From July 2019 to March 2020, a total of 23 consecutive patients with medically refractory idiopathic TGN were assessed at the pain and palliative outpatient clinic of Imam Reza University Hospital, Tabriz, Iran, of whom 10 patients did not satisfy the inclusion criteria and 2 rejected participation in the study.

Adults aged 18–70 years with confirmed TGN with at least three pain attacks per day, pain intensity of four or more on a pain intensity numerical rating scale (PI-NRS) on at least 7 days before the start of treatment, history of previous intake of carbamazepine 600–900 mg/day, gabapentin 900–1800 mg/day, or pregabalin 300–450 mg/day and tramadol 400 mg/day for more than 3 months with poor clinical response and a desire to participate throughout the study were included. The criteria for TGN were according to the International Classification of Headache Disorders [5].

Exclusion criteria were previous radiofrequency ablation and/or surgical treatment for TGN, existence of a tumor or autonomic symptoms based on brain magnetic resonance imaging (MRI), or other neuropathic pain, cognitive dysfunction, history of drug abuse, or any coagulation conditions or platelet disorders. Imaging was performed to confirm the lack of a secondary cause.

Finally, 11 Iranian patients (4 male, 7 female) were included in this study. The right and left side was involved in seven and four patients, respectively. The mean age was 45.64  ±  11.58 years (Table 1).

Table 1 Demographic characteristics

The research proposal was approved by the Ethics Committee of the Tabriz University of Medical Sciences on 20/05/2019 (IR.TBZMED.REC.1398.170) in accordance with the Helsinki Declaration of the World Medical Association (version 19 October 2013).

All patients were visited by a palliative care medicine fellow at the study center, who assessed the eligibility criteria, presented necessary information concerning the study, product, alternatives, and risks, and obtained written informed consent. The participants then completed all the baseline questionnaires.

All patients who met the eligibility criteria listed above received diagnostic brain MRI with contrast to rule out any condition or disorder that would deprive them of participation such as compression of Gasser ganglion. Comprehensive demographic information of patients, including age, gender, occupation, and education, was recorded. Medical history concerning consumption of all medications (doses and duration) was obtained.

All patients were accurately evaluated concerning the location, duration, nature, and pain intensity. They were asked to rate their pain on a NRS varying from 0 (“none”) to 10 (“unbearable”).

Procedure for Orthokine preparation

Fifty milliliters of whole blood samples were taken from each participant using a special syringe (EOT®II) [38]. Medical-grade glass beads in the syringes expand the nonpyrogenic surface area. These glass spheres induce the release of IL-1Ra from white blood cells in venous blood samples incubated for 7 hours at 37 °C. The blood-filled syringes were then centrifuged (3000×g) for 15 minutes. Before injection, the serum supernatant was filtered and tested for human immunodeficiency virus, syphilis, and hepatitis B and C.

Procedure for Orthokine injection

Orthokine serum (2 mL per injection) was injected under fluoroscopy direction. All patients had an appointment for an injection once per week for three consecutive weeks (four injections).

We asked the patient to lie in supine position. Then, a sterile 21-gauge needle with a 10-mm naked needle tip was inserted into the skin 1.5–2 cm lateral to the corner of the mouth, below the lower lip, under fluoroscopy direction in aseptic conditions, and advanced into the foramen ovale (FO), then aspirated. The needle was left in place (Fig. 1). An anesthetic consisting of approximately 2 mL 2% lidocaine was injected to prevent post-injection pain due to the injection itself, then 2 mL Orthokine was injected (Fig. 2). This procedure was the same for each participant. All procedures were done outpatient by one physician, considering all aseptic provisions inside the operation room.

Fig. 1
figure 1

Needle insertion and advancing into the foramen ovale

Fig. 2
figure 2

Fluoroscopic image of Orthokine injection

Patient evaluation and follow-up

Patients who received ≥ 1 dose of Orthokine were asked to document their daily pain intensity, drug usage, and adverse events (AEs) carefully at 1 week before (T0) and 1 month after treatment end (T5). Additionally, the patients were followed up at 1 week (T1), 2 weeks (T2), 3 weeks (T3), and 1 month (T4) after the start of the study, at the pain outpatient clinic.

No drugs were recommended in participants with complete pain relief (NRS < 3). Otherwise, they were counseled to continue carbamazepine up to 400 mg three times a day orally. The same technician executed all follow-up evaluations. The safety profile of ACS was also examined by analysis of AEs at each study visit.

Any AEs, comprising bleeding at the injection site, infection, and other possible AEs, were recorded at weeks 1, 2, 3, and 4, and month 2.

Statistical methods

Statistical analyses were carried out using SPSS 18.0 software. Continuous variables are presented as mean ± standard deviation, and categorical data as number and percentage. The Shapiro–Wilk test was applied to analyze the distribution. Repeated-measure analysis of variance (ANOVA) testing was applied. p-Value < 0.05 was considered significant.

Pretreatment pain severity

Patients most frequently reported multiple pain attacks daily (eight patients, 72.7%). Two and one patients reported one attack daily and continuous pain, respectively. The mean best and worst pretreatment pain intensity (current 24 hours) was 5.36 ± 2.37 and 10.00 ± 0.00, respectively.

Efficacy data

Table 2 presents the pain intensity and carbamazepine consumption in all patients. Orthokine injection led to 31.00 ± 29.33%, 49.31 ± 26.81%, 60.04 ± 32.75%, 56.46 ± 49.69%, and 52.92 ± 49.16% reduction in pain (NRS) at 1 week, 2 weeks, 3 weeks, 4 weeks, and 2 months after beginning treatment. Pain intensity was significantly reduced in the first 3 weeks of follow-up in comparison with baseline (T0 to T3), an effect that was retained at week 4 (T4) and month 2 (T5) follow-ups. Three (27.3%) patients were completely pain free at week 2 follow-up, while two and none of them remained pain free at week 3 and month 1 follow-up, respectively (Fig. 3).

Table 2 Pain severity and carbamazepine consumption in all participants
Fig. 3
figure 3

Pain intensity in participants throughout the study

All patients had used at least one medication for TGN on enrollment in the study. However, they were permitted to continue carbamazepine up to 400 mg three times a day. Carbamazepine consumption was significantly reduced in the first 3 weeks of follow-up compared with baseline (T0 to T3), an effect that was retained at week 4 and month 2 follow-ups (Fig. 4).

Fig. 4
figure 4

Carbamazepine consumption in participants throughout the study

Costs

The overall and per-patient costs were calculated in US $. We considered the costs related to Orthokine as well as the consumables (needle and syringe) needed for its administration. The total cost of Orthokine and consumables per dose administered was US $35.71 and US $1.54, respectively.

Safety data

Analysis of safety records showed that two transient AEs were reported in five participants: high blood pressure during injection (n = 1) and postinjection pain for several days (n = 4). There were no serious AEs in participants. No patients were removed from the study because of an AE.

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