How May Placebo Mechanisms Influence Orofacial Neuropathic Pain?

The conceptualization of placebo has changed from inactive pills to a detailed understanding of how patients' perception of receiving a treatment influences pain processing and overall treatment outcome. Large placebo effects were recently demonstrated in chronic neuropathic pain, thereby opening the question of whether placebo effects also apply to orofacial neuropathic pain. In this article, we review the new definitions, magnitude, and social, psychological, neurobiologic, and genetic mechanisms of placebo effects in pain, especially neuropathic pain, to illustrate that placebo effects are not simply response bias but psychoneurobiological phenomena that can be measured at many levels of the neuroaxis. We use this knowledge to carefully illustrate how patients' perceptions of the treatment, the relationship with the health care provider, and the expectations and emotions toward a treatment can influence test and treatment outcome and potentially skew the results if they are not taken into consideration. Orofacial neuropathic pain is a new research area, and we review the status on definition, diagnosis, mechanisms, and pharmacologic treatment of neuropathic pain after trigeminal nerve injury, as this condition may be especially influenced by placebo factors. Finally, we have a detailed discussion of how knowledge of placebo mechanisms may help improve the understanding, diagnosis, and treatment of orofacial neuropathic pain, and we illustrate pitfalls and opportunities of applying this knowledge to the test of dental treatments.

Combination Drug Therapy of Pioglitazone and D-cycloserine Attenuates Chronic Orofacial Neuropathic Pain and Anxiety by Improving Mitochondrial Function Following Trigeminal Nerve Injury.

OBJECTIVES: The study aim was to determine how peripheral trigeminal nerve injury affects mitochondrial respiration and to test efficacy of combined treatment with 2 Federal Drug Administration approved drugs with potential for improving mitochondrial bioenergetics, pain and anxiety-related behaviors in a chronic orofacial neuropathic pain mouse model. METHODS: Efficacy of (R)-(+)-4-amino-3-isoxazolidinone (D-cycloserine, DCS), an N-Methyl-D-aspartate antagonist/agonist, and Pioglitazone (PIO), a selective agonist of nuclear receptor peroxisome proliferator-activated receptor gamma was investigate in the trigeminal inflammatory compression (TIC) neuropathic nerve injury mouse model. Combined low doses of these drugs (80 mg/kg DCS and 100 mg/kg PIO) were given as a single bolus or daily for 7 days post-TIC to test ability to attenuate neuropathic nociceptive and associated cognitive dependent anxiety behaviors. In addition, beneficial effects of the DCS/PIO drug combination were explored ex vivo in isolated cortex/brainstem mitochondria at 28 weeks post-TIC. RESULTS: The DCS/PIO combination not only attenuated orofacial neuropathic pain and anxiety-related behaviors associated with trigeminal nerve injury, but it also improved mitochondrial bioenergetics. DISCUSSION: The DCS/PIO combination uncoupled mitochondrial respiration in the TIC model to improve cortical mitochondrial dysfunction, as well as reduced nociceptive and anxiety behaviors present in mice with centralized chronic neuropathic nerve injury. Combining these drugs could be a beneficial treatment for patients with depression, anxiety, or other psychological conditions due to their chronic pain status.

The psychosocial and affective burden of posttraumatic neuropathy following injuries to the trigeminal nerve.

AIMS: To explore the impact of trigeminal nerve injuries on quality of life, including the effect of pain on psychological and affective function. METHODS: An observational, cross-sectional survey design was employed. Fifty-six patients with inferior alveolar nerve injury (IANI) and 33 patients with lingual nerve injury (LNI) completed standardized self-report measures of pain intensity, pain catastrophizing, self-efficacy to cope with pain, and mood, in addition to generic and oral health-related quality of life (HRQoL) indicators. The impact of pain severity on these aspects of psychosocial function was examined. Summary statistics were calculated for all measures and compared with norms or values of other relevant studies, when available, using t tests. The impact of pain severity on these aspects of psychosocial function was examined using analysis of variance and hierarchical multivariate regression models. RESULTS: The majority of patients reported pain associated with their nerve injury (86%). Nerve injury had a significant impact on all investigated domains, and this was closely linked with reported pain levels. Patients with severe pain showed particularly elevated levels of depression and pain catastrophizing, as well as substantially reduced HRQoL and coping efficacy levels. Pain intensity level was a significant predictor in all models except anxiety, uniquely contributing between 17% and 26% of variance to the prediction of pain catastrophizing, depression, coping efficacy, and generic and oral HRQoL. CONCLUSION: Traumatic injury to the trigeminal nerve is associated with a substantial patient burden, particularly in patients who experience severe neuropathic pain as part of their condition. These findings highlight the need to identify, develop, and evaluate more effective treatments for neuropathic pain in trigeminal nerve injury that will not only provide clinically meaningful reductions in pain but also improve patients' quality of life.

Trigeminal neurosensory deficit and patient reported outcome measures: the effect on life satisfaction and depression symptoms.

OBJECTIVES: To investigate the effect of persistent neurosensory disturbance of the lingual nerve (LN) or inferior alveolar nerve (IAN) on life satisfaction and depression symptoms. METHODS: This study recruited patients with persistent LN or IAN deficit as a consequence of lower third molar surgery for 12 months or more to form the study group. A control group was formed by matching age and gender of recruited subjects in the study group with patients without the neurosensory complications. Life satisfaction was assessed with Satisfaction With Life Scale (SWLS) and depression symptoms were assessed with 20-item Center for Epidemiological Studies Depression scale (CESD-20). RESULTS: Fourty-eight participants (24 cases and 24 controls) were recruited. Patients with LN or IAN deficits after lower third molar surgery were less satisfied with their lives when compared to the control group (p<0.001). They were presenting with more depression symptoms (p = 0.001). 45.8% of the study group subjects had a CESD-20 score of 16 or above. Older patients presented with more depression symptoms among the subjects with neurosensory disturbance after lower third molar surgery (p = 0.02). CONCLUSIONS: Individuals with permanent trigeminal neurosensory deficit after lower third molar surgery have worse life satisfaction and more depressive symptoms when compared to those who did not suffer from the surgical complication.

Capsaicin avoidance as a measure of chemical hyperalgesia in orofacial nerve injury models.

Many patients suffer from trigeminal neuralgia and other types of orofacial pain that are poorly treated, necessitating preclininal animal models for development of mechanisms-based therapies. The present study assessed capsaicin avoidance and other nocifensive behavioral responses in three models of orofacial nerve injury in rats: chronic constriction injury (CCI) of the mental nerves, partial tight ligation of mental nerves, and CCI of lingual nerves. We additionally investigated if nerve injury resulted in enhanced capsaicin-evoked activation of neurons in trigeminal caudalis (Vc) or nucleus of the solitary tract (NTS) based on expression of Fos-like immunoreactivity (FLI). Mental nerve CCI resulted in an enhancement of capsaicin avoidance in a two-bottle preference paradigm, while neither mental nerve injury produced thermal hyperalgesia or mechanical allodynia. CCI of lingual nerves did not affect capsaicin avoidance. Counts of FLI in Vc were significantly higher in the lingual sham and mental nerve CCI groups compared to mental shams; FLI counts in NTS did not differ among groups. Mental nerve CCI may have induced central sensitization of chemical nociception since increased capsaicin avoidance was accompanied by greater activation of Vc neurons in response to oral capsaicin.

The impact of altered sensation affecting the lower lip after orthognathic treatment.

PURPOSE: Inferior dental nerve paresthesia is a well-known risk of orthognathic surgery, but little is known about the effects of altered sensation in day-to-day life. Therefore the aim of this study was to assess the impact of altered sensation after orthognathic treatment. PATIENTS AND METHODS: The study was divided into 2 parts: the first phase involved semistructured, in-depth interviews with 13 post-treatment orthognathic patients who presented with altered sensation affecting the lower lip. In the second part of the study, the data from the interviews were used to develop a questionnaire that was distributed to 40 post-orthognathic patients (75% completion [n = 30]). The results were analyzed by use of descriptive statistical methods. RESULTS: In both stages of the study, common descriptors used to describe the altered sensation were "tingling" and "numb." The majority of patients were aware of the neurosensory disturbance when touching their lips, face, or jaw, and patients also expressed difficulties knowing when food was left on their lip. It was noted that patients who were aware of the altered sensation all of the time expressed the greatest distress in their everyday life. When it came to emotions associated with the altered sensation, the majority of patients were disappointed, but few were upset or angry. CONCLUSIONS: The impact of altered sensation due to inferior dental nerve damage after orthognathic surgery varied from patient to patient, but altered sensation had a significant effect on the majority of patients' everyday lives. The information obtained from this study makes an important contribution to the informed consent process.