Endogenous pain modulation in chronic orofacial pain: a systematic review and meta-analysis

Abstract

Abnormal endogenous pain modulation was suggested as a potential mechanism for chronic pain, ie, increased pain facilitation and/or impaired pain inhibition underlying symptoms manifestation. Endogenous pain modulation function can be tested using psychophysical methods such as temporal summation of pain (TSP) and conditioned pain modulation (CPM), which assess pain facilitation and inhibition, respectively. Several studies have investigated endogenous pain modulation function in patients with nonparoxysmal orofacial pain (OFP) and reported mixed results. This study aimed to provide, through a qualitative and quantitative synthesis of the available literature, overall estimates for TSP/CPM responses in patients with OFP relative to controls. MEDLINE, Embase, and the Cochrane databases were searched, and references were screened independently by 2 raters. Twenty-six studies were included for qualitative review, and 22 studies were included for meta-analysis. Traditional meta-analysis and robust variance estimation were used to synthesize overall estimates for standardized mean difference. The overall standardized estimate for TSP was 0.30 (95% confidence interval: 0.11-0.49; P = 0.002), with moderate between-study heterogeneity (Q [df = 17] = 41.8, P = 0.001; I = 70.2%). Conditioned pain modulation's estimated overall effect size was large but above the significance threshold (estimate = 1.36; 95% confidence interval: -0.09 to 2.81; P = 0.066), with very large heterogeneity (Q [df = 8] = 108.3, P < 0.001; I = 98.0%). Sensitivity analyses did not affect the overall estimate for TSP; for CPM, the overall estimate became significant if specific random-effect models were used or if the most influential study was removed. Publication bias was not present for TSP studies, whereas it substantially influenced CPM's overall estimate. These results suggest increased pain facilitation and trend for pain inhibition impairment in patients with nonparoxysmal OFP.

Endogenous pain modulation in chronic temporomandibular disorders: Derivation of pain modulation profiles and assessment of its relationship with clinical characteristics

“…Inability to induce pain inhibition using a CPM testing paradigm in both fibromyalgia cases and healthy controls has been reported recently, leading the authors of that study to speculate about the possibility of positive publication bias influencing the currently accepted significance of CPM for chronic pain conditions . This reasoning is supported at least in part by the publication bias identified for CPM studies of TMD cases reported in a meta‐analysis recently done by our group …”

“…The present study specifically controlled for gender, age and avoidance of acute pain medications intake 24 hours prior to testing, while data on time of the day testing occurred, caffeine and other pain medications intake and menstrual cycle phase were recorded, with no significant differences between TMD cases and control groups. Given these factors, it is possible that EPM assessment using TSP and CPM testing protocols as done in the present and previous studies may not be sensitive enough to distinguish chronic TMD patients from pain‐free controls. Reliability of EPM testing has been challenged recently, and there is a need for further studies to refine EPM testing methodology in order to improve its reliability.…”

“…Power analysis suggested that our sample size was overpowered to detect between‐group face PPT differences based on published results; however, the effect size found (g = −0.21) was much smaller than the one used for power calculations (g = 2.08). Similar to TSP, conflicting results are reported in the literature for CPM responses differences between TMD cases and controls with substantial heterogeneity across studies . CPM response seems to be greatly dependent on the experimental protocol used to the point of influencing its reliability .…”

“…Reliability of EPM testing has been challenged recently, and there is a need for further studies to refine EPM testing methodology in order to improve its reliability. Another possibility is that EPM plays a smaller role in chronic pain pathophysiology than previously suggested, as recent meta‐analyses suggested that patients suffering from different chronic pain conditions such as fibromyalgia and TMD presented small to medium effect sizes when comparing TSP and CPM responses between patients and pain‐free controls …”

“…Studies using pinprick stimuli to induce TSP found varied results when comparing TMD cases to pain‐free controls: one reported similar results of non‐facilitated TSP when tested over the face and facilitated TSP over the hand, another study found increased TSP responses on both face (trigeminal) and leg (non‐trigeminal) test sites while a third study showed non‐increased TSP over the face, trapezius and hand (both non‐trigeminal) test sites . Despite these conflicting results, a meta‐analysis showed increased TSP in TMD cases relative to pain‐free controls when assessed using varied test stimuli and body sites . In addition, the OPPERA case‐control study reported that in their large sample (185 chronic TMD patients, 1633 pain‐free controls) increased pain facilitation in TMD patients relative to controls was present over the fingers when induced with pinprick but no increased TSP was present over the forearm using noxious heat .…”