Impact of potential pregabalin or duloxetine drug–drug interactions on health care costs and utilization among Medicare members with fibromyalgia

Figures & data

Table 1 Pregabalin and duloxetine drug–drug interactions

Severity	Brief description of potential harm due to DDI	Interacting drug
Pregabalin
Major	Reduced pregabalin effectiveness	naproxen, ketorolac
Duloxetine
Contraindicated	CNS toxicity or serotonin syndrome	isocarboxazid, linezolid, procarbazine, rasagiline, selegiline, tranylcypromine
	Increased serum concentrations of interacting drug and risk of cardiac arrhythmia	thioridazine
	Increased risk of extrapyramidal reactions or neuroleptic malignant syndrome	metoclopramide
	Increased risk of serotonin syndrome or neuroleptic malignant syndrome-like reactions	methylene blue
Major	Increased interacting drug plasma level and increased risk of QT prolongation	clozapine
	Increased risk of bleeding	antiplatelet agents, escitalopram
	Increased risk of serotonin syndrome	almotriptan, citalopram, cyclobenzaprine, desvenlafaxine, dextromethorphan, eletriptan, fluoxetine, fluvoxamine, frovatriptan, hydroxytryptophan, lithium, lorcaserin, methadone, milnacipran, naratriptan, paroxetine, rizatriptan, sertraline, sumatriptan, tapentadol, tramadol, trazodone, tryptophan, venlafaxine, zolmitriptan
	Increased risk of serotonin syndrome or neuroleptic malignant syndrome-like reactions	vilazodone
	Increased serum concentrations of interacting drugs and an increased risk of cardiotoxicity	Class 1C antiarrhythmic agents
Moderate	Decreased plasma concentrations of the active metabolites of interacting drug	tamoxifen
	Increased duloxetine serum concentrations and risk of adverse effects	ciprofloxacin, clobazam, enoxacin, mirabegron, quinidine
	Increased exposure to interacting drug and potential toxicity	phenothiazines, tamsulosin, tricyclic antidepressants
	Increased risk of bleeding	acenocoumarol, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, nonsteroidal anti-inflammatory agents, phenindione, phenprocoumon, tinzaparin, warfarin

Notes: Reprinted with permission. Source: Micromedex 2.0 (Truven Health Analytics Inc.), accessed May 31, 2013. Copyright 1974–2014 Truven Health Analytics Inc. All rights reserved. Drugs with primary use in the hospital setting (eg, lepirudin) were excluded.

Table 2 Patient Characteristics

	Pregabalin N=794		Duloxetine N=794		P value*
	n	%	n	%
Sex					0.8577
Male	180	22.7	183	23.0
Female	614	77.3	611	77.0
Race/Ethnicity					0.6976
White	692	87.2	704	88.7
Black	76	9.6	67	8.4
Hispanic	13	1.6	14	1.8
Other	13	1.6	9	1.1
Geographic Region					0.9929
Northeast	12	1.5	13	1.6
Midwest	187	23.6	185	23.3
South	531	66.9	534	67.3
West	64	8.1	62	7.8
Low Income Status	150	18.9	142	17.9	0.6043
Dual Eligibility Status	93	11.7	97	12.2	0.7571
	Mean	SD	Mean	SD
Age, years	62.9	12.6	62.4	12.0	0.3415
Propensity Score	0.32	0.12	0.32	0.12	0.9582

Notes:

* All P values for categorical variables calculated using chi-square tests. All P values for continuous variables calculated using Wilcoxon rank-sum tests.

Abbreviation: SD, Standard Deviation.

Table 3 Preindex comorbid conditions

	Pregabalin N=794		Duloxetine N=794		P value*
	n	%	n	%
Abdominal pain/cramping	228	28.7	223	28.1	0.7808
Anxiety disorder	184	23.2	196	24.7	0.4803
Arthritis	368	46.3	377	47.5	0.6509
Back pain with neuropathic involvement	315	39.7	323	40.7	0.6822
Causalgia and other painful neuropathies	211	26.6	210	26.4	0.9547
Depression	247	31.1	243	30.6	0.828
Diabetes	150	18.9	143	18.0	0.6507
Epilepsy	20	2.5	23	2.9	0.6428
Fatigue	278	35.0	277	34.9	0.958
Irritable bowel syndrome	26	3.3	29	3.7	0.6806
Migraine headache	59	7.4	58	7.3	0.9235
Muscle weakness	62	7.8	54	6.8	0.4404
Neck pain with neuropathic involvement	129	16.2	131	16.5	0.8921
Other back pain	461	58.1	468	58.9	0.7215
Other mental disorders	5	0.6	6	0.8	0.7622
Other musculoskeletal pain	693	87.3	690	86.9	0.8224
Other neck pain (spinal)	216	27.2	223	28.1	0.6945
Sleep disorders	169	21.3	180	22.7	0.505
Substance abuse or dependence	142	17.9	146	18.4	0.7945
Tension headache	7	0.9	8	1.0	0.7953
Thinking/memory loss	23	2.9	20	2.5	0.6428
Trigeminal nerve disorders	7	0.9	14	1.8	0.1241
	Mean	SD	Mean	SD
Deyo–Charlson	0.9	1.2	0.9	1.2	0.9188
Comorbidity Index score

Notes:

* All P values for categorical variables calculated using chi-square tests. All P values for continuous variables calculated using Wilcoxon rank-sum tests.

Abbreviation: SD, standard deviation.

Table 4 Observed pregabalin and duloxetine drug–drug interactions by severity and interacting drug

Severity*	Interacting drug	Number of interactions
Pregabalin
Major	ketorolac	4
Major	naproxen	37
Total major for pregabalin		41
Grand total for pregabalin		41
Duloxetine
Contraindicated	metoclopramide	22
Contraindicated	rasagiline	1
Total contraindicated for duloxetine		23
Major	tramadol	132
Major	trazodone	118
Major	cyclobenzaprine	88
Major	meloxicam	86
Major	citalopram	71
Major	clopidogrel	62
Major	methadone	60
Major	fluoxetine	51
Major	Ibuprofen	46
Major	escitalopram	45
Major	sertraline	44
Major	diclofenac	40
Major	sumatriptan	34
Major	paroxetine	29
Major	celecoxib	24
Major	naproxen	23
Major	venlafaxine	22
Major	nabumetone	20
Major	etodolac	15
Major	aspirin	15
Major	piroxicam	9
Major	lithium	8
Major	indomethacin	6
Major	cilostazol	6
Major	milnacipran	5
Major	flecainide	4
Major	salsalate	4
Major	oxaprozin	3
Major	dipyridamole	3
Major	ketorolac	2
Major	zolmitriptan	2
Major	sulindac	2
Major	rizatriptan	2
Major	ticlopidine	1
Major	eletriptan	1
Total major for duloxetine		1,083
Moderate	amitriptyline	81
Moderate	warfarin	42
Moderate	promethazine	38
Moderate	ciprofloxacin	36
Moderate	tamsulosin	21
Moderate	doxepin	17
Moderate	nortriptyline	11
Moderate	prochlorperazine	6
Moderate	enoxaparin	6
Moderate	imipramine	5
Moderate	chlorpromazine	3
Moderate	perphenazine	3
Moderate	fluphenazine	2
Total moderate for duloxetine		271
Grand total for duloxetine		1,377

Notes:

* Severity category according to Micromedex 2.0 (Truven Health Analytics Inc.), as of May 31, 2013.

Table 5 Six-month postindex all-cause health care utilization stratified by drug–drug interaction status

	Pregabalin			Duloxetine
	No DDI present n=762	DDI present n=32	P value*	No DDI present n=223	DDI present n=571	P value*
All-cause inpatient visits
Members with hospitalization, n (%)	160 (21.0)	7 (21.9)	0.905	41 (18.4)	118 (20.7)	0.4706
Hospitalizations per member, mean (SD)	0.4 (1.7)	0.4 (0.9)	0.8637	0.4 (1.4)	0.5 (1.8)	0.4578
All-cause emergency room visits
Members with visit, n (%)	200 (26.2)	10 (31.3)	0.5296	54 (24.2)	164 (28.7)	0.2010
Visits per member, mean (SD)	0.5 (1.3)	0.5 (0.8)	0.6506	0.5 (1.2)	0.6 (1.4)	0.1886
All-cause outpatient visits (nonphysical therapy)
Members with visit, n (%)	752 (98.7)	32 (100.0)	0.5143	220 (98.7)	566 (99.1)	1.0
Visits per member, mean (SD)	15.5 (10.2)	19.2 (12.7)	0.0943	13.0 (8.5)	16.0 (10.8)	0.0009
All-cause physical therapy visits
Members with visit, n (%)	123 (16.1)	7 (21.9)	0.3905	37 (16.6)	85 (14.9)	0.5492
Visits per member, mean (SD)	0.9 (3.3)	1.5 (4.0)	0.3359	0.9 (3.5)	0.6 (2.5)	0.4887

Notes:

* All P values for categorical variables calculated using chi-square tests. All P values for continuous variables calculated using Wilcoxon rank-sum tests.

Abbreviations: DDI, potential drug–drug interaction; SD, standard deviation.

Table 6 Six-month postindex all-cause health care costs and component costs stratified by drug–drug interaction status

	Pregabalin			Duloxetine
	No DDI present n=762	DDI present n=32	P value*	No DDI present n=223	DDI present n=571	P value*
All-cause total health care costs, mean (SD)	9,089 (12,064)	11,896 (14,781)	0.3974	7,228 (11,389)	9,373 (13,022)	<0.0001
All-cause total medical costs, mean (SD)	6,559 (11,539)	9,304 (14,391)	0.427	5,480 (11,231)	6,532 (11,488)	0.0082
Outpatient-related (nonphysical therapy), mean (SD)	2,651 (3,950)	2,929 (2,618)	0.2273	1,946 (2,408)	2,476 (3,552)	0.002
Physical therapy-related, mean (SD)	112 (442)	144 (342)	0.339	98 (405)	79 (318)	0.7411
Inpatient-related, mean (SD)	2,876 (9,269)	5,078 (11,656)	0.6729	2,656 (9,541)	2,985 (9,460)	0.5224
ER-related, mean (SD)	304 (9,001)	205 (390)	0.6413	239 (612)	351 (991)	0.1900
All-cause total pharmacy costs, mean (SD)	2,529 (3,041)	2,591 (2,872)	0.7218	1,748 (1,603)	2,841 (5,476)	<0.0001

Notes: All costs are in US dollars.

* All P values for categorical variables calculated using chi-square. All P values for continuous variables calculated using Wilcoxon rank-sum tests.

Abbreviations: DDI, potential drug–drug interaction; SD, standard deviation.

Table 7 Model-based* 6-month postindex all-cause total health care costs by index medication and DDI status and difference-in-difference comparison between pregabalin and duloxetine

	All-cause health care costs
	Mean	95% confidence interval
Pregabalin
No DDI present	$17,337	$10,322–$29,118
DDI present	$18,382	$9,959–$33,930
Difference**	$1,045	–
P value	0.727	–
Duloxetine
No DDI present	$14,541	$8,499–$24,878
DDI present	$15,678	$9,368–$26,239
Difference**	$1,137	–
P value	0.3124	–
Difference-in-difference comparison	$1,045 versus $1,137 P=0.8500

Notes:

* GLMM model with gamma distribution and log link. Model-based means, standard errors, and confidence intervals were derived from model and transformed into dollar values through exponentiation. All P values are calculated using Wald chi square tests through LSMEANS option. Presence of potential DDI, drug used (duloxetine versus pregabalin), DDI*Drug interaction term, baseline demographic characteristics, baseline comorbidities present, and preindex medication utilization controlled for in GLMM model;

** represents the additional health care costs associated with the presence of a potential DDI.

Abbreviations: DDI, potential drug–drug interaction; GLMM, generalized linear mixed model; LSMEANS, least square means.

Table 8 Opioid utilization* in 6-month pre- and postindex periods and difference-in-difference comparison between pregabalin and duloxetine

	Long-acting opioids	Short-acting less potent opioids	Short-acting more potent opioids
	%	%	%
Pregabalin
Preindex	15.4	60.8	22.7
Postindex	17.0	62.2	25.1
Difference	+1.6	+1.4	+2.4
Duloxetine
Preindex	14.5	60.2	23.4
Postindex	17.9	59.4	25.6
Difference	+3.4	−0.8	+2.1
Difference-in-difference comparison**	1.6 vs 3.4	1.4 vs −0.8	2.4 vs 2.1
Statistical difference**	t=−1.77, P=0.077	t=0.80, P=0.424	t=0.04, P=0.970

Notes:

* Defined as one or more opioid prescription fills during period;

** difference-in-difference t-statistic derived from a generalized linear mixed model with a logit link and binary distribution, adjusting for baseline demographics, Deyo–Charlson Comorbidity Index, and pre- and postindex nonopioid pain medication utilization.

Abbreviations: vs, versus.

Table 9 Morphine equivalents utilization in pre- and postindex 6-month periods and difference-in-difference comparison between pregabalin and duloxetine

	Morphine equivalents milligrams/30 days
	Mean	Standard deviation
Pregabalin
Preindex	930.6	2,300.9
Postindex	1,070.2	2,609.7
Difference	139.6	1,245.3
Duloxetine
Preindex	968.0	2,294.2
Postindex	1,149.4	2,549.6
Difference	181.3	1,384.4
Difference-in-difference comparison*	139.6 versus 181.3 t=−0.63, P=0.528

Notes:

* Difference-in-difference t-statistic derived from a generalized linear mixed model with an identity link and a Gaussian distribution, adjusting for baseline demographics, Deyo–Charlson Comorbidity Index, and pre- and postindex nonopioid pain medication utilization.