Psychologic Impact of Chronic Orofacial Pain: A Critical Review

Aalia Karamat; Jared G Smith; Lydia Nabil Fouad Melek; Tara Renton

doi:10.11607/ofph.3010

. 2022 Jun 2;36(2):3010. doi: 10.11607/ofph.3010

Psychologic Impact of Chronic Orofacial Pain: A Critical Review

Aalia Karamat ^1,^2,³, Jared G Smith ^4,^5,⁶, Lydia Nabil Fouad Melek ^7,^8,^9,¹⁰, Tara Renton ^11,^12,¹³

PMCID: PMC10586586 PMID: 35943323

Abstract

Aims:

To explore the prevalence of clinically significant anxiety and depression in adult patients with chronic orofacial pain (COFP) conditions.

Methods:

A systematic online search of the Medline (PubMed) and Ovid databases was performed for articles published from 2006 to 2019. Observational studies—including cross-sectional, case-control, and case series—and longitudinal prospective studies were included. A total of 118 articles were selected for inclusion, and the prevalence rates of clinically significant anxiety and depression were summarized.

Results:

Most studies focused on temporomandibular disorder (TMD) pain and less often on neuropathic COFP conditions. Prevalence rates varied widely across studies according to OFP condition and assessment measure; most questionnaire-based assessments yielded rates of clinically significant depression and anxiety in, respectively, 40% to 60% and 40% to 65% of individuals with TMD and in 20% to 50% and 25% to 55% of patients with neuropathic, mixed, or idiopathic/atypical COFP conditions. Rates of anxiety and depression were lower in studies using diagnostic instruments and in TMD studies with nonpatient samples. Most controlled studies showed a higher prevalence of anxiety and depression in individuals with COFP than in those without. Higher COFP pain levels and the presence of comorbid conditions such as migraines or widespread pain increased the likelihood of anxiety and/or depressive symptoms in individuals.

Conclusion:

Clinically significant anxiety and depression were commonly observed in patients with COFP, were present at higher rates than in pain-free participants in controlled studies, and were closely linked to pain severity. More research is needed to evaluate the psychologic impact of multiple COFP conditions in an individual and the prevalence of precondition psychologic morbidity. J Oral Facial Pain Headache 2022;36:103–140. doi: 10.11607/ofph.3010

Keywords: anxiety, depression, neuropathic/nonneuropathic pain, orofacial pain, TMD

Orofacial pain is a noxious, painful experience in the region of the face and/or oral cavity.¹ According to the International Association for the Study of Pain (IASP), pain is defined as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”² Chronic pain continues after the expected time of recovery.³ There is evidence that pre-existing psychologic factors can predict the onset of postsurgical chronic pain.⁴

Patients with chronic pain frequently undergo a change in their beliefs and cognitions, and these affective and cognitive pathways contribute to the sensory perception of pain.⁵ Over time, individuals with chronic pain may lose the capability to function optimally, and some may retire from work early.⁶ Nonorofacial chronic pain conditions can cause a significant degree of disability.⁷ In the United States, they are responsible for 21% of visits to accident and emergency departments and for 25% of absenteeism from work annually, significantly increasing the economic burden.⁸ Orofacial pain (OFP) is specifically linked to increased workday loss and excessive use of health care systems.⁹^,¹⁰

The prevalence of OFP ranges from 17% to 26%, with up to 11% considered chronic orofacial pain (COFP).¹¹ COFP is often associated with psychologic disorders, and there is a strong link between long-standing OFP and depression and anxiety symptoms, with subsequently impaired psychologic function.⁶ Pain management is limited without an acknowledgment of psychologic factors, and the recovery process is often compromised because differences in an individual’s psychologic predisposition result in differential responses to pain.¹²

The aim of this review was to investigate studies of psychologic functioning (ie, anxiety and depression) in patients with COFP, with consideration of both neuropathic and nonneuropathic COFP conditions.

Materials and Methods

The review protocol, including the search strategy, was registered with PROSPERO (International Prospective Register of Systematic Reviews, registration number: CRD42016043703).¹³ It was not possible to perform meta-analyses due to the heterogeneity of the included studies. The cumulative evidence from the included studies was assessed, summarized, and narrated.

Search Strategy and Selection Criteria

The present review included observational studies published between 2006 and 2019. These studies were cross-sectional, case series, and prospective and retrospective cohort studies. The information sources were the Medline (PubMed) and Ovid databases. Gray literature was searched via Google Scholar. Studies in the English language investigating at least one type of COFP condition in adults (aged 18 and older) and exploring psychologic factors such as depression, somatization, posttraumatic stress disorder, and catastrophizing were selected. Studies recruiting individuals under the age of 18 years and studies exploring dental and periodontal inflammatory conditions and their psychosocial impacts or influences were excluded.

Definitions

Chronic pain is defined as a pain that exceeds a duration of 3 months,³ and this definition was applied to COFP for the present study.

Psychology is defined as the scientific study of an individual’s behaviors and their mental processes.¹⁴ According to the World Health Organization (WHO), depression is a mental disorder that presents with depressed mood, loss of interest or pleasure, a decreased level of interest and concentration, disturbed sleep, lack of appetite, and feelings of hopelessness and worthlessness.¹⁵ Depression can often be associated with anxiety symptoms.¹⁵ Generalized anxiety disorder (GAD) was defined as 6 months of excessive worry about daily issues and may be associated with autonomic symptoms.¹⁵ State anxiety is a temporary emotional arousal to a perceived threat, and trait anxiety is a personality characteristic and pattern of response (with anxiety) to a threat.¹⁶ Phobias, obsessive-compulsive disorder, and panic disorders were included in anxiety disorders. A phobia is a constant and pronounced fear of a situation that can result in either avoidance or panic attacks.¹⁵

Search Terms

The keywords used were: psychosocial; psychologic; depression; psychiatric comorbidity; posttraumatic stress disorder (PTSD); and anxiety. These keywords were used with “OR” and “AND” with the following conditions: orofacial pain; temporomandibular joint pain/disorder; trigeminal neuralgia; trigeminal nerve injury; burning mouth syndrome; persistent dento-alveolar pain; atypical facial pain; and atypical odontalgia.

Outcome Measures

The objective of the present review was to investigate studies on anxiety and depression in patients with COFP and, more specifically, to identify the reported prevalence of anxiety and depression in affected individuals and their relationships with pain chronicity, pain severity, and demographic factors, such as gender and age.

Data Extraction

The initial search yielded 5,024 articles. Suitable articles were identified (n = 252) during title and abstract screening through the process of selection and filtration. Duplicates were removed. Full-text screening of 134 articles was carried out. Based on the inclusion and exclusion criteria, a total of 118 articles were selected (Fig 1).

Fig 1 — Flow diagram of study selection.

Initially, to establish their relevance for the review, one reviewer (A.K.) read the title and abstract of each article. After reading the abstract and ensuring that the article provided the necessary information for the review, the entire article was retrieved and read to further establish whether it fulfilled the eligibility criteria. Any study that was unclear about its inclusion criteria was read by the second (J.S.), third (L.M.), and fourth (T.R.) reviewers. After discussion, consensus was reached for all articles included. The bibliographies of the selected articles were also manually searched for additional studies.

The studies on COFP were categorized according to classification (diagnostic) system: the International Classification of Headache Disorders-3 (ICHD-3),¹⁷ the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD),¹⁸ and the IASP and American Academy of Orofacial Pain (AAOP).¹⁹^,²⁰ All studies were assessed on the following parameters: type of study, type of pain under investigation, sample size, psychologic scale used, psychologic comorbidities under investigation, the reported prevalence of psychologic comorbidities in each study, and the year of publication.

Meta-analyses were not considered appropriate, as there was an insufficient number of studies with a required level of homogeneity in study design, COFP population under study, and depression/anxiety scale or method of assessment used.²¹

Risk of Bias Assessment

This study used a method previously employed in systematic reviews of oral conditions to assess the risk of bias (RoB).²²^–²⁴ Studies were evaluated on the following criteria: (1) Study group characteristics (whether consecutive or unselected patient selection was performed); (2) presence of an appropriate control group (sex- and age-matched); (3) prospective study or data collected purposely for the specific study; and (4) whether participants or the investigators were blinded if appropriate according to the study design.

The criteria were assessed as met, unmet, or unclear for each. Three factors were used to assess the study’s overall validity: (1) There is a low risk of bias because all of the criteria were met according to the study design; (2) There is a high risk of bias because at least one criterion was unmet or three criteria were unclear; (3) There is a moderate risk of bias because one or two criteria were unclear, or one or two criteria were not applicable according to study design. All four reviewers independently evaluated the RoB, and all studies were distributed equally among the reviewers.

Results

The defining characteristics and key findings of the included studies are summarized in Table 1.

Table 1.

Study Characteristics

Study, y (country)	Study type	Orofacial pain group types and sample sizes, n	No. of patients (% gender distribution)	Psychosocial scales	Psychologic comorbidity	Prevalence, %	Reference no.
1. Adamo et al, 2020 (Italy)	Cross-sectional	BMS: 52	52 (M: 19, F: 81)	HARS HDRS	Anxiety Depression	– –	102
2. Bäck et al, 2020 (Sweden)	Cross-sectional	TMD with sev pain/TMD with headache cases: 82 Controls: 977	1,059 (F: 100)	HADS	Anxiety Depression	Cases: 51.2 Controls: 21.2 Cases: 32.9 Controls: 7.2	71
3. Chang et al, 2019 (China)	Retrospective cross-sectional	TN cases: 45 Controls: 61	106 (M: 44, F: 56)	HARS HDRS	Anxiety Depression	– –	110
4. Godazandeh et al, 2019 (UK)	Cross-sectional	TN: 68 TN with MS: 26	94 (TN M: 21, F: 79; TN with MS M: 23, F: 77)	HADS	Anxiety (Mild/Sev) Depression (Mild/Sev)	TN: 63.3 (43.3/20.0) TN with MS: 53.9 (23.1/30.8) TN: 33.3 (15.0/18.3) TN with MS: 56.0 (16.0/40.0)	111
5. Heinskou et al, 2019 (Denmark)	Prospective observational	TN after medicine intervention: 103 TN after surgical intervention: 50	103 (M: 35, F: 65)	Self-report survey	Anxiety and/or depression	TN after medicine intervention: 14.6 TN after surgical intervention: 14.0	109
6. Huttunen et al, 2019 (Finland)	Randomized controlled trial	TMD: 80	80 (M: 23, F: 77)	RDC/TMD	Depression (Mod/Sev) B	42.5 (27.5/15.0)	72
7. Jivnani et al, 2019 (India)	Cross-sectional	TMD pain and headaches: 15 TMD pain with disc displacement:19 No TMD: 34	68 (M: 49, F: 51)	HADS	Anxiety (BClin/Clin) Depression (BClin/Clin)	TMD pain and headaches: 47.0 (27.0/20.0) TMD pain with disc displacement: 53.0 (42.0/11.0) No TMD: 6.0 (6.0/0.0) TMD pain and headaches: 66.0 (13.0/53.0) TMD pain with disc displacement: 63.0 (26.0/37.0) No TMD: 24.0 (18.0/6.0)	73
8. Le Bris et al, 2019 (France)	Retrospective cohort	BMS: 38	38 (M: 16, F: 84)	Self-report questionnaire	Depression symptoms	50	101
9. Lira et al, 2019 (Brazil)	Cross-sectional	TMD cases: 92 Controls: 37	129 (F: 100)	HADS	Anxiety Depression	– –	74
10. Melek et al, 2019 (UK)	Cross-sectional	Ne: TN: 40 PTTN: 97	137 (M: 30, F: 70)	GAD-7 PHQ	Anxiety (Clin) Depression (Mild-Mod/Mod-Sev to Sev)	TN: 38.5 PTTN: 34.4 TN: 53.6 (35.7/17.9) PTTN: 35.9 (25.0/10.9)	125
11. Yang et al, 2019 China	Cross-sectional	BMS cases: 30 Controls: 18	48 (M: 17, F: 83)	ZSAS ZSDS	Anxiety (Mild) Depression (Mild) Depression (Mod)	BMS: 30 BMS: 50 BMS: 36.6	100
12. Adamo et al, 2018 (Italy)	Cross-sectional	BMS: 200 Controls: 200	400 (M: 17, F: 83)	HARS HDRS	Anxiety (Mild-Mod) Anxiety (Mod-Sev) Depression (Mild) Depression (Mod-Sev)	BMS: 27 BMS: 18 BMS: 32 BMS: 34	99
13. Daher et al, 2018 (Brazil)	Cross-sectional	TMD A: 10 TMD MP: 15 Controls: 10	35 (M: 20, F: 80)	HADS	Anxiety	–	75
14. Di Stasio et al, 2018 (Italy)	Cross-sectional	BMS cases: 25 Controls: 24	49 (M: 13, F: 87)	STAI HDRS	Anxiety Depression	– –	98
15. Fernandes Azevedo et al, 2018 (Brazil)	Cross-sectional	TMD cases: 38 Controls: 67	105	STAI	St Anxiety (Mod) Tr Anxiety (Mod)	TMD: 39.5 No TMD: 29.9 TMD: 36.8 No TMD: 46.3	76
16. Lee and Chon, 2020 (Korea)	Cross-sectional	BMS with sleep problems: 15 BMS without sleep problems: 10	25 (F: 100)	SCL-90-R	Anxiety Depression	– –	97
17. Miura et al, 2018 (Japan)	Retrospective cross-sectional	AO: 383	383 (M: 15, F: 85)	DSM-V ZSDS	Anxiety Depression	10.1 15.4	133
18. Moura et al, 2018 (Brazil)	Case-control	BMS cases: 15 Controls: 15	30 (M: 20, F: 80)	BAI BDI	Anxiety (Mild/Mod) Anxiety (Mod) Depression BMS (Mod/Sev)	BMS: 16.6/33.3 Controls: 13.3 BMS: 16.7/8.3 Controls: 0.0/0.0	96
19. Natu et al, 2018 (Singapore)	Cross-sectional	No TMD: 142 Mild TMD: 79 Mod TMD: 23	244 (M: 16, F: 84)	DASS-21	Anxiety Depression	– –	77
20. Nazeri et al, 2018 (Iran)	Case-control	TMD MP and migraines: 50 TMD MP: 25 Migraines: 15 Controls: 38	128 (M: 24, F: 76)	HADS	Anxiety and/or depression	TMD MP and migraines: 90.0 TMD MP: 24.0 Migraines: 66.7 Controls: 31.6	78
21. Paulino et al, 2018 (Brazil)	Cross-sectional	TMD cases: 171 Controls: 132	303 (M: 31, F: 69)	HADS	Anxiety Depression	TMD: 46.8 No TMD: 26.5 TMD: 10.5 No TMD: 9.1	79
22. Reiter et al, 2018 (Israel)	Cross-sectional	TMD	163 (M: 25, F: 75)	GAD-7 PHQ-9	Anxiety (Mild/Mod/Sev) Depression (Mild/Mod/Sev)	19.6/8.0/4.9 26.4/12.3/8.0	80
23. Sikora et al, 2018 (Croatia)	Cross-sectional	BMS cases: 43 Controls: 50	93 (M: 18, F: 82)	STAI BDI	Anxiety Depression	– –	95
24. Sruthi et al, 2018 (India)	Cross-sectional	TMD MP: 27 TMD JP: 26 TMD mixed: 23 Controls: 24	100 (M: 46, F: 54)	DASS-42	Anxiety Depression	– –	81
25. Tu et al, 2018 (Japan)	Cross-sectional	AO: 272 AO and BMS: 83	355 (M: 12, F: 88)	ZSDS	Depression	–	124
26. Yoo et al, 2018 (Korea)	Cross-sectional	BMS cases: 50 Controls: 50	100 (M: 42, F: 58)	SCL-90-R	Anxiety Depression	– –	94
27. Mitsikostas et al, 2017 (Greece)	Case series	BMS: 8	8 (F: 100%)	HARS HDRS	Anxiety (Mild-Mod) Anxiety (Mod-Sev) Dep (Mod-Sev)	50.0 12.5 100	93
28. Naikoo et al, 2017 (India)	Case-control	TMD cases: 100 Controls: 100	220 (M: 36, F: 64)	HADS	Anxiety Depression	TMD: 53.0 No TMD: 21.0 –	82
29. Reiter et al, 2017 (Israel)	Cross-sectional	TMD: RDC: 142 DC: 157	299 (M: 24, F: 76)	RDC/TMD DC/TMD (GAD-7, PHQ-9)	RDC Anxiety (Mod/Sev) RDC Depression (Mod/Sev) DC Anxiety (Mod/Sev) DC Depression (Mod/Sev)	51.4 (27.9/23.5) 54.2 (29.6/24.6) 10.2 (7.6/2.6) 17.8 (9.6/8.2)	83
30. Su et al, 2017 (China)	Cross-sectional	TMD low pain intensity n = 156 TMD high pain intensity n = 164	320 (M: 22, F: 78)	GAD-7 PHQ-9	Anxiety (Mild/Mod/Sev) Depression (Mild/Mod/Sev)	Low pain: 23/8.9/2.5 High pain: 9.5/16.4/11.5 Low pain: 31.4/7.0/3.2 High pain: 26.8/15.8/17.7	84
31. Tan et al, 2017 (Malaysia)	Cross-sectional	TN: 75	75 (M: 31, F: 69)	HADS	Anxiety Depression	41.3 24.0	108
32. Tournavitis et al, 2017 (Greece)	Cross-sectional	TMD: 75	75 (M: 48, F: 52)	STAI CES-D	Anxiety Depression	– –	85
33. van Selms et al, 2017 (Netherlands)	Cross-sectional	TMD cases: 268 Controls: 254	522 (M: 14, F: 86)	GAD-7 PHQ-15	Anxiety Depression	– –	86
34. Yeung et al, 2017 (UK)	Cross-sectional	TMD: 162	162 (M: 20, F: 80)	GAD-7 PHQ-9	Anxiety (Mild/Mod/Sev) Depression (Mild/Mod/Sev)	27/12/8 27/20/14	87
35. Zakrzewska et al, 2017 (UK)	Cross-sectional	TN no IMP: 155 TN with IMP: 32 TN with AN: 38	225 (M: 37, F: 63)	HADS	Anxiety (BClin/Clin) Depression (BClin/Clin)	TN no IMP: 46.4 (21.5/25.2) TN with IMP: 40.7 (11.1/29.6) TN with AN: 77.8 (50.0/27.8) TN no IMP: 30.6 (15.3/15.3) TN with IMP: 29.6 (18.5/11.1) TN with AN: 55.5 (22.2/33.3)	107
36. Bertoli and de Leeuw, 2016 (USA)	Cross-sectional	TMD: 1,241	1,241 (M: 12, F: 88)	SCL-90-R	Anxiety Depression	28.9 30.4	70
37. Braud and Boucher, 2016 (France)	Cross-sectional	BMS: 18	18 (M: 6, F: 94)	HADS	Anxiety Depression	38.8 33.3	139
38. das Neves de Araújo Lima et al, 2016 (Brazil)	Cross-sectional	BMS: 64 SOB: 99	163 (M: 19, F: 81)	BAI BDI	Anxiety (Mild/Mod/Sev) Depression (Mild-Mod/Mod-Sev)	BMS: 30.0/6.7/13.3 SOB: 20.0/10.0/0 BMS: 53.1/28.1 SOB: 16.1/6.0	138
39. Davies et al, 2016 (UK)	Cross-sectional	BMS: 30 Other oral conditions: 11	41 (M: 12, F: 88)	Customized questionnaire and clinical interviews	Anxiety Depression	– –	164
40. Duraçoğlu et al, 2016 (Turkey)	Cross-sectional	TMD: 273	273 (M: 22, F: 78)	HADS	Anxiety Depression Anxiety and/or depression	31.1 40.7 49.8	67
41. Mousavi et al, 2016 (USA)	Cross-sectional	TN: 21	21 (M: 14, F: 86)	DSM-IV	Anxiety (Diag) Depression (Diag)	52.3 42.8	137
42. Patil et al, 2016 (India)	Cross-sectional	Chronic TMD cases: 60 Controls: 60	120 (M: 25, F: 75)	BDI	Depression (BClin/Mod/Sev)	Cases: 30.0 (13.3/13.3/3.3) Controls: 10.0 (6.7/3.3/0.0)	68
43. Sevrain et al, 2016 (France)	Retrospective	BMS: 35	35 (M: 9, F: 91)	HADS	Anxiety Depression	54.3 25.7	92
44. Tang et al, 2016 (China)	Cross-sectional	TN: 167	167 (M: 40.7, F: 59.3)	BAI BDI	Anxiety Depression	20.4 72.5	134
45. Visscher et al, 2016 (Netherlands)	Retrospective	TMD: 112	112 (M: 13, F: 87)	SCL-90	Depression	25.8	69
46. Al-Havaz et al, 2015 (Iran)	Cross-sectional	TMD: 171	171 (M: 43, F: 57)	RDC/TMD	Depression (Mod-Sev)	TMD: 7.0	62
47. Brailo and Zakrzewska, 2015 (UK)	Cross-sectional	TN: 48 TMD: 112 CIFP: 85	245 (M: 24, F: 76)	HADS	Anxiety (BClin/Clin) Depression (BClin/Clin)	TN: 39.3 (17.9/21.4) TMD: 55.7 (26.2/29.5) CIFP: 38.5 (15.4/23.1) TN: 32.1 (25.0/7.1) TMD: 32.8 (19.7/13.1) CIFP: 42.3 (11.5/30.8)	122
48. Kotiranta et al, 2015 (Finland)	Cross-sectional	TMD: 399	399 (M: 17, F: 83)	RDC/TMD (SCL-90-R)	Anxiety Depression	– –	63
49. Lei et al, 2015 (China)	Cross-sectional	TMD: MFP: 128 No MFP: 382	510 (M: 24, F: 76)	DASS-21	Anxiety Depression	TMD: 36.5 MFP: 62.5 No MFP: 27.7 TMD: 17.6 MFP: 31.3 No MFP: 13.1	64
50. Lopez-Jornet et al, 2015 (Spain)	Cross-sectional	BMS cases: 70 Controls: 70	140 (M: 9, F: 91)	HADS	Anxiety Depression	– –	91
51. Majumder et al, 2015 (India)	Cross-sectional	TMD cases: 311 Controls: 689	1,000 (M: 45, F: 55)	HADS	Anxiety and/or Depression	TMD: 66.2 No TMD: 31.1	65
52. Marino et al, 2015 Italy	Case-control	BMS cases: 58 Controls: 58	116 (M: 21, F: 79)	HARS MADRS	Anxiety (Mild-Mod/Mod-Sev) Depression (Mild/Mod/Sev)	BMS: 80.7 (31.6/49.1) BMS: 49.1 (47.3/1.8/0)	136
53. Reiter et al, 2015 (Israel)	Retrospective observational	Acute TMD: 49 Chronic TMD: 139	207 (M: 24, F: 76)	RDC/TMD (SCL-90-R)	Anxiety (Mod/Sev) Depression (Mod/Sev)	TMD: 54.1 (29.5/24.6) Acute: 44.9 (28.6/16.3) Chronic: 58.3 (30.2/28.1) TMD: 56.0 (33.3/22.7) Acute: 40.8 (26.5/14.3 Chronic: 61.2 (36.0/25.2)	66
54. Tokura et al, 2015 (Japan)	Cross-sectional	BMS cases: 65 Controls: 116	181 (M: 19, F: 82)	BDI	Depression (Diag MDD)	BMS: 14	135
55. Wu et al, 2015 (Korea)	Retrospective cohort	TN cases: 3,273 Controls: 13,092	16,365 (M: 62, F: 38)	ICD-9 CM	Anxiety (Diag) Depression (Diag)	TN: Cases: 1.8 Controls: 0.60 TN: Cases: 2.2 Controls: 0.79	106
56. Calixtre et al, 2014 (Brazil)	Longitudinal	TMD: 19	19 (M: 5, F: 94)	HADS	Anxiety Depression	– –	54
57. Cioffi et al, 2014 (Italy)	Cross-sectional	TMD/migraine: TMD MP: 676 Migraine: 39 TMD MP + migraine: 66	781 (M: 22, F: 78)	RDC/TMD (SCL-90)	Depression	–	121
58. Davis et al, 2014 (USA)	Cross-sectional	TMD: 50	50 (M: 8, F: 92)	Psych Diag-(MR) STAI	Anxiety (Diag) Depression (Diag)	30.0 18.0	55
59. Gerrits et al, 2014 (Netherlands)	Longitudinal cohort	OFP: 13	614 (M: 39, F: 61)	DSM-IV CIDI version 2.1	Anxiety Depression	– –	131
60. Komiyama et al, 2014 (Japan)	Cross-sectional	TMD: 1,437	1,437 (M: 29, F: 71)	RDC/TMD	Depression	–	56
61. Minghelli et al, 2014 (Portugal)	Cross-sectional	TMD cases: 633 Controls: 860	1,493 (M: 32, F: 68)	HADS	Anxiety or depression	Cases: 61.4 Controls: 38.6	57
62. Reissmann et al, 2014 (Germany)	Case-control	TMD cases: 320 Controls: 888	1,208 (M: 36, F: 64)	STAI RDC/TMD	State Anxiety (Mod/Sev) Depression (Mod/Sev)	Cases: 56.6 (25.3/31.3) Controls: 32.2 (22.2/10) Cases: 45.9 (20.6/25.3) Controls: 38.5 (16.9/21.6)	58
63. Smriti et al, 2014 (India)	Cross-sectional	TMD cases: 27 Controls: 123	150 (M: 31, F: 69)	ZSAS	Anxiety (Mild-Mod)	TMD: 25.9 No TMD: 6.5	59
64. Sood et al, 2014 (India)	Cross-sectional	TMD cases: 104 Controls: 396	400 (M: 25, F: 75)	HADS	Anxiety Depression	– –	60
65. Vasudeva et al, 2014 (India)	Case-control	TMD cases: 255 Controls: 250	505 (M: 64, F: 36)	HADS	Anxiety (BClin/Clin)	TMD 55.9 (45.0/10.9) No TMD: 20.4 (19.2/0.8)	61
66. Castelli et al, 2013 (Italy)	Case-control	TMD (chronic MP) cases: 45 Controls: 45	90 (F: 100)	BDI STAI-Y1	Anxiety Depression	– –	51
67. Chen et al, 2013 (USA)	Case-control, secondary analysis	TMD: TMD cases, no pain: 14 TMD cases with chronic pain: 145 Controls: 131	290 (F: 100)	STAI SCL-90-R	Anxiety Depression	– –	52
68. Ligthart et al, 2013 (Netherlands)	Longitudinal cohort	OFP: Facial pain: 401 (at 2-y follow-up)	2,981 (total); (M: 34, F: 66)	BAI IDS-SR	Anxiety Depression	– –	129
69. Ozdemir-Karatas et al, 2013 (Turkey)	Cross-sectional	TMD: 104	104 (M: 38, F: 62)	RDC/TMD (SCL-90-R)	Depression	–	53
70. Sipilä et al, 2013 (Finland)	Longitudinal cohort	Chronic OFP: Cases: 162 Controls: 200 Follow-up: 63 Follow-up controls: 85	Baseline: 362 Follow-up: 148	SCL-25	Depression symptoms Depression (Diag)	Baseline cases: 17.5 Controls: 7.0 Follow-up cases: 6.3 Controls: 1.2	130
71. Smith et al, 2013 (UK)	Cross-sectional	Ne: PPTN: 89	89 (M: 32, F: 68)	HADS	Anxiety (BClin/Clin) Depression (BClin/Clin)	51.2 (17.5/33.7) 29.8 (14.3/15.5)	105
72. de Lucena et al, 2012 (Brazil)	Longitudinal population-based prospective	TMD (two time periods; T1 and T2): Cases: 99 Controls: 54	153 (M: 46, F: 54)	HADS	Anxiety Depression	Cases: T1 = 61.6/T2 = 60.6 Controls: T1 = 22.2/T2 = 37.0 Cases: T1 = 16.2/T2 = 26.3 Controls: T1 = 5.6/T2 = 14.8	45
73. de Souza et al, 2012 (Brazil)	Cross-sectional	BMS cases: 30 Controls: 31	61 (M: 3, F: 97)	MINI-Plus HDRS BDI STAI	Anxiety (Diag) Depression (Diag)	Cases: 36.7 Controls: 9.7 Cases: 46.7 Controls: 12.9	89
74. Diniz et al, 2012 (Brazil)	Longitudinal cohort	Baseline TMD: 20 Controls: 35 Follow-up TMD: 28 Follow-up controls: 27	55	BAI	Anxiety (Mild/Mod-Sev)	Baseline TMD: 65.0 (55.0/10) Follow-up TMD: 64.3 (18.6/39.3)	46
75. Guarda-Nardini et al, 2012 (Italy)	Cross-sectional	Acute TMD: 51 Chronic TMD: 59	110 (M: 19, F: 81)	HARS HDRS SCL-90-R	Anxiety Depression (Mod-Sev)	– TMD (acute and chronic): 48.0 (30–18)	47
76. Kindler et al, 2012 (Germany)	Prospective cohort	TMD: TMD JP: 122 No TMD JP: 2,884 TMD MP: 50 No TMD MP: 2,984	6,040 (M: 49, F: 51)	CID-S	Anxiety symptoms Depression symptoms	JP: 64.8 No JP: 47.1 MP: 78.0 No MP: 47.3 JP: 49.2 No JP: 28.3 MP: 46.0 No MP: 29.0	48
77. Komiyama et al, 2012 (Japan)	Cross-sectional	Ne: BMS: 282 (acute: 169, chronic: 113) TN n = 83 (acute: 43, chronic: 40)	365 (M: 20, F: 80)	RDC/TMD (SCL-90-R)	Depression	–	120
78. Rodrigues et al, 2012 (Brazil)	Cross-sectional	TMD: TMD pain: 54 TMD no pain: 129	183 (M: 42, F: 58)	RDC/TMD	Depression (Mod/Sev)	TMD: 41.5 (30.2/11.3)	49
79. Schiavone et al, 2012 (Italy)	Cross-sectional	BMS: Chronic BMS: 53 Controls: 51	104 (M: 30, F: 70)	HDRS STAI-Y1/Y2	Anxiety Depression	– –	90
80. Schwahn et al, 2012 (Germany)	Cross-sectional	TMD: 3,904	3,904 (M: 50, F: 50)	CID-S	Depression	–	50
81. Wan et al, 2012 (Hong Kong)	Cross-sectional	OFP: CD: 200 IE: 200	400	GHQ-12	Psychologic distress	CD: 4 IE: 11.0	128
82. Celić et al, 2011 (Croatia)	Cross-sectional	Acute TMD: 126 Chronic TMD: 28	154 (M: 24, F: 76)	RDC/TMD (SCL-90-R)	Depression (Sev)	TMD (acute and chronic): 19.5	40
83. Dworkin, 2011 (Italy, Israel, Amsterdam)	Cross-sectional	TMD: 1,149	1,149 (M: 20, F: 80)	SCL-90-R	Depression (Mod-Sev)	45.4	41
84. Gustin et al, 2011 (Australia)	Case-control	Ne/TMD: TNP: 24 TMD: 21 Controls: 38	83 (M: 24, F: 76)	STAI BDI	Anxiety Depression	– –	16
85. Mačianskytė et al, 2011 (Lithuania)	Cross-sectional	Ne/IP: TN + Chronic facial pain: 30 ATFP: 30	60 (M: 15, F: 85)	CAS BDI	Anxiety Depression (Mod/Sev)	– TN: 76.7 (46.7/30.0) ATFP: 0	118
86. Monteiro et al, 2011 (Brazil)	Cross-sectional	Chronic TMD: 49 Controls: 101	150 (M: 78, F: 22)	STAI	State anxiety Trait anxiety	– –	42
87. Taiminen et al, 2011 (Finland)	Cross-sectional	Ne/IP: BMS: 40 ATFP: 23	63 (M: 10, F: 90)	SCID-I	Anxiety (Diag) Depression (Diag)	BMS: 47.5 ATFP: 30.4 BMS: 35 ATFP: 26	119
88. van Seventer et al, 2011 (UK, Netherlands, Canada)	Secondary analysis of a randomized controlled trial	Ne (posttraumatic peripheral neuropathic pain): TN: unknown	254 (M: 49, F: 51)	HADS	Anxiety Depression	– –	104
89. Velly et al, 2011 (USA)	Prospective cohort	TMD chronic pain onset (GCPS I): 261 Pain prognosis (GCPS II-IV): 309	Baseline: 570 (M: 15, F: 85) –	BDI	Depression (Mod/Sev), baseline	TMD: 10.3 GCPS I: 7.0 GCPS II-IV: 14.0	43
90. Xu et al, 2011 (China)	Cross-sectional	TMD: 162	162 (F: 100)	SCL-90-R	Anxiety Depression	7.4 11.7	44
91. Bakhtiari et al, 2010 (Iran)	Cross-sectional	BMS: BMS: 50 Controls: 50	100 (M: 17, F: 83)	CAS	State anxiety Trait anxiety	– –	103
92. Giannakopoulos et al, 2010 (Germany)	Case-control	TMD: MP: 88 JP: 43 NonTMD facial pain: 45 Controls n = 46	222 (M: 27, F: 73)	HADS	Anxiety Depression	– –	35
93. Kim et al, 2010 (Korea)	Cross-sectional	TMD: TMD trauma: 34 TMD no trauma: 340	374 (M: 29, F: 71)	SCL-90-R	Anxiety Depression	– –	116
94. Lajnert et al, 2010 (Croatia)	Cross-sectional	Acute TMD: 30 Chronic TMD: 30 Controls: 30	90 (F: 100)	RDC/TMD	Depression (Mod/Sev)	Acute: 52.7 (28.0/24.7) Chronic: 77.4 (30.0/6.0) Controls: 36.0 (30.0/6.0)	36
95. Manfredini et al, 2010a (Italy)	Cross-sectional	TMD: 11	111 (M: 19, F: 81)	RDC/TMD (SCL-90-R)	Depression (Mod/Sev)	41.4 (1.8/39.6)	37
96. Manfredini et al, 2010b (Italy, Israel, Netherlands)	Cross-sectional	Acute TMD: 293 Chronic TMD: 856	1,149 (M: 20, F: 80)	RDC/TMD (SCL-90)	Depression (Mod/Sev)	Acute: 45.0 (23.1/21.9) Chronic: 47.7 (25.1/22.6)	38
97. McMillan et al, 2010 (Hong Kong)	Cross-sectional, case-control	OFP cases: 200 Controls: 200	400 (M: 36, F: 64)	SCL-90	Depression	Cases: 31.0 Controls: 11.0	127
98. Pesqueira et al, 2010 (Brazil)	Cross-sectional, case-control	TMD cases: 61 Controls: 89	150	STAI RDC/TMD	State anxiety Trait anxiety	– –	39
99. Takenoshita et al, 2010 (Japan)	Cross-sectional IASP	Ne/IP: BMS: 125 AO: 37	162 (M: 13, F: 87)	SDS Psych Diag MR	Depressive tendencies Depression (Diag) Anxiety (Diag)	BMS: 32.1 AO: 33.3 BMS: 32.0 AO: 21.6 BMS: 9.6 AO: 10.8	117
100. Bonjardim et al, 2009 (Brazil)	Cross-sectional	TMD cases: 98 Controls: 98	196 (M: 49, F: 51)	HADS	Anxiety (BClin/Clin) Depression (BClin)	TMD: 43.9 (26.5/17.3) No TMD: 24.5 (21.4/3.1) TMD: 6.6 No TMD: 3.1	31
101. Choi et al, 2009 (Korea)	Retrospective	Ne/PIFP/TMD: TN: 8 Ne: 9 PIFP: 8 TMD: 138 (TMD MP: 73, TMD JP: 24, TMD MP + JP: 41)	163 (M: 40, F: 60)	HADS	Anxiety Depression	– –	115
102. Gao et al, 2009 (China)	Case-control	BMS cases: 87 Controls: 82	169 (M: 24, F: 76)	SAS SDS	Anxiety Depression	– –	165
103. Licini et al, 2009 (Italy)	Cross-sectional	TMD: 308	308 (M: 25, F: 75)	RDC/TMD	Depression (Mod/Sev)	65.7 (13.3/52.6)	32
104. Macfarlane et al, 2009 (UK)	Prospective cohort	TMD: OFP in young adults: 78	337 (M: 43, F: 57)	CES-D PSS	Depression	OFP: 33.3 No OFP: 18.9	33
105. Stavrianos et al, 2009 (UK)	Prospective cohort	TMD: 22	22 (M: 36, F: 64)	IAS	Heart phobia Cancer phobia	– –	34
106. Streffer et al, 2009 (Switzerland)	Cross-sectional	OF: 102	102 (M: 22, F: 78)	HADS	Anxiety (BClin/Clin) Depression (BClin/Clin)	51.7 (33/18.7) 32.6 (16.9/15.7)	126
107. Baad-Hansen et al, 2008 (Denmark)	Cross-sectional	TMD: 41 AO: 46	87 (M: 17, F: 83)	SCL-90-R	Depression	–	113
108. Ballegaard et al, 2008 (Denmark)	Cross-sectional	TMD/headache: TMD with headache: 55 Headache without TMD: 44	99 (M: 23, F: 76)	RDC/TMD	Depression (Mod-Sev)	TMD with headache: 70.9 Headache without TMD: 34.1	123
109. Buljan et al, 2008 (Croatia)	Cross-sectional	BMS cases: 42 Controls: 78	120 (M: 39, F: 61)	BAI SDS	Anxiety Depression	– –	88
110. Castro et al, 2008 (Brazil)	Cross-sectional	TN: 15 TMD: 15	30 (M 27, F: 73)	HADS	Anxiety Depression	– –	114
111. Lee et al, 2008 (China)	Cross-sectional	TMD: 87	87 (M: 12, F: 88)	RDC/TMD	Depression (Mod/Sev)	42.5 (26.4/16.1)	29
112. Reissmann et al, 2008 (Germany)	Cross-sectional	TMD: 225	225 (M: 14, F: 86)	RDC/TMD	Depression	47.6 (21.8–25.7)	30
113. Bertoli et al, 2007 (USA)	Retrospective	TMD: 445	445 (M: 9, F: 91)	SCL-90-R	Depression	–	26
114. John et al, 2007 (Germany)	Cross-sectional	Chronic TMD: 416	416 (M: 21, F: 79)	RDC/TMD Axis II	Depression (Mod/Sev)	46.2 (19.7/26.5)	27
115. List et al, 2007 (Sweden)	Case-control	AO cases: 46 Controls: 35	81 (M: 22, F: 78)	SCL-90-R	Depression (Mod/Sev)	Cases: 74 (26.0/48.0) Controls: 54 (37.0/17.0)	132
116. Mongini et al, 2007 (Italy)	Cross-sectional	TMD/OFP: TMD MP: 462 TMD A: 70, Ne (TN + PNe): 68 FPD: 49	649 (M: 22, F: 78)	SCID-DSM-IV	Anxiety (Diag) Depression (Diag)	TMD MP: 33.5 TMD A: 15.7 Ne: 16.2 FPD: 30.6 TMD MP: 22.3 TMD A: 15.7 Ne: 10.3 FPD: 44.9	112
117. Nifosi et al, 2007 (Italy)	Cross-sectional	TMD MFP: 19 TMD JP: 26 TMD MFP + JP: 18	63 (M: 25, F: 75)	SCID-DSM-IV HARS HDRS SCL-90-R	Anxiety (Diag) Depression (Diag) Anxiety and depression symptoms	TMD: 15.9 TMD: 20.6 –	28
118. GaldÓn et al, 2006 (Spain)	Cross-sectional	TMD MP: 58 TMD A: 56	114 (M: 11, F: 89)	BSI-18	Anxiety General distress	– –	25

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Note: Only percentages of psychologic functioning impact of orofacial pain conditions were included (at the decimal point level presented in study papers).

AN = autonomic symptoms; AO = atypical odontalgia; ATFP = atypical facial pain; BAI = Beck Anxiety Inventory (BAI); BClin = borderline clinically significant; BDI = Beck Depression Inventory; BMS = Burning Mouth Syndrome; BSI-18 = Brief Symptom Inventory-18; CAS = Covi Anxiety Scale; CD = community dwellers; CES-D = Centre for Epidemiological studies Scale; CIDI = Composite International Diagnostic Interview; CID-S = Composite International Diagnostic-Screener; CIFP = chronic idiopathic facial pain; Clin = clinically significant (Clin); DASS-21 = Depression, Anxiety and Stress Scale; DC/TMD = Diagnostic Criteria for Temporomandibular Disorders; Diag = diagnosis; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders; FPD = facial pain disorder; GAD-7 = Generalized Anxiety Disorder questionnaire; GCPS = Graded Chronic Pain Scale (grades I to IV); GHQ = General Health Questionnaire; HADS = Hospital Anxiety and Depression Scale; HARS = Hamilton Anxiety Rating Scale; HDRS = Hamilton Depression Rating Scale; IAS = Illness Attitude Scale (IAS); ICD-9 = International Classification of Diseases, 9th Revision; IDS-SR = Inventory of Depressive Symptomatology; IE = institutionalized elderly; IMP = intermittent pain; IP = idiopathic pain; JP = TMD joint pain; MADRS = Montgomery-Åsberg Depression Rating Scale; MDD = major depressive disorder; MFP/MP = myofascial pain/TMD muscle pain; MINI-Plus = International Neuropsychiatric Interview; MR = medical record; MS = multiple sclerosis; Ne = neuropathic pain; OFP = orofacial pain; PHQ = Patient Health Questionnaire; PIFP = persistent idiopathic facial pain; PNe = persistent neuropathic pain; PPTNI = painful posttraumatic nerve injury; PSS = Perceived Stress Scale; Psych Diag = psychiatric diagnosis; RDC/TMD = Research Diagnostic Criteria/Temporomandibular Disorders Axis II questionnaire; SAS/SDS = self-rating anxiety/depression scale; SCID = Structured Clinical Interview for DSM-IV; STAI (Y1/Y2) = State-Trait Anxiety Inventory (Form 1/Form 2); SCL-25 = Symptom Checklist-25; SCL-90-R = Symptom Checklist-90-Revised; SOB = secondary oral burning; TMD A = arthrogenous TMD; TNP = trigeminal neuropathic pain; TN = trigeminal neuralgia; ZSAS = Zung Self Rating Anxiety Scale; ZSDS = Zung Self-Rating Depression Scale.

Participant Characteristics

Diagnosis

The majority of included studies (n = 63) focused exclusively on TMD pain²⁵^–⁶⁷^,⁶⁹^–⁸⁷^,¹¹⁶^,¹²¹^,¹²³ and its impact on psychologic wellbeing (ie, anxiety/depression). Thirty-three studies recruited patients with a single neuropathic pain condition (23 burning mouth syndrome [BMS],⁸⁸^–¹⁰³^,¹²⁰^,¹³⁵^,¹³⁶^,¹³⁸^,¹³⁹^,¹⁶⁴^,¹⁶⁵ 2 posttraumatic neuropathic pain [PTNP],¹⁰⁴^,¹⁰⁵ and 8 trigeminal neuralgia [TN]).¹⁰⁶^–¹¹¹^,¹³⁴^,¹³⁷ Eleven studies compared patients with various types of OFP conditions¹⁶^,¹¹²^–¹¹⁵^,¹¹⁷^,¹¹⁹^,¹²⁰^,¹²²^,¹²⁴^,¹²⁵; these included studies comparing BMS to TN; PTNP/TN to TMDs; idiopathic continuous orofacial neuropathic pain to TMDs; TN to TMDs; TMDs to migraine and headaches (ie, neurovascular pain); TN to atypical facial pain, hereby referred to as persistent idiopathic facial pain (PIFP); and BMS to atypical odontalgia (AO), hereby referred to as persistent idiopathic dentoalveolar pain (PDAP). Seven studies focused on COFP in general (where pain types were not specified),⁵⁶^,¹²⁶^–¹³¹ and 2 recruited patients with AO.¹³²^,¹³³ Sample sizes across all studies ranged from 8 to 3,904 participants.

Gender

With the exception of a clinical trial on PTNP patients, where gender was evenly distributed,¹⁰⁴ mixed-gender studies involving clinical COFP populations employed samples that predominantly comprised women (range: 60% to 97%), with the exception of two studies where women were in the minority (36% and 38%).⁶¹^,¹⁰⁶ Eight studies included women (TMDs and BMS) only.³⁶^,⁴⁴^,⁵¹^,⁵²^,⁷¹^,⁷⁴^,⁹³^,⁹⁷ Aside from a community survey of elderly people (77% women),¹²⁸ studies recruiting patients from the (general) health care population tended to have a small majority of women (range: 51% to 64%).³¹^,⁴⁸^,⁵⁸^,¹³¹ The age range of the study population across most studies was 18 to 80 years, except for one where the upper limit was 100 years.¹¹⁸

Study Design

A total of 86 studies were cross-sectional in design, ²⁵^,²⁷^–³²^,³⁴^,³⁶^–⁴²^,⁴⁴^,⁴⁷^,⁴⁹^,⁵⁰^,⁵³^,⁵⁵^–⁵⁷^,⁵⁹^,⁶⁰^,⁶²^–⁶⁵^,⁶⁷^–⁷¹^,⁷³^–⁷⁷^,⁷⁹^–⁸¹^,⁸³^–⁹¹^,⁹⁴^,⁹⁵^,⁹⁷^–¹⁰⁰^,¹⁰²^,¹⁰³^,¹⁰⁵^,¹⁰⁷^,¹⁰⁸^,¹¹⁰^–¹¹⁴^,¹¹⁶^–¹²⁴^,¹²⁶^–¹²⁸^,¹³³^,¹³⁴ and 11 were longitudinal prospective studies. ³³^,⁴³^,⁴⁵^,⁴⁶^,⁴⁸^,⁵⁴^,¹⁰⁹^,¹¹¹^,¹²⁹^–¹³¹ Ten were designed as case-control,¹⁶^,³⁵^,⁵¹^,⁵²^,⁵⁸^,⁶¹^,⁷⁸^,⁸²^,⁹⁶^,¹³² 8 were retrospective, ²⁶^,⁶⁶^,⁹²^,¹⁰¹^,¹⁰⁶^,¹¹⁰^,¹¹⁵^,¹³³ 1 was a case series,⁹³ and 2 were clinical trials.⁷²^,¹⁰⁴ An exception was made to include the 2 clinical trials, as these studies measured the postintervention association between the level of pain experienced and the degree of observed anxiety and depression.

Study Characteristics

A total of 67 studies ¹⁶^,²⁸^,³¹^,³⁵^,⁴⁴^,⁴⁵^,⁴⁷^,⁴⁸^,⁵¹^,⁵²^,⁵⁴^,⁵⁵^,⁵⁷^,⁵⁸^,⁶⁰^,⁶⁴^–⁶⁷^,⁷⁰^,⁷¹^,⁷³^,⁷⁴^,⁷⁷^,⁷⁹^–¹⁰⁰^,¹⁰²^,¹⁰⁴^–¹¹²^,¹¹⁴^–¹¹⁶^,¹¹⁸^,¹¹⁹^,¹²²^,¹²⁵^,¹²⁶^,¹²⁹^,¹³¹^,¹³³ investigated the association of COFP with anxiety and depression, 9 studies²⁵^,³⁹^,⁴²^,⁴⁶^,⁵⁹^,⁶¹^,⁷⁵^,⁷⁶^,¹⁰³ with anxiety only, 31 studies²⁶^,²⁷^,²⁹^,³⁰^,³²^,³³^,³⁶^–³⁸^,⁴⁰^,⁴¹^,⁴³^,⁴⁹^,⁵⁰^,⁵³^,⁵⁶^,⁶²^,⁶³^,⁶⁸^,⁶⁹^,⁷²^,¹⁰¹^,¹¹³^,¹¹⁷^,¹²⁰^,¹²¹^,¹²³^,¹²⁴^,¹²⁷^,¹³⁰^,¹³² with depression only, 1 with psychologic distress, ¹²⁸ and 1 with hypochondriacal beliefs.³⁴ Seventy-seven²⁷^–³³^,³⁶^–³⁸^,⁴⁰^–⁴⁹^,⁵⁵^,⁵⁷^–⁶²^,⁶⁴^–⁷³^,⁷⁶^,⁷⁸^–⁸⁰^,⁸²^–⁸⁴^,⁸⁷^,⁸⁹^,⁹²^,⁹³^,⁹⁶^,⁹⁹^–¹⁰¹^,¹⁰⁵^–¹⁰⁹^,¹¹¹^,¹¹²^,¹¹⁷^–¹¹⁹^,¹²²^,¹²³^,¹²⁵^–¹³⁰^,¹³²^,¹³³^,¹³⁵^–¹³⁹ provided prevalence data for anxiety and/or depression, although 3 studies did not report prevalence rates separately for COFP and non-OFP groups. ⁴²^,⁶⁰^,¹²⁹ Most of the research was carried out in Europe (n = 56), followed by Asia (n = 38), Latin America (n = 15), the USA (n = 6), and Australia (n = 1), while 2 spanned across continents. There were 33 (28.0%) low RoB studies and 27 (22.9%) high RoB studies; almost half of the studies (n = 58 [49.2%]) had a moderate risk of bias (Table 2).

Table 2.

Risk of Bias of Individual Studies

Study	Study design	Study group	Control group	Prospective design	Blinded	Cumulative risk of bias	Reference no.
1. Adamo et al, 2020	Cross-sectional	Met	Met	Met	N/A	Low	102
2. Bäck et al, 2020	Cross-sectional	Unmet	Met	Met	N/A	High	71
3. Chang et al, 2019	Retrospective cross-sectional	Met	Met	Unmet	N/A	High	110
4. Godazandeh et al, 2019	Cross-sectional	Met	N/A	Met	N/A	Moderate	111
5. Heinskou et al, 2019	Prospective observational	Met	N/A	Met	N/A	Moderate	109
6. Huttunen et al, 2019	Randomized controlled trial	Met	Met	Met	N/A	Low	72
7. Jivnani et al, 2019	Cross-sectional	Met	Met	Met	N/A	Low	73
8. Le Bris et al, 2019	Retrospective cohort	Met	N/A	Unclear	N/A	Moderate	101
9. Lira et al, 2019	Cross-sectional	Unclear	Unmet	Met	N/A	High	74
10. Melek et al, 2019	Cross-sectional	Met	N/A	Met	N/A	Moderate	125
11. Yang et al, 2019	Cross-sectional	Met	Unclear	Met	N/A	Moderate	100
12. Adamo et al, 2018	Cross-sectional	Met	Met	Met	N/A	Low	99
13. Daher et al, 2018	Cross-sectional	Unmet	Unclear	Met	N/A	High	75
14. Di Stasio et al, 2018	Cross-sectional	Met	Met	Met	N/A	Low	98
15. Fernandes Azevedo et al, 2018	Cross-sectional	Met	Unclear	Met	N/A	Moderate	76
16. Lee and Chon, 2020	Cross-sectional	Met	N/A	Met	N/A	Moderate	97
17. Miura et al, 2018	Retrospective cross-sectional	Met	N/A	Unmet	N/A	High	133
18. Moura et al, 2018	Case-control	Met	Met	Met	N/A	Low	96
19. Natu et al, 2018	Cross-sectional	Unmet	Met	Met	N/A	High	77
20. Nazeri et al, 2018	Case-control	Met	Met	Met	N/A	Low	78
21. Paulino et al, 2018	Cross-sectional	Met	Unmet	Met	N/A	High	79
22. Reiter et al, 2018	Cross-sectional	Met	Unmet	Unmet	N/A	High	80
23. Sikora et al, 2018	Cross-sectional	Met	Met	Met	N/A	Low	95
24. Sruthi et al, 2018	Cross-sectional	Met	N/A	Met	N/A	Moderate	81
25. Tu et al, 2018	Cross-sectional	Met	Met	Unmet	N/A	High	124
26. Yoo et al, 2018	Cross-sectional	Met	Met	Met	N/A	Low	94
27. Mitsikostas et al, 2017	Case series	Met	N/A	Met	N/A	Moderate	93
28. Naikoo et al, 2017	Case-control	Met	Met	Met	N/A	Low	82
29. Reiter et al, 2017	Cross-sectional	Met	Met	Met	N/A	Low	83
30. Su et al, 2017	Cross-sectional	Met	N/A	Met	N/A	Moderate	84
31. Tan et al, 2017	Cross-sectional	Met	N/A	Met	N/A	Moderate	108
32. Tournavitis et al, 2017	Cross-sectional	Met	N/A	Met	N/A	Moderate	85
33. van Selms et al, 2017	Cross-sectional	Met	Met	Met	N/A	Low	86
34. Yeung et al, 2017	Cross-sectional	Met	N/A	Met	N/A	Moderate	87
35. Zakrzewska et al, 2017	Cross-sectional	Met	N/A	Met	N/A	Moderate	107
36. Bertoli and de Leeuw, 2016	Cross-sectional	Met	N/A	Unmet	N/A	High	70
37. Braud and Boucher, 2016	Cross-sectional	Met	N/A	Met	N/A	Moderate	139
38. das Neves de Araújo Lima et al, 2016	Cross-sectional	Met	Unclear	Met	N/A	Moderate	138
39. Davies et al, 2016	Cross-sectional	Met	Unclear	Met	N/A	Moderate	164
40. Duraçoğlu et al, 2016	Cross-sectional	Met	Unmet	Met	N/A	High	67
41. Mousavi et al, 2016	Cross-sectional	Met	N/A	Met	N/A	Moderate	137
42. Patil et al, 2016	Cross-sectional	Met	Met	Met	N/A	Low	68
43. Sevrain et al, 2016	Retrospective study	Unmet	NA	Met	NA	High	92
44. Tang et al, 2016	Cross-sectional	Met	N/A	Met	N/A	Moderate	134
45. Visscher et al, 2016	Retrospective study	Unmet	N/A	Unmet	N/A	High	69
46. Al-Havaz et al, 2015	Cross-sectional	Unmet	N/A	Met	N/A	High	62
47. Brailo and Zakrzewska, 2015	Cross-sectional	Unclear	N/A	Met	N/A	Moderate	122
48. Kotiranta et al, 2015	Cross-sectional	Met	N/A	Met	N/A	Moderate	63
49. Lei et al, 2015	Cross-sectional	Met	N/A	Met	N/A	Moderate	64
50. Lopez-Jornet et al, 2015	Cross-sectional	Met	Met	Met	N/A	Low	91
51. Majumder et al, 2015	Cross-sectional	Unmet	N/A	Met	N/A	High	65
52. Marino et al, 2015	Case-control	Met	Met	Met	N/A	Low	136
53. Reiter et al, 2015	Retrospective observational	Met	N/A	Unmet	N/A	High	66
54. Tokura et al, 2015	Cross-sectional	Met	Met	Met	N/A	Low	135
55. Wu et al, 2015	Retrospective cohort	Unmet	Met	Met	N/A	High	106
56. Calixtre et al, 2014	Longitudinal study	Unmet	NA	Met	NA	High	54
57. Cioffi et al, 2014	Cross-sectional	Unmet	N/A	Met	N/A	High	121
58. Davis et al, 2014	Cross-sectional	Met	N/A	Met	N/A	Moderate	55
59. Gerrits et al, 2014	Longitudinal cohort	Unmet	N/A	Met	N/A	High	131
60. Komiyama et al, 2014	Cross-sectional	Met	N/A	Met	N/A	Moderate	56
61. Minghelli et al, 2014	Cross-sectional	Unmet	N/A	Met	N/A	High	57
62. Reissmann et al, 2014	Case-control	Met	Unclear	Met	N/A	Moderate	58
63. Smriti et al, 2014	Cross-sectional	Met	N/A	Met	N/A	Moderate	59
64. Sood et al, 2014	Cross-sectional	Met	N/A	Met	N/A	Moderate	60
65. Vasudeva et al, 2014	Case-control	Met	Met	Met	N/A	Low	61
66. Castelli et al, 2013	Case-control	Met	Met	Met	N/A	Low	51
67. Chen et al, 2013	Case-control	Met	Met	Met	N/A	Low	52
68. Ligthart et al, 2013	Longitudinal cohort	Met	N/A	Met	N/A	Low	129
69. Ozdemir-Karatas et al, 2013	Cross-sectional	Met	N/A	Met	N/A	Moderate	53
70. Sipilä et al, 2013	Longitudinal cohort	Met	Met	Met	N/A	Low	130
71. Smith et al, 2013	Cross-sectional	Met	N/A	Met	N/A	Moderate	105
72. de Lucena et al, 2012	Longitudinal prospective	Met	Unclear	Met	N/A	Moderate	45
73. de Souza et al, 2012	Cross-sectional	Met	Met	Met	N/A	Low	89
74. Diniz et al, 2012	Longitudinal cohort	Met	N/A	Met	N/A	Moderate	46
75. Guarda-Nardini et al, 2012	Cross-sectional	Met	N/A	Met	N/A	Moderate	47
76. Kindler et al, 2012	Prospective cohort	Met	N/A	Met	N/A	Moderate	48
77. Komiyama et al, 2012	Cross-sectional	Met	N/A	Met	N/A	Moderate	120
78. Rodrigues et al, 2012	Cross-sectional	Met	N/A	Met	N/A	Moderate	49
79. Schiavone et al, 2012	Cross-sectional	Met	Met	Met	N/A	Low	90
80. Schwahn et al, 2012	Cross-sectional	Met	N/A	Met	N/A	Moderate	50
81. Wan et al, 2012	Cross-sectional	Unclear	N/A	Met	N/A	Moderate	128
82. Celić et al, 2011	Cross-sectional	Unclear	N/A	Met	N/A	Moderate	40
83. Dworkin, 2011	Cross-sectional	Met	N/A	Met	N/A	Moderate	41
84. Gustin et al, 2011	Case-control	Met	Met	Met	N/A	Low	16
85. Mačianskytė et al, 2011	Cross-sectional	Met	N/A	Met	N/A	Moderate	118
86. Monteiro et al, 2011	Cross-sectional	Unmet	N/A	Met	N/A	High	42
87. Taiminen et al, 2011	Cross-sectional	Unclear	N/A	Met	N/A	Moderate	119
88. van Seventer et al, 2011	Secondary analysis of a randomized clinical trial	Met	Met	Met	Met	Low	104
89. Velly et al, 2011	Prospective cohort	Met	N/A	Met	N/A	Moderate	43
90. Xu et al, 2011	Cross-sectional	Met	N/A	Met	N/A	Moderate	44
91. Bakhtiari et al, 2010	Cross-sectional	Met	Met	Met	N/A	Low	103
92. Giannakopoulos et al, 2010	Case-control	Met	Unclear	Met	N/A	Moderate	35
93. Kim et al, 2010	Cross-sectional	Met	Unclear	Met	N/A	Moderate	116
94. Lajnert et al, 2010	Cross-sectional	Met	Met	Met	N/A	Low	36
95. Manfredini et al, 2010a	Cross-sectional	Met	N/A	Met	N/A	Moderate	37
96. Manfredini et al, 2010b	Cross-sectional	Met	N/A	Met	N/A	Moderate	38
97. McMillan et al, 2010	Cross-sectional	Met	Met	Met	N/A	Low	127
98. Pesqueira et al, 2010	Cross-sectional	Met	N/A	Met	N/A	Moderate	39
99. Takenoshita et al, 2010	Cross-sectional	Met	N/A	Met	N/A	Moderate	117
100. Bonjardim et al, 2009	Cross-sectional	Unmet	N/A	Met	N/A	High	31
101. Choi et al, 2009	Retrospective	Unclear	N/A	Unmet	N/A	High	115
102. Gao et al, 2009	Case-control	Met	Met	Met	N/A	Low	165
103. Licini et al, 2009	Cross-sectional	Met	N/A	Met	N/A	Moderate	32
104. Macfarlane et al, 2009	Prospective cohort	Unmet	N/A	Met	N/A	High	33
105. Stavrianos et al, 2009	Prospective cohort	Met	N/A	Met	N/A	Moderate	34
106. Streffer et al, 2009	Cross-sectional	Met	N/A	Met	N/A	Moderate	126
107. Baad-Hansen et al, 2008	Cross-sectional	Met	Met	Met	N/A	Low	113
108. Ballegaard et al, 2008	Cross-sectional	Met	N/A	Met	Met	Low	123
109. Buljan et al, 2008	Cross-sectional	Unmet	N/A	Unclear	N/A	High	88
110. Castro et al, 2008	Cross-sectional	Met	N/A	Met	N/A	Moderate	114
111. Lee et al, 2008	Cross-sectional	Met	N/A	Met	N/A	Moderate	29
112. Reissmann et al, 2008	Cross-sectional	Met	N/A	Met	N/A	Moderate	30
113. Bertoli et al, 2007	Retrospective	Unmet	N/A	Unmet	N/A	High	26
114. John et al, 2007	Cross-sectional	Met	N/A	Met	N/A	Moderate	27
115. List et al, 2007	Case-control	Met	Met	Met	N/A	Low	132
116. Mongini et al, 2007	Cross-sectional	Met	N/A	Met	N/A	Moderate	112
117. Nifosi et al, 2007	Cross-sectional	Met	N/A	Met	Met	Low	28
118. GaldÓn et al, 2006	Cross-sectional	Met	N/A	Met	N/A	Moderate	25

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COFP Assessment Criteria

Of the included studies, 97% followed an established diagnostic criteria/classification system for the COFP conditions. These included the RDC/TMD,²⁵^–³⁰^,³²^,³⁴^–⁴²^,⁴⁷^,⁴⁹^,⁵²^–⁵⁴^,⁵⁶^,⁵⁸^,⁶¹^–⁶⁴^,⁶⁶^,⁶⁸^,⁷⁰^,⁷³^,⁷⁵^,⁷⁶^,⁷⁸^,⁸⁰^,⁸¹^,⁸³^,⁸⁴^,⁸⁶^,⁸⁷^,¹¹⁴^,¹¹⁵^,¹²¹^,¹²³ the Helkimo Clinical Dysfunction Index for TMD,³¹^,³³^,⁵⁷^,⁵⁹^,⁶⁰^,⁶⁵^,⁷⁷^,⁷⁹ the International Headache Society (IHS) ICHD-3 criteria, ⁷⁸^,⁸⁹^,⁹¹^,⁹³^,⁹⁴^,⁹⁶^,⁹⁷^,⁹⁹^,¹⁰⁰^,¹⁰²^,¹⁰⁸^,¹⁰⁹^,¹¹²^,¹¹⁵^,¹²²^–¹²⁵^,¹²⁹^,¹³³ the AAOP criteria,⁴⁶^,⁴⁸^,⁵⁰^,⁵¹^,¹¹²^,¹¹⁴ the IASP criteria, ⁹⁰^,¹⁰⁷^,¹¹⁴^,¹¹⁵^,¹¹⁷^,¹²⁰ the Craniomandibular Index (CMI), ⁴³^,¹¹⁶ and the European Academy of Craniomandibular Disorders (EACD) criteria.⁴⁵ The Liverpool criteria for trigeminal nerve pain were used in one study,¹⁶ while another used the Ma and Zhang classification for TMD pain.⁴⁴

Psychologic Screening Tools Used

The State-Trait Anxiety Inventory (STAI) was used by 14 studies,¹⁶^,³⁹^,⁴²^,⁵¹^,⁵²^,⁵⁵^,⁵⁸^,⁷⁶^,⁸⁵^,⁸⁹^,⁹⁰^,⁹⁵^,⁹⁸^,¹⁶⁴ the Zung Self-Rating Depression Scale (ZSDS) used by 6 studies,⁸⁸^,¹⁰⁰^,¹¹⁷^,¹²⁴^,¹³³^,¹⁶⁵ and the Zung Self-Rating Anxiety Scale (ZSAS) used by 3 studies.⁵⁹^,¹⁰⁰^,¹⁶⁵ A total of 69 studies used a single psychologic tool, while 49 used a combination of psychologic assessment tools. The RDC/TMD Axis II questionnaire ²⁵^–²⁷^,²⁹^,³²^,³⁶^–⁴¹^,⁴⁷^,⁴⁹^,⁵³^,⁵⁶^,⁵⁸^,⁶²^,⁶³^,⁶⁶^,⁷⁰^,⁷²^,⁸³^,¹²¹^,¹²³^,¹³² was used exclusively for TMD pain, the Symptom Checklist-90-Revised (SCL-90-R) ²⁶^,²⁸^,³⁷^,³⁸^,⁴⁰^,⁴¹^,⁴⁴^,⁴⁷^,⁵²^,⁵³^,⁶³^,⁶⁶^,⁶⁹^,⁷⁰^,⁹⁴^,⁹⁷^,¹¹³^,¹¹⁶^,¹²⁰^,¹²¹^,¹²⁷ was used to assess psychologic symptoms/distress, and the Hospital Anxiety and Depression Scale (HADS) ³¹^,³⁵^,⁴⁵^,⁵⁴^,⁵⁷^,⁶⁰^,⁶¹^,⁶⁵^,⁶⁷^,⁷¹^,⁷³^–⁷⁵^,⁷⁸^,⁷⁹^,⁹¹^,⁹²^,¹⁰⁴^,¹⁰⁵^,¹⁰⁷^,¹¹¹^,¹¹⁴^,¹¹⁵^,¹²²^,¹²⁶ was most commonly used to screen for anxiety and/or depression. Five studies used the Structured Clinical Interview for Diagnosis-Diagnostic and Statistical Manual of Mental Disorders (SCID-DSM-4/5) guide. ²⁸^,¹¹²^,¹¹⁹^,¹³¹^,¹³³

Prevalence of Anxiety and Depression in Patients with COFP

The prevalence of depression and/or anxiety in COFP, according to COFP group and assessment instrument, are summarized in Figs 2 and 3. With respect to standardized questionnaire assessments, rates were included only for those patients evidencing moderate or severe symptoms (where questionnaires included an umbrella classification of mild to moderate, patients scoring in this range were also considered), or, in the case of HADS, those showing borderline clinical or clinically significant levels. Where studies included assessments at two time points, only the first was included.

Fig 2 — **(a)** Depression and **(b)** anxiety across TMD studies. Studies are ordered according to TMD condition, depression/anxiety measure, and percentage of depression/anxiety reported. DD = disc displacement; HA = headache. See other abbreviations in Table 1 legend.

Fig 3 — Rates of **(a)** depression and **(b)** anxiety across neuropathic, mixed, and idiopathic/atypical orofacial pain (OFP) condition studies. Studies are ordered according to OFP condition, depression/anxiety measure, and percentage of depression/anxiety reported. CH = chronic; FP = facial pain. See other abbreviations in Table 1 legend.

For TMDs, the prevalence of observed depression ranged from 7.0% to 77.4% (Fig 2a). In general, studies using the RDC/TMD or SCL-90-R assessments reported the most consistent prevalence rates, with 14 of 20 (70%) studies observing depression in 41.4% to 56.0% of participants. Studies adopting other standardized questionnaires (eg, HADS/Beck Depression Inventory [BDI]) reported lower rates of depression, although this varied considerably across studies, while diagnostic assessments of depression were consistently around 20% (15.7% to 22.3%). Rates of clinically significant anxiety in TMD also varied widely across studies (7.4% to 78.0%; Fig 2b), although the observed prevalence in studies using the RDC/TMD and SCL-90-R or the HADS assessments were more comparable, with 11 of 14 studies adopting one of the measures and yielding anxiety case rates between 43.9% and 63.0% with either measure. The single study that estimated the prevalence of anxiety using the CID-S⁴⁸ reported high rates of anxiety in both TMD MP (78.0%) and TMD JP (64.8%). In contrast, the GAD-7 questionnaire assessments of TMD anxiety⁸⁰^,⁸⁴^,⁸⁷ resulted in lower prevalence rates, ranging from 11.4% to 20.0%. Notably, irrespective of assessment method, studies with a low prevalence of depression and/or anxiety tended to recruit nonclinical samples³¹^,⁴⁶^,⁶²^,⁷⁹ or TMD samples with low pain disability levels,⁴⁴ while higher rates were observed in clinical studies of patients with TMD and headache.⁷³^,¹²³

The prevalence of depression and anxiety for neuropathic, mixed, and idiopathic/atypical COFP conditions ranged from 2.2% to 100% and from 0% to 80.7%, respectively (Fig 3). Rates of depression and anxiety varied widely in TN samples, with low prevalence rates reported in studies using diagnostic assessments¹⁰⁶^,¹¹² and higher rates in TN with associated comorbidities, such as chronic facial pain¹¹⁸ and MS.¹¹¹ Prevalence rates of depression and anxiety in BMS were more consistent. Aside from one small clinical study of 8 patients with treatment-resistant BMS that observed depression in all patients,⁹³ questionnaire-based assessments yielded moderate to severe symptoms for a quarter to a half of BMS patients across studies. Clinically significant levels of anxiety in BMS were highest in studies using the Hamilton Anxiety Rating Scale (HARS) and HADS (39.3% to 80.7%)⁹²^,⁹³^,¹³⁶^,¹³⁹ assessments and lowest in those employing the Beck Anxiety Inventory (BAI; 21.0% to 33.3%).⁹⁶^,¹³⁸ Three of the four BMS studies with diagnostic assessments reported anxiety disorders in a third to a half of participating patients.⁸⁹^,¹¹⁷^,¹¹⁹ In one study of PTNP pain, clinically significant anxiety was found in 51.2% of individuals and depression in 30.0% of cases.¹⁰⁵ Depression in AO was reported at 74.0% in one study using the SCL-90-R,¹³² but at only 15.4% in a diagnostic assessment study.¹³³ Similarly, rates of diagnosed anxiety disorders in PDAP samples were uncommon in two studies (10.1% to 10.8%).¹¹⁷^,¹³³

Prevalence of Anxiety and Depression in COFP Conditions vs Control Participants

A number of studies comparing prevalence rates in TMD and control participants reported significantly higher rates of anxiety,³¹^,⁴⁵^,⁵⁸^,⁵⁹^,⁶¹^,⁷¹^,⁷³^,⁷⁹^,⁸² depression,³⁶^,⁵⁸^,⁶⁸^,⁷¹^,⁷³ or anxiety and/or depression⁵⁷^,⁶⁵ in individuals with TMD. One TMD study of dental students failed to find significant differences in state and trait anxiety between those with and without TMD,⁷⁶ while another three studies of pre-university/university students reported significantly higher anxiety prevalence rates in TMD cases vs controls, but nonsignificant elevations in depression.³¹^,⁴⁵^,⁷⁹ Significantly higher rates of depression were also observed in studies comparing mixed COFP patients to individuals without OFP.³³^,¹²⁷^,¹³⁰

Although studies comparing mean scores of standardized questionnaires assessing anxiety and depression in neuropathic COFP conditions, such as TN or BMS, against control participants have reported elevated scores in the former (indicative of greater levels of symptoms of anxiety/depression),⁹¹^,¹⁰²^,¹¹⁰ fewer controlled studies have compared prevalence rates of clinically relevant anxiety or depression. However, two controlled studies observed significantly elevated rates of both anxiety and depressive disorders in patients with TN¹⁰⁶ and BMS,⁸⁹ while another study comparing BMS and secondary oral burning patients reported elevated rates of moderate to severe depression according to the BDI in BMS, but comparable rates of anxiety according to the BAI.¹³⁸ Finally, one study comparing PDAP and control participants found significantly more of the PDAP patients showed moderate to severe depression levels.¹³²

Single-Study Comparisons of Different COFP Conditions

Thirteen studies compared two or more types of COFP conditions.¹⁶^,¹¹²^–¹¹⁵^,¹¹⁷^–¹²²^,¹²⁴^,¹²⁵ In one study, neuropathic pain (TN and trigeminal neuropathy) and TMD pain patients were significantly (but comparably) impaired in domains of anxiety (state and trait anxiety) and depression when compared to controls.¹⁶ Another study reported that TN patients showed numerically higher scores on measures of psychologic impairment than TMD patients, although there were no statistically significant differences between the two groups.¹¹⁴ When TN and PIFP were investigated, it was observed that TN patients evidenced significantly higher levels of pain perception than PIFP patients and were significantly more likely to exhibit moderate to severe depression levels (76% vs 0%).¹¹⁸ Another study reported that BMS and PIFP demonstrated comparable levels of depressive symptoms.¹¹⁹ Komiyama et al compared patients with BMS and TN and reported that pain levels were higher in TN than BMS. However, regression analyses indicated the associated risk of depression in BMS patients was significantly higher than in TN patients.¹²⁰ Takenoshita et al investigated mood in COFP patients (BMS and PDAP) using the Zung Self-Rating Depression Scale and observed depressive tendencies in 32.1% of BMS patients and 33.3% of individuals with PDAP.¹¹⁷ The large-scale study of Gerrits et al on chronic pain suggested the onset of anxiety and/or depression with pain and observed that pain specifically in the orofacial region was associated with depressive symptoms.¹³¹ A study on BMS and PIFP using SCID guides reported high rates of psychiatric disorders, most commonly major depression (30.2%), social phobia (15.9%), specific phobia (11.1%), and panic disorder (7.9%); in these cases, illness runs a chronic course and is difficult to treat.¹¹⁹ Another study on TMD pain using the same interview technique exhibited frequent presence of psychiatric history in myofascial pain patients.²⁸ Melek et al compared TN to peripheral painful traumatic trigeminal neuropathy (PPTTN), and depression was reported in 54% of TN and 36% of PPTTN, while anxiety was comparable in both groups (34% and 39%, respectively).¹²⁵

Association Between Orofacial Pain Severity and Chronicity with Anxiety and Depression

The majority of selected studies (with both neuropathic and nonneuropathic pain samples) demonstrated that an increase in pain intensity and/or pain chronicity (more than 3-month duration)³ elevated patients’ anxiety and depressive symptom levels.

Neuropathic Orofacial Pain

For patients with neuropathic pain, consistent associations of anxiety and depression with pain intensity were identified. For example, patients with severe trigeminal nerve injury pain showed elevated levels of depression on the HADS compared to patients with moderate and mild pain levels in one study.¹⁰⁵ In another study, change in posttraumatic peripheral neuropathic pain levels was significantly associated with change in anxiety and depression levels¹⁰⁴; every 2-point decrease in level of pain on a 0–10 numeric rating scale was associated with a 1.5-point reduction in anxiety and a 1.2-point reduction in depression on the HADS.¹⁰⁴ BMS patients also demonstrated a positive association between levels of depression and BMS symptom severity.⁸⁸ Additionally, one study found an association between presence of anxiety symptoms and pain severity among elderly individuals with neuropathic pain (BMS).¹⁰³

TMD Pain

For TMD pain, cases were divided into acute and chronic by some investigators for comparison. Depression was more prevalent in patients with chronic TMD pain,³⁶^,⁴⁰^,⁴³^,⁶⁶^,⁶⁹ and severity of depression and anxiety increased with higher graded chronic pain scores.⁴⁴^,⁴⁷^,⁴⁹^,⁶³^,⁶⁶^,⁶⁸^,¹¹⁶ Su et al compared TMD patients with high- and low-intensity pain and reported marked differences in prevalence of both moderate to severe anxiety (27.9% vs 11.4%) and moderate to severe depression (33.5% vs 10.2%).⁸⁴ Multiple pain sites were also associated with higher levels of depression in another study.⁴⁰ A number of investigators also reported significant associations between anxiety levels and chronic TMD pain,³¹^,³⁹^,⁴²^,⁵⁸^,⁶¹^,⁷⁰ most predominantly for the myofascial subtype of TMD.²⁵^,⁴⁵^,⁴⁸^,⁶⁴ Patients with TMD pain, especially muscle pain, presented with more psychologic problems compared to patients with TMD joint pain in one study.²⁸ Moderate-to-severe anxiety and depression in chronic TMD were reported as high as 58.3% and 61.2%, respectively, in another study.⁶⁶

Some studies with TMD patients reported significant associations between the level of physical/psychologic disability and pain intensity using a hierarchical pain grading approach (Graded Chronic Pain Scale [GCPS]), which classifies pain/disability into four broad categories: grade I (low pain intensity/low disability); grade II (high intensity/low disability); grade III (moderately limiting pain/high disability); and grade IV (severely limiting pain/high disability).¹⁴⁰ For example, in one study, psychologic impact tended to be greater in patients with grade III or IV pain, and anxiety was identified in 53.8% of these individuals and depression in 76.9% of these individuals⁴⁴; in another study, severe depression was prevalent in 40.7% of patients with grade III or IV pain.³⁸

Orofacial Pain, Gender/Age, and Anxiety and Depression

Most, but not all, studies considering gender suggested women with OFP may report higher levels of anxiety or depressive symptoms than men. For example, in one study, younger (under the age of 24 years) and middle aged (between 35 and 55 years) women with OFP scored higher on a depression scale compared to men of similar ages.⁵⁶ Licini et al³² reported that moderate to severe depression was evident in 56.1% of women with TMD pain compared to only 10% of men. Women with chronic TMD myofascial pain also scored marginally higher on a depression scale than men in another study,³⁵ although men with other chronic facial painful conditions (postsurgical pain, posttraumatic, or neuropathic pain) and not specifically TMD pain were more depressed compared to women.³⁵ In contrast, Giannakopoulos et al did not find any differences in anxiety between men and women with TMD, suggesting poorer psychologic well-being in women is not uniformly observed in studies of OFP.³⁵

Impact of Comorbid Conditions on Anxiety and Depression in Individuals with Orofacial Pain

Both neuropathic and nonneuropathic (ie, TMD) OFP can coexist with other medical conditions, such as degenerative disease, migraine, and widespread pain, and the reviewed studies suggest that their presence can increase the likelihood of significant psychologic disability in affected individuals.³⁰^,⁷¹^,⁷⁸^,¹¹¹^,¹¹³^,¹¹⁹^,¹²¹^,¹²³^,¹²⁷^,¹²⁹ For example, a study of acute TMD subtypes showed that individuals with muscle and joint pain, along with a history of degenerative joint disorder, have significantly higher levels of depression compared to those with a single condition.³⁰ The study by Cioffi et al on TMD pain and migraine found that individuals with a combination of chronic TMD myofascial pain and migraine were experiencing significantly higher levels of depression compared to isolated TMD groups.¹²¹ Ballegaard et al studied depressive symptoms in patients with headache and compared them to patients having headache and comorbid TMD, reporting that 34.1% of headache patients had depressive symptoms compared to more than 70% (70.9%) of those with headache and comorbid TMD pain.¹²³

A similar pattern of results emerged from studies on neuropathic OFP. For instance, Lopez-Jornet et al observed a positive association among BMS, poor sleep quality, and comorbid anxiety/depression (as measured using HADS). Regression analyses indicated that for every 1-point increase in HADS depression score, the odds of sleep quality deterioration increased by 1.26 times.⁹¹ McMillan et al found that while patients with OFP were 3.5 times more likely to exhibit moderate to severe depression than control participants, psychologic distress was observed most often in individuals with OFP who had widespread pain symptoms; these patients constituted 13.5% of their OFP sample.¹²⁷

Discussion

The purpose of this study was to review research describing anxiety and depression in patients with neuropathic and/or nonneuropathic OFP. The results showed that experience of OFP is associated with both anxiety and depression that can be disabling in nature and markedly influences individuals’ emotional well-being. This review of 118 studies identified positive associations between pain intensity, chronicity, and symptom severity and the presence of anxiety and/or depression. The prevalence of clinically significant or moderate to severe anxiety in neuropathic, mixed, and idiopathic/atypical orofacial pain conditions ranged from 0% to 80.7% of cases, while the prevalence of clinically significant or moderate to severe depression ranged from 2.2% to 100% of cases. In nonneuropathic (ie, TMD) pain conditions, the observed ranges were also wide; anxiety ranged from 7.4% to 78.0% of cases, and depression from 7.0% to 77.4% of cases. The large variance in the observed rates across studies likely reflects the differential methods of assessment and/or nature of the recruited samples in the included studies. For TMD conditions, the majority of RDC/TMD or SCL-90-R assessments yielded depression rates of around 40% to 60%, and most RDC/TMD, SCL-90-R, or HADS assessments resulted in an anxiety prevalence of 40% to 65%; diagnostic assessments of depression and anxiety suggested disorder rates of 15% to 20% and 15% to 35%, respectively. Irrespective of assessment method, the lowest observed prevalence rates were in TMD studies employing student samples rather than clinical populations. The majority of questionnaire-based assessment in patients with TN yielded rates of depression and anxiety of around 20% to 35% and 40% to 55%, respectively, with lower rates in studies reporting diagnostic assessments, while questionnaire-based assessments of depression and anxiety in BMS studies showed moderate-severe symptoms in a quarter to a half of patients, with similar rates reported in most diagnostic studies of BMS patients.

The association between pain and depression is complicated due to their common neurobiology, complex environmental influences, and negative cognitions.¹⁴¹ Neurotransmitters such as serotonin, norepinephrine, glutamate, and gamma-Aminobutyric acid (GABA) are intimately linked with pain processing as well as mood.¹⁴¹ For instance, serotonin and norepinephrine reduction are associated with an impeded gate control mechanism and mood disorder progression.¹⁴² The present review identified a close association between COFP and psychologic comorbidities. This is in line with available literature, where psychologic factors are now recognized as important comorbid features in the presentation of OFP.¹⁴³^,¹⁴⁴ All types of pain are influenced by psychologic components; however, negative affect appears particularly important in the emergence and maintenance of chronic pain syndromes.¹⁴⁵^,¹⁴⁶ COFP has a profound influence on the psychologic health of individuals; this includes anxiety, stress, phobias, depressive symptoms, catastrophizing, and emotional disturbances,¹² as well as oral health–related quality of life.⁹ Increased pain intensity also negatively impacts quality of life.¹⁰ The American Psychiatric Association (APA) has recognized that mental illnesses such as anxiety disorders, somatoform disorders, and mood disorders are closely related to medical conditions, including hypersensitive pain perception.¹⁴⁵ TMD myofascial pain patients are more likely to have higher levels of psychologic symptoms.¹⁴⁷ This concurs with the findings of a recent systematic review reporting the frequent cooccurrence of psychiatric disorders and masticatory muscle pain.¹⁴⁸

Pain perception and experience differ considerably across individuals and vary according to gender. The overrepresentation of women in OFP pain samples, especially in studies of TMD pain, was illustrated in this review. Furthermore, gender differences in the few studies directly addressing the role of gender in psychologic correlates of OFP suggested that both anxiety and depression are more often observed in women with TMD pain than in men with TMD pain. There are reports that estrogen may have a role in the pain-regulatory mechanisms of TMD pain subgroups.¹⁴⁹ However, this needs further investigation. The impact of gender on comorbid anxiety and/or depression in individuals with neuropathic OFP is less clear and needs to be addressed in future studies.

The present review also suggests that individuals presenting with multiple pain conditions are more likely to have pronounced psychologic problems.¹²¹^,¹²³^,¹³¹ More specifically, across reviewed studies, individuals with multiple OFP conditions were more likely to have severe negative psychologic impairment, most obviously high levels of depression, compared to those with single conditions. Similar findings have been reported in the OFP literature¹⁵⁰ and are broadly consistent with studies of body pain, where patients with widespread chronic pain (eg, fibromyalgia) often present with marked negative affective and cognitive states.¹⁵¹

There was a substantial degree of variability in the designs and associated RoBs of studies included in this review, which contributed to the difficulty in arriving at a consensus. Eleven studies used a longitudinal prospective design, 10 were designed as case-control, and 8 were retrospective. The absence of (pain-free) control groups was a frequent shortcoming of studies included in this review. Nevertheless, the overwhelming majority of studies (46) where a control sample was employed evidenced higher rates of anxiety and/or depression in OFP patients (neuropathic, mixed OFP, and TMD) compared to pain-free controls.¹⁶^,¹³² The only exception to this was a small number of TMD studies which recruited student (nonpatient) populations in which the individuals diagnosed with TMD were not currently receiving or seeking treatment.³¹^,⁴⁵^,⁷⁶^,⁷⁹

Most studies, particularly those with neuropathic OFP samples, were conducted at tertiary care units through opportunity sampling. Of course, patient recruitment from a tertiary care unit may not be representative of the general population, reducing the generalizability and external validity of the included studies. More specifically, this may have resulted in overpresentation of anxiety and/or depression in individuals with OFP. Most studies (n = 86) were cross-sectional, where the data were collected at a single point in time, rendering it difficult to differentiate between cause and effect through simple association.¹⁵² As such, from this review, a clear association on the etiologic pathway could not be established; specifically, whether pain resulted in psychologic morbidity or vice versa. However, both pain and psychologic morbidity are related to a common etiologic factor (for example, early psychologic or physical trauma could predispose individuals to both pain and psychologic distress in the future), and it is important to consider that a number of studies have suggested that a range of premorbid psychologic variables can predict the development of OFP, particularly TMD.¹⁵³^,¹⁵⁴ However, the available evidence suggests a bidirectional relationship between anxiety and/or depression and pain,¹⁵⁵ supported in part by functional neuroimaging studies suggesting shared underlying neuro mechanisms.¹⁵⁶

Significant variation in the use of psychologic tools for data collection was found. Various self-report questionnaires were utilized, and the majority of studies did not make a distinction between acute and chronic pain, although most of the patients included in studies had OFP for more than 3 months. This may have affected the validity of the data due to variation in personal characteristics, level of patients’ education, their ethnicity, culture, and social beliefs.¹⁵⁷ The majority of studies in the current review employed only a single psychologic scale, and most adopted the questionnaire-specific cut-off points for cases of anxiety or depression, which remain difficult to interpret across measures. For example, comparisons between the State-Trait Anxiety Inventory (STAI)-State¹⁵⁸ can be made with HADS, but a compelling comparison dataset is as yet not available,³⁵ and STAI-Trait also includes a number of depression items related to depressive symptomatology.¹⁵⁹ Few studies have used the SCID-DSM-IV,²⁸^,¹¹²^,¹¹⁹^,¹³¹ which is a formal diagnostic tool, as opposed to questionnaires such as HADS, which better serve as screening instruments (ie, do not allow for definite diagnoses) and provide dimensional rather than categorical representations of mood.¹⁶⁰ More research is needed through employment of a standardized set of questionnaires and screening tools that also address wider psychologic and social aspects of psychologic function in patients with OFP.

Notable differences emerged in the diagnostic procedures of COFP conditions across studies, inasmuch as there were several classification systems used that do not entirely concur with one another; therefore, results across different studies with OFP samples are not completely comparable. Literature on OFP classifications has discussed this issue in detail,¹⁴³^,¹⁶¹ emphasizing the need for a standardized biopsychosocial classification of OFP, which is highlighted again in the present review.

Limited datasets were considered for this review, and only English-language articles were searched, reducing the scope of reviewed studies. Nevertheless, the review demonstrated substantive evidence for associations of anxiety and depression with both neuropathic and nonneuropathic OFP conditions. Both within and across studies, no meaningful differences in anxiety or depression levels between patients with neuropathic conditions and those with nonneuropathic (ie, TMD) pain were found,¹⁶^,¹²¹ consistent with broader evidence that the psychologic impact of chronic pain is universal irrespective of neuropathic or nociceptive characteristics of experienced symptoms.¹⁶² Differences in the study designs and psychologic assessment tools employed may have limited the ability to detect differential rates of psychologic comorbidities according to presenting OFP symptoms. Due to the heterogeneity of the studies, meta-analyses were not possible, although this does reduce the strength of the findings. Nevertheless, the present results are consistent with the hypothesis that OFP conditions have an impact on the psychologic well-being of individuals and are meaningful in the context of formulating treatment strategies.

Conclusions

OFP has a significant impact on patients’ psychologic well-being. This critical review, within its limitations, highlighted an association between OFP and psychologic comorbidity. Due to the heterogeneity across studies, it was not possible to conduct meta-analyses in order to substantiate this evidence in a robust manner. Most work to date involves patients with TMD pain (nonneuropathic), and much less concerns other types of pain, such as neurovascular, neuropathic, and idiopathic OFP. OFP requires a biopsychosocial approach for holistic management.¹⁶³ Future research should focus on comparing psychologic morbidity in different types of COFP with a view to develop more tailored treatment strategies for individuals according to presenting symptomatology. There is also a need for studies exploring precondition psychologic morbidity, which may have a significant role in predisposing individuals to developing chronic pain.⁴^,¹⁴²

Clinical Implications

COFP causes distress and disability, affects life negatively, and often leads to anxiety and/or depression and extensive use of the health care system. Holistic management for OFP requires a biopsychosocial approach.

Acknowledgments

No funding body supported this work.

The authors declare no conflicts of interest.

Author contributions: A.K., J.G.S., L.M., and T.R. designed the review. A.K. extracted the articles, and J.G.S., L.M., and T.R. confirmed the relevance. A.K. and J.G.S. contributed to the write-up of the manuscript. L.M. and T.R. checked the draft. All authors commented on the manuscript draft and approved the final draft.

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PERMALINK

Psychologic Impact of Chronic Orofacial Pain: A Critical Review

Aalia Karamat, BDS, MSc, MPhil

Jared G Smith, PhD

Lydia Nabil Fouad Melek, BDS, MSc, PhD

Tara Renton, BDS, MDSc, PhD

Abstract

Aims:

Methods:

Results:

Conclusion:

Materials and Methods

Search Strategy and Selection Criteria

Definitions

Search Terms

Outcome Measures

Data Extraction

Fig 1.

Risk of Bias Assessment

Results

Table 1.

Participant Characteristics

Diagnosis

Gender

Study Design

Study Characteristics

Table 2.

COFP Assessment Criteria

Psychologic Screening Tools Used

Prevalence of Anxiety and Depression in Patients with COFP

Fig 2.

Fig 3.

Prevalence of Anxiety and Depression in COFP Conditions vs Control Participants

Single-Study Comparisons of Different COFP Conditions

Association Between Orofacial Pain Severity and Chronicity with Anxiety and Depression

Neuropathic Orofacial Pain

TMD Pain

Orofacial Pain, Gender/Age, and Anxiety and Depression

Impact of Comorbid Conditions on Anxiety and Depression in Individuals with Orofacial Pain

Discussion

Conclusions

Clinical Implications

Acknowledgments

References

ACTIONS

PERMALINK

RESOURCES

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