50.01	Cost saving

BID, twice a day; ICER, incremental cost-effectiveness ratio; CI, confidence interval.

Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum 2007;56:1336-44

 PubMed Web of Science ®Google Scholar

Arnold LM, Russell IJ, Diri EW, et al. A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia. J Pain 2008;9:792-805

 PubMed Web of Science ®Google Scholar

Mease PJ, Russell IJ, Arnold LM, et al. A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol 2008;35:502-14

 PubMed Web of Science ®Google Scholar

Pauer L, Winkelmann A, Arsenault P, et al. An International, randomized, double-blind, placebo-controlled, phase iii trial of pregabalin monotherapy in treatment of patients with fibromyalgia. J Rheumatol 2011;38:2643-52

 PubMed Web of Science ®Google Scholar

Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 2004;50:2974-84

 PubMed Web of Science ®Google Scholar

Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 2005;119:5-15

 PubMed Web of Science ®Google Scholar

Russell IJ, Mease PJ, Smith TR, et al. Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. Pain 2008;136:432-44

 PubMed Web of Science ®Google Scholar

Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol 2005;32:1975-85

 PubMed Web of Science ®Google Scholar

Clauw DJ, Mease P, Palmer RH, et al. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clin Ther 2008;30:1988-2004

 PubMed Web of Science ®Google Scholar

Mease PJ, Clauw DJ, Gendreau RM, et al. The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial. J Rheumatol 2009;36:398-409

 PubMed Web of Science ®Google Scholar

Bennett RM, Kamin M, Karim R, et al. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med 2003;114:537-45

 PubMed Web of Science ®Google Scholar

Russell IJ, Kamin M, Bennett RM, et al. Efficacy of tramadol in treatment of pain in fibromyalgia. J Clin Rheumatol 2000;6:250-7

 PubMed Web of Science ®Google Scholar

Carette S, Bell MJ, Reynolds WJ, et al. Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia. A randomized, double-blind clinical trial. Arthritis Rheum 1994;37:32-40

 PubMed Web of Science ®Google Scholar

Carette S, McCain GA, Bell DA, et al. Evaluation of amitriptyline in primary fibrositis. A double-blind, placebo-controlled study. Arthritis Rheum 1986;29:655-9

 PubMed Web of Science ®Google Scholar

Carette S, Oakson G, Guimont C, et al. Sleep electroencephalography and the clinical response to amitriptyline in patients with fibromyalgia. Arthritis Rheum 1995;38:1211-7

 PubMed Web of Science ®Google Scholar

Ginsberg F, Mancaux A, Joos E, et al. A randomized placebo-controlled trial of sustained release amitriptyline in primary fibromyalgia. J Musculoskeletal Pain 1996;4:37-47

 Google Scholar

Hannonen P, Malminiemi K, Yli-Kerttula U, et al. A randomized, double-blind, placebo-controlled study of moclobemide and amitriptyline in the treatment of fibromyalgia in females without psychiatric disorder. Br J Rheumatol 1998;37:1279-86

 PubMedGoogle Scholar

Medicaid. Drug utilization data. Baltimore, MD: Centers for Medicare & Medicaid Services/US Department of Health & Human Services, 2010

 Google Scholar

Goldenberg D, Gerwin R, McNett M, et al. The economic burden of mild, moderate and severe fibromyalgia: results from a cross-sectional survey among working-age adults in the United States. J Manag Care Pharm 2011;9:71

 Google Scholar