A review of the clinical utility of duloxetine in the treatment of diabetic peripheral neuropathic pain

Figures & data

Table 1 Summary of pain outcomes from clinical trials

Reference and study size	Treatment groups	Design	Duration (weeks)	Evaluation method	Results
Tesfaye et al^Citation22 N=804	Group 1: DUL 60 mg QD Group 2: PRE 300 mg QD 8-weeks: stop, or continue at higher (DUL 120, PRE 600) or combination doses (DUL + PRE)	Multinational, randomized, double-blind, parallel group	18	BPI-MSF score	No difference between combination and high dose monotherapy
Raskin et al^Citation18 N=449	Group 1: DUL 60 mg BID Group 2: DUL 120 mg QD	Multinational, randomized, open-label, parallel group	28	BPI and CGI-S	Both groups had significantly lower scores (P<0.001) on all pain measurements
Raskin et al^Citation16 N=348	Group 1: DUL 60 mg QD Group 2: DUL 60 mg BID Group 3: Placebo	Multicenter, randomized, double-blind, parallel group	12	Likert pain scale	Compared with placebo, both DUL groups improved significantly on pain scores (P<0.001)
Raskin et al^Citation17 N=237	Group 1: DUL 60 mg BID Group 2: Routine care	Open-label extension of Raskin 2006	52	SF-36 and EQ-5D	Not statistically significant between-group differences in efficacy endpoint
Wernicke et al^Citation23 N=334	Group 1: DUL 60 mg QD Group 2: DUL 60 mg BID Group 3: Placebo	Multicenter, randomized, double-blind	12	Likert pain scale	DUL performed significantly better than placebo, however no differences were observed between DUL doses
Wernicke et al^Citation24 N=293	Group 1: DUL 60 mg BID Group 2: Routine care	Randomized, open-label	52	SF-36 and EQ-5D	Significant treatment-group differences were observed in favor of DUL in the SF-36, but not in EQ-5D
Tanenberg et al^Citation21 N=407	Group 1: PRE 300 mg QD Group 2: DUL 60 mg QD + PRE current dose Group 3: DUL 60 mg QD	Randomized, open-label, non-inferiority	12	Numerical rating scale	DUL established non-inferiority compared to PRE
Rowbotham et al^Citation19 N=280	Group 1: DUL 60 mg QD Group 2: *ABT-894 4 mg BID Group 3: Placebo	Multinational, randomized, double-blind, parallel group, placebo-controlled	8	BPI	DUL demonstrated statistically significant differences in the change of the pain score from baseline to final observation (P=0.032 vs placebo)
Boyle et al^Citation25 N=83	Group 1: PRE 600 mg QD Group 2: DUL 120 mg QD Group 3: AMI 75 mg QD	Randomized, double-blind	4	BPI	There was no significant difference in analgesic efficacy between DUL, AMI, and PRE
Gao et al^Citation14 N=215	Group 1: DUL 60–120 mg QD Group 2: Placebo	Multicenter, randomized, double-blind, parallel group	12	BPI	Mean change from baseline to endpoint in BPI average pain was not statistically different between the treatment groups (P=0.124)
Goldstein et al^Citation15 N=457	Group 1: Placebo Group 2: DUL 20 mg QD Group 3: DUL 60 mg QD Group 4: DUL 60 mg BID	Randomized, double-blind, parallel group	12	Likert pain scale	DUL 60 and DUL 120, but not DUL 20, demonstrated significantly improved pain scores compared to placebo
Kaur et al^Citation26 N=65	Group 1: AMI 10, 25, or 50 mg QD Group 2: DUL 20, 40, or 60 mg QD	Randomized, cross-over	6	Visual analog scale	AMI and DUL showed significant improvements from baseline, but there were no between-group differences
Skljarevski et al^Citation20 N=216	Group 1: 60 mg QD 8-weeks: non-responders increased dose Group 2: 120 mg QD	Multi-center, open-label	34	BPI	Non-responders showed statistically significant pain reduction with increased doses to 120 mg QD

Note:

* is ABT-894 is a drug molecule that never reached the US market.

Abbreviations: CGI-S, Clinical Global Impressions – Severity; DUL, duloxetine; EQ-5D, European Quality of Life-5 Dimensions; PRE, pregabalin; AMI, amitriptyline; QD, once daily; BID, twice daily; BPI, brief pain inventory; BPI-MSF, brief pain inventory modified short form; SF-36, Medical Outcomes Study Short Form 36.

Table 2 Opioid-utilization in real-world studies following initiation of duloxetine or comparator

Reference and study size	Enrollment period	Data source	Post-index duration	Opioid use at baseline	Treatment	Opioid-utilization			Bias adjustment	Comments
						Measurement	Unadjusted post-index	Adjusted difference
Chen et al^Citation28 N=234	Mar 2005– Dec 2005	Thomson Reuters MarketScan^®	12 months	Opioid-naïve in 90 days pre-index	DUL	Users (%) Days on Rx No Rx dispensed Days before 1st use Morphine equivalent	52.1 31.8 2.1 246 1,047	NR	Propensity score matching	Percentage of users of any opioid decreased in the post-index period for DUL, but increased for SOC; all observed differences were from short-acting opioids
					SOC	Users (%) Days on Rx No Rx dispensed Days before 1st use Morphine equivalent	84.6* 59.0* 3.8* 125* 2,862*	NR
Wu et al^Citation29 N=499	Mar 2005– Dec 2005	Thomson Reuters MarketScan^®	12 months	Opioid-naïve in 90 days pre-index	DUL	Users (%) Days on Rx No Rx dispensed Days before 1st use Morphine equivalent	54.0 26.9 1.9 240.5 1,404	0.38*,§ −20.0*,¶ 0.60*,†† 0.55*,‡‡ −865.3¶	Multiple regression models utilized	After adjusting for baseline differences, only yearly morphine equivalents became insignificant
					SOC	Users (%) Days on Rx No Rx dispensed Days before 1st use Morphine equivalent	76.7* 51.4* 3.6* 158.8* 2,496*	Ref
Zhao et al^Citation30 N=1,281	Mar 2005–Dec 2005	Thomson Reuters MarketScan^®	12 months	Concurrent opioid use in 90 days pre-index required	DUL cont**	Days on med No Rx dispensed Morphine equivalent	186.3 9.4 19,145	Ref	Multiple regression models utilized	After adjusting for baseline differences, only days on opioid medications remained significant; compared to DUL cont, all other groups experienced less decrease in the number of days on medication
					DUL non-cont‡	Days on Rx No Rx dispensed Morphine equivalent	171.2 9.5 16,844	−24.4*,¶ −0.8¶ −3,298¶
					SOC cont**	Days on Rx No Rx dispensed Morphine equivalent	163.5 9.3 16,891	−23.7*,¶ −1.5¶ −2,850¶
					SOC non-cont‡	Days on Rx No Rx dispensed Morphine equivalent	143.3* 8.4 11,977	−18.5*,¶ −1.0¶ −1,253¶
Gore et al^Citation34 N=1,426	On or after Jan 2005	PharMetrics^® Patient-Centric Database	12 months	Not specified	DUL	Users (%) No Rx dispensed	63.8 9.0	Reported qualitatively	Propensity score matching; Regression models	After adjusting for baseline differences, no differences were observed for any opioid; differences remained for strong opioids, favoring PRE
					PRE	Users (%) No Rx dispensed	63.0 7.3*	Reported qualitatively
Margolis et al^Citation36 N=946	Oct 2005–Mar 2009	MarketScan^® Commercial Database	6 months	Not specified	DUL	Users (%)	17.3	1.7***	Difference-in-difference	DUL was associated with a significant increase from pre- to post-index; no between-group differences were seen
					PRE	Users (%)	16.7	Ref

Notes:

* Statistically significant at P<0.05;

** continuous use defined as a medication possession ratio ≥0.8;

‡ non-continuous use defined as a medication possession ratio <0.8;

§ Odds ratio from logistic regression, where <1 is interpreted as lower likelihood of any opioid use;

¶ Adjusted difference from linear regression;

†† Incidence rate ratio from Poisson regression, where <1 is interpreted as lower likelihood to have an additional opioid prescription filled;

‡‡ Hazard ratio from Cox regression model, where <1 is interpreted as lower likelihood of having the first opioid dispensed at any time;

*** Difference-in-differences is DUL pre- to post-index differences minus PRE DUL pre- to post-index differences. Numbers are mean or proportion.

Abbreviations: DUL, duloxetine; SOC, standard of care; PRE, pregabalin; cont, continuous; non-cont, non-continuous; NR, not reported; Ref, referent; Rx, prescription.

Table 3 Health care costs following initiation of duloxetine or comparator

Reference and study size	Enrollment period	Data source	Post-index duration	Treatment	Unadjusted health care costs post-index (USD)	Adjusted difference	Comments
Chen et al^Citation28 N=234	Mar 2005–Dec 2005	Thomson Reuter’s MarketScan^®	12 months	Duloxetine Standard of care	$18,623±$18,106 $30,602±$36,283*	NR NR	Adjustment: Propensity score matching; no subsequent cost adjustment
Wu et al^Citation29 N=499	Mar 2005–Dec 2005	Thomson Reuter’s MarketScan^®	12 months	Duloxetine Standard of care	$25,466±$36,976 $37,524±$57,327*	−$8,088* Ref	Adjustment: GLM with log-link and gamma distribution
Zhao et al^Citation30 N=1,281	Mar 2005–Dec 2005	Thomson Reuter’s MarketScan^®	12 months	Duloxetine cont** Duloxetine non-cont‡ Standard of care cont** Standard of care non-cont‡	$31,898±$26,481 $43,796±$76,575 $34,993±$38,874* $40,634±$64,602	Ref $12,729* $3,973 $4,392	Adjustment: GLM with log-link and gamma distribution
Gore et al^Citation34 N=1,426	On or after Jan 2005	PharMetrics^® Patient-Centric Database	12 months	Duloxetine Pregabalin	$30,881 [$17,686] $30,914 [$15,760]	NR NR	Adjustment: Propensity score matching; GLM with log-link Authors stated that only medication costs remained significant after adjustment
Zhao et al^Citation32 N=2,573	Jan 2006–Dec 2006	Thomson Reuter’s MarketScan^®	12 months	Duloxetine Pregabalin	$34,146±$35,658 $34,897±$40,043*	NR NR	Adjustment: Propensity score stratification
Burke et al^Citation33 N=2,136	Mar 2006–Dec 2008	PharMetrics^® Patient-Centric Database	6 months	Duloxetine Pregabalin	$12,540±$21,439 $15,420±$31,804	NR NR	Adjustment: difference-in-difference models; no difference between cohorts from pre- to post-index period (cost ratio)

Notes:

* Statistically significant at P<0.05;

** continuous use defined as a medication possession ratio ≥0.8;

‡ non-continuous use defined as a medication possession ratio <0.8; Numbers are mean ± standard deviation or mean [median].

Abbreviations: NR, not reported; GLM, generalized linear model; cont, continuous; non-cont, non-continuous; Ref, referent.

Table 4 Pharmacoeconomic evaluation of duloxetine

Reference and study size	Methods	Time-horizon	Perspective	Strategies	Result	Comments
Wu et al^Citation40 N=233	CEA alongside an RCT/52-week extension	50 weeks	United States; third-party payer, employer and societal	DUL Usual care	Base-case: Payer, DUL not significantly cost-effective Employer, DUL dominant Society, DUL dominant Sensitivity analysis: Similar results	Did not use QALYs as outcome and appropriate WTP threshold for increase in SF-36 BP remains uncertain
Beard et al^Citation41 N=1,000	Decision tree analysis	6 months	United Kingdom; health care payer (the National Health Service)	DUL as 1st, 2nd, 3rd, or 4th line No DUL (TCA, GABA, opioids)	Base-case: DUL 2nd dominated no DUL, DUL 3rd, or DUL 4th DUL 1st vs DUL 2nd £75,036/QALY Sensitivity analyses: DUL 2nd dominant in 1-way SA; 94% probability of being cost-saving vs No DUL in PSA	Considers important question regarding order of treatments used; probabilistic sensitivity analyses did not include all comparators
O’Connor et al^Citation42 N=N/A	Decision tree analysis	3 months	United States; third-party payer	PRE DUL GABA DES	Base-case: DUL vs DES $47,700/QALY gained PRE dominated by either DUL or DES GABA dominated by either DUL or DES Sensitivity analyses: DUL had 50% probability of being cost-effective, DES had 48%, PRE had ≈2%, and GABA had ≈0% at a $50,000/QALY WTP in PSA	Incorporated data from unpublished trials; did not consider treatment after discontinuation for LOE or AE; base-case analysis did not incorporate risk of SAE for DUL, PRE, or GABA
Bellows et al^Citation43 N=N/A	Decision tree analysis	6 months	United States; third-party payer	PRE DUL	Base-case: DUL dominated PRE Sensitivity analyses: DUL ≈85% and ≈75% probability of being cost-effective at a WTP of $50,000/QALY in base-case and real-world PSA, respectively	Incorporated real-world estimates of adherence and costs; patients with LOE may have had opioid therapy added to regimen
Carlos et al^Citation44 N=1,000	Decision tree analysis	3 months	Mexico; health care payer (public health care system)	DUL PRE Branded GABA Generic GABA	Base-case: DUL dominated PRE and branded GABA DUL vs generic GABA $8,194/QALY gained Sensitivity analyses: DUL had 61% probability of being cost-effective, generic GABA 25%, and PRE 14%	Included both generic and branded GABA; lack of detail regarding methods and results due to it being abstract presented at a conference with no manuscript available; WTP threshold not provided

Abbreviations: CEA, cost-effectiveness analysis; RCT, randomized controlled trial; DUL, duloxetine; TCA, tricyclic antidepressants; GABA, gabapentin; PRE, pregabalin; DES, desipramine; QALY, quality-adjusted life-year; WTP, willingness-to-pay; PSA, probabilistic sensitivity analysis; LOE, lack of efficacy; AE, adverse event; SAE, serious adverse event; SF-36 BP, Medical Outcomes Study Short Form 36 Bodily Pain scale; SA, sensitivity analysis; N/A, not applicable.

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