NMDA receptor antagonist amantadine in treatment of neuropathic orofacial pain

Neuropathic orofacial pain caused by trauma to the distal branches of the trigeminal nerve is most often an iatrogenic complication in the practice of dentists, maxillofacial surgeons, ENT surgeons, cosmetologists and plastic surgeons. The pain is often high-intensity, persistent, and difficult to treat with pain medications. Early signs of spontaneous pain aggravate the course of the disease. There is evidence of the use of N-methyl-d-aspartate (NMDA) receptor antagonists in the treatment of neuropathic pain in the practice of oncologists and diabetologists. The present study was designed to test the efficacy of administration of the NMDA receptor antagonist amantadine (PK-Merz) in the treatment of neuropathic orofacial pain in patients with posttraumatic trigeminal neuropathy (PTN). Our task was to study the effect of amantadine (PK-Merz) on spontaneous burning and evoked types of pain.

Objective. To present a treatment protocol using amantadine (PK-Merz) and evaluate the effect of a three-time infusion of the drug on the clinical manifestations of pain in patients with post-traumatic trigeminal neuropathy.

Materials and methods. 30 patients were examined (22 women, 8 men). The average age is 42.6 years. Patients are experiencing amantadine (PK-Merz, Merz + Co., Germany) – 200 mg (500 ml) intravenously, drip, for 2 hours with a frequency of 1 time per week. A total of three infusions were performed. Spontaneous and evoked pain was measured within 48 hours before treatment, during treatment (after 1 hour), immediately after infusion (after 2 hours), as well as after 7, 14 and 21 days from the start of therapy. The effectiveness of therapy was studied according to the highest criteria: VAS, questionnaires for neuropathic pain DN 4 and Pain DETECT. Spontaneous and induced pain were considered separately. To assess the immediate effects of treatment, spontaneous pain was measured using a visual analog scale (VAS) before, after 1 hour, and at the end of each treatment (after 2 hours), as well as at visits on days 7th, 14th, and 21st. A series of mechanical and thermal stimuli was applied to each patient before, after 1 hour, and at the end of each treatment session to study the pain evoked. Pain caused by these stimuli was also measured using VAS.

Results. The patients were divided into two groups, which were formed according to the duration of the disease. Group 1 (n = 12) included patients in the acute period – the time after nerve injury ranged from 5 to 30 days. In group 2, patients were in subacute and chronic periods (time after injury ranged from 30 days to 1.5 years). The mean score of spontaneous pain according to VAS in patients of group 2 was significantly higher than in patients of group 1 (6.1 ± 2.1 vs 4.2 ± 1.6; p = 0.0001). A mean pain reduction of 71 % was reported at the end of amantadine infusion (after 2 hours) in patients in the acute period (Group 1) compared with 29 % in patients in Group 2. The difference in pain reduction between the two patient groups was statistically significant (p = 0.009). Further dynamics of pain also showed the best analgesic result in patients of group 1 – after the completion of treatment with amantadine (PK-Merz), in patients of group 1, a significant decrease in the average score of spontaneous burning pain according to VAS was demonstrated from 4.2 ± 1.6 points to 1.2 ± 1.1 points (p = 0.006; 71 ± 10 % reduction). After treatment of patients in group 2, only a slight and insignificant decrease in VAS was found from 6.1 ± 2.1 to 5.0 ± 1.7 (p = 0.400; 18.0 ± 8.5 %). Symptoms of induced pain were determined mainly among patients of the 2nd group – allodynia (n = 12), hyperalgesia to a needle prick (n = 10), thermal (cold) hyperalgesia (n = 10), "inflated" pain in response to repeated injections (n = 10). A mean decrease in allodynia of 52 % ± 8 % was found at the end of the course of treatment (3.8 ± 1.1 points at the beginning and 1.9 ± 1.1 points at the end; p = 0.006). Indicators of cold hyperalgesia (4.4 ± 1.4 points at the beginning, 2.7 ± 1.4 points at the end; p = 0.004) and ‘inflated’ pain (2.9 ± 1.1 points at the beginning, 1.5 ± 1.2 at the end; p = 0.004) before treatment and at the end of therapy (after 21 days) also differed significantly.

Conclusions. We concluded that amantadine (PK-Merz) infusion is a safe and effective treatment for neuropathic pain in the acute period of KITN, and also has a positive effect on the manifestations of induced pain in patients with chronic orofacial pain. Further trials of long-term oral or parenteral treatment with amantadine should be conducted.

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