Duloxetine in addition to self-management for painful temporomandibular disorders: a <i>post hoc</i> responder analysis of a randomized, placebo-controlled clinical trial

FERREIRA, Dyna Mara Araújo Oliveira; SOARES, Flávia Fonseca Carvalho; RAIMUNDINI, Amanda Ayla; BONJARDIM, Leonardo Rigoldi; COSTA, Yuri Martins; CONTI, Paulo César Rodrigues

doi:10.1590/1678-7757-2024-0035

Brasil

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Original Article • J. Appl. Oral Sci. 32 • 2024 • https://doi.org/10.1590/1678-7757-2024-0035 linkcopy

Duloxetine in addition to self-management for painful temporomandibular disorders: a post hoc responder analysis of a randomized, placebo-controlled clinical trial^*

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Aim To identify the phenotypic characteristics of individuals with temporomandibular disorders (TMD) who may benefit from adding duloxetine to self-management (SM) strategies.

Methodology This was a post hoc exploratory analysis of a randomized, placebo-controlled clinical trial with SM-duloxetine (duloxetine 60 mg/day plus SM strategies for 12 weeks) in adult participants with painful TMD. The primary outcome was the proportion of responders to treatment (individuals with ≥ 30% reduction in pain intensity) in SM-duloxetine and SM-placebo group at week 12. For responder analysis, five phenotyping domains recommended by Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials were assessed: pain, psychological, sleep, quantitative sensory testing, and conditioned pain modulation. Relative risk (RR), 95% confidence intervals (CI), and absolute risk reduction were calculated.

Results Among participants treated with SM-duloxetine, severe pain intensity (RR 1.33, 95% CI: 0.56, 3.17), pain disability (RR 1.30, 95% CI: 0.63, 2.67), ≥ 1 painful comorbidity (RR 1.48, 95% CI: 0.57, 3.79), and anxiety symptoms (RR 1.80, 95% CI: 0.75, 4.34) were associated with greater likelihood of response to treatment. Among individuals treated with SM-placebo, only temporal summation of pain was associated with greater likelihood of response to treatment.

Conclusion Personalized medicine may be implemented in painful TMD management, and phenotype characteristics related to pain and psychological domains may predict which individuals with painful TMD are more likely to respond to the addition of serotonin and norepinephrine reuptake inhibitors to SM strategies to clinically and significantly reduce pain intensity.

Keywords Temporomandibular Joint Dysfunction Syndrome; Pain management; Duloxetine hydrochloride; Self-management; Phenotype

	SM-duloxetine (n = 40)	SM-placebo (n = 38)
Age (years)	38.8 (10.6)	39.7 (11.2)
Sex (female)	38 (95%)	37 (97.5%)
TMD pain
Duration of pain (years)	7.3 (7.6)	7.8 (8.9)
Pain intensity (0 - 10 NRS)	7.1 (1.6)	6.9 (1.4)
Pain disability (0 - 6 scale)	2.1 (1.9)	2.1 (1.6)
Presence of ≥1 painful comorbidity	27 (67.5%)	27 (71.1%)
Central sensitization inventory	48.1 (13.8)	49.7 (16.2)
Psychological
HADS anxiety (0 - 21 scale)	9.6 (3.7)	9.1 (4.3)
HADS depression (0 - 21 scale)	6.5 (3.3)	7.2 (4.0)
Sleep
PSQI (0 - 21 scale)	8.9 (4.0)	9.1 (3.8)
QST, z-score
MPT	1.88	1.81
TSP	4.46	4.16
PPT	0.40	0.70
CPM, absolute value ^¶
Masseter	- 0.046 (0.5)	- 0.045 (0.4)

	SM-Duloxetine		Relative risk (95% CI)	Absolute risk reduction
Domain	Responders (n= 15)	Non responders (n= 25)	Relative risk (95% CI)	Absolute risk reduction
Pain
Pain intensity
Mild to moderate (<7)	33.3%	44%	1.33	0.10
Severe (≥7)	66.6%	66%	(0.56, 3.17)
Pain disability
Without (<3)	46.7%	76%	1.30	0.14
With (≥3)	53.3%	24%	(0.63, 2.67)
Pain Comorbidities
Without	27%	40%	1.48	0.14
At least 1	73%	60%	(0.57, 3.79)
Central Sensitization
Without (<40)	40%	24%	0.64	-0.18
With (≥40)	60%	76%	(0.29, 1.40)
Psychological
HADS Anxiety
Without (≤8)	33.4%	56%	1.80	0.21
With (>8)	66.6%	44%	(0.75, 4.34)
HADS Depression
Without (≤8)	80%	68%	0.65	-0.14
With (>8)	20%	32%	(0.22, 1.89)
Sleep
Normal (PSQI ≤5)	33.3%	20%	0.66	-0.17
Impaired (PSQI >5)	66.6%	80%	(0.29, 1.48)
QST
MPT
Normal	60%	52%	0.81	-0.07
Abnormal	40%	48%	(0.35, 1.85)
TSP
Normal	13.4%	24%	1.62	0.15
Abnormal	86.6%	76%	(0.45, 5.79)
PPT
Normal	80%	92%	1.75	0.26
Abnormal	20%	8%	(0.74, 4.09)
CPM
Normal (<0)	73.4%	48%	0.49	-1.1
Impaired (≥0)	26.6%	52%	(0.18, 1.28)

	SM-Placebo		Relative risk (95% CI)	Absolute risk reduction
Domain	Responders (n=17)	Non responders (n= 21)	Relative risk (95% CI)	Absolute risk reduction
Pain
Pain intensity
Mild to moderate (<7)	53%	20%	0.50	-0.35
Severe (7)	47%	80%	(0.26, 0.94)
Pain disability
Without (<3)	70.6%	57.2%	0.71	-0.15
With (≥3)	29.4%	42.8%	(0.31,1.60)
Pain Comorbidities
Without	35.3%	19.1%	0.65	-0.21
At least 1	64.7%	80.9%	(0.33, 1.29)
Central Sensitization
Without (<40)	46%	34%	0.74	-0.14
With (≥40)	64%	76%	(0.36, 1.51)
Psychological
HADS Anxiety
Without ( ≤8)	58.8%	38.1%	0.63	-0.20
With (>8)	41.2%	61.9%	(0.30,1.30)
HADS Depression
Without (≤8)	82.4%	47.7%	0.36	-0.37
With (>8)	17.6%	52.3%	(0.12, 1.05)
Sleep
Normal (PSQI ≤5)	29.4%	23%	0.85	-0.08
Impaired (PSQI >5)	70.6%	77%	(0.40,1.82)
QST
MPT
2Normal	63%	58%	0.88	-0.05
Abnormal	47%	52%	(0.43, 1.80)
TSP
Normal	28%	28.6%	1.44	0.15
Abnormal	82%	71.4%	(0.53, 3.92)
PPT
Normal	100%	81%	-	-
Abnormal	0%	19%
CPM
Normal (< 0)	64.7%	47.6%	0.67	-1.13
Impaired (≥0)	35.3%	52.4%	(0.31, 1.44)

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[TFN1] ^§ Data are means (SD) or numbers (%). ^¶ Negative value means pain inhibition along the protocol. CPM= Conditioned Pain Modulation test, HADS= Hospital Anxiety and Depression Scale, MPT= Mechanical Pain Threshold, PPT= Pressure Pain Threshold, PSQI= Pittsburg Sleep Quality Index, QST= Quantitative Sensory Testing, SM= Self-Management, TMD= Temporomandibular Disorder, TSP= Temporal Summation of Pain

Duloxetine in addition to self-management for painful temporomandibular disorders: a post hoc responder analysis of a randomized, placebo-controlled clinical trial*

Abstract

Duloxetine in addition to self-management for painful temporomandibular disorders: a post hoc responder analysis of a randomized, placebo-controlled clinical trial^*