Computed Tomography–Guided Dorsal Root Ganglion Ozone Injection Combined With Pulsed Radiofrequency for Acute Herpes Zoster Neuralgia Treatment of Middle-aged and Elderly People

Abstract

Objectives:

To investigate the efficacy and safety of pulsed radiofrequency of the dorsal root ganglion combined with ozone injection for treating acute herpes zoster (HZ) neuralgia in middle-aged and elderly adults.

Methods:

A total of 164 middle-aged and elderly patients with acute HZ were randomly assigned to 2 groups: the pulsed radiofrequency combined with ozone injection group (group A) and the pulsed radiofrequency group (group B). The therapeutic effects were evaluated using Numeric Rating Scale (NRS) scores and the average doses of gabapentin (mg/d) preoperatively and 1 day, 2 weeks, 4 weeks, 12 weeks, and 24 weeks postoperatively. The incidence of clinically significant postherpetic neuralgia (PHN) and complications in the 2 groups were recorded.

Results:

The data showed that the NRS scores and the doses of gabapentin after treatment were significantly lower when compared with the baseline values in both groups. Compared with group B, the NRS scores and the doses of postoperative gabapentin were significantly lower in group A. The incidence of PHN was significantly lower at weeks 4, 12, and 24 in group A than in group B. No adverse reactions occurred in either of the 2 groups post-treatment.

Conclusions:

The results indicated that ozone injection in the dorsal root ganglion combined with pulsed radiofrequency therapy was more effective in treating acute HZ neuralgia in middle-aged and elderly adults. It provides patients with longer-lasting pain relief, decreased incidence of PHN and the doses of medication, and improved quality of life than with Pulsed Radiofrequency treatment.

Herpes zoster (HZ) is caused by the reactivation of the varicella-zoster virus. The primary infection with varicella-zoster virus is latent in the dorsal root and cranial ganglia; when the immune function of the body declines, these viruses reactivate and replicate, resulting in inflammatory responses in the ganglia and peripheral nerves; which, in turn, results in tissue damage in the corresponding distribution areas of the nerves.^1–3 The annual incidence of HZ is 1 to 3 per 1000 in young adults and 4 to 12 per 1000 in elderly adults.⁴ Approximately 9 to 34 of 100 individuals with shingles may develop postherpetic neuralgia (PHN), and the incidence increases with age.⁵ PHN is the most common and serious complication of HZ. It seriously affects the quality of life of patients and is the primary reason for clinical treatment.^6,7 A previous study⁸ reported that early HZ treatment decreases acute pain and PHN incidence and accelerates the healing process of rash. Therefore, early treatment is recommended to improve the therapeutic effects and prevent PHN occurrence.

Early treatment can be achieved through pharmacological intervention. The tricyclic antielipetic pregabalin and gabapentin are recommended as the first-line medications, whereas nonsteroidal anti-inflammatory drugs and opioids are frequently used to suppress pain. However, medication alone remains insufficient for most patients. Although nerve blocks and epidural injections can be used to temporarily relieve patients’ pain, they do not exert any significant effect on PHN prevention.⁹ Moreover, electrical stimulation of the spinal cord may decrease PHN incidence; however, its use is limited in clinical settings owing to the risk of infection and the expensive medical costs that may be associated with the placement of an electrode in the spinal canal. Pulsed Radiofrequency (PRF) is a neuromodulation technique, wherein alternating and repetitive pulsed currents emitted by a radiofrequency instrument act around the diseased nerves to modulate disturbed electrical signals, thereby exerting analgesic effects.^9,10 Because the temperature of the electrode head end is <42 °C, it rarely results in nerve tissue damage. However, some patients continue to have poor results and require additional treatments.

Ozone is a strong oxidizing agent with analgesic, anti-inflammatory, and immunomodulatory effects.¹¹ Owing to these remarkable biological effects, ozone is currently used to treat various pain disorders, including musculoskeletal disorders, vascular disorders, rheumatic immune disorders, neuropathic pain, and metabolic disorders.^12–14 A previous study reported that ozone therapy has almost no side effects and is safe for clinical application.¹⁵ Presently, it has been reported that ozone therapy can relieve HZ-associated neuralgia.^16,17 However, previous studies were retrospective and conducted on a small sample size. Therefore, in the present study, we focused on the clinical efficacy of dorsal root ganglion (DRG) ozone injection combined with pulsed radiofrequency for treating acute HZ neuralgia in middle-aged and elderly adults, as well as explored its preventive effect on the occurrence of PHN.

METHODS

Study Design

The current study was a prospective, randomized, controlled, clinical trial. It was approved by the Medical Ethics Committee of our Hospital. This study recruited patients who were treated at the Affiliated Hospital of Jiaxing University from February 2022 to 2023 with a diagnosis of acute HZ neuralgia. All patients provided their written informed consent.

Inclusion and Exclusion Criteria

The inclusion criteria were as follows: (1) patients clinically diagnosed with acute zoster pain, (2) disease duration of ≤30 days, (3) patients age 40 years or older, (4) numerical rating scale (NRS) score ≥4 before the operation, and (5) those who completely understood the risks of surgeries and agreed to undergo computed tomography (CT)-guided PRF or ozone injection. The exclusion criteria were as follows: (1) individuals with cardiopulmonary insufficiency, poor blood sugar control, or other severe diseases, (2) those with puncture site infection, (3) those who were allergic to lidocaine, ozone, and other related drugs, (4) those who refused to provide treatment information and clinical data for scientific research, and (5) those who received PRF or other minimally invasive treatments.

Randomization and Blinding

A total of 170 patients were enrolled in this trial, and they were assigned randomly to 2 groups through a computer-generated random allocation sequence: (1) pulsed radiofrequency combined with ozone injection group (group A, n = 81) and (2) pulsed radiofrequency group (group B, n = 83). Patients in the 2 groups received corresponding treatments and follow-ups at different time points, as shown in Figure 1. The procedures were performed by the same investigator, and all follow-ups were performed by another investigator. Patients and investigators who were in charge of the follow-up and data collection were unaware of the randomization. The post-treatment assessment was administered by a nurse who was not involved in this study.

FIGURE 1.

Flow diagram depicting the study protocol.

PROCEDURES

In both patient groups, the operation was performed under the guidance of a CT scan. The patients were asked to lie in the prone position on the CT scan bed with soft pillows under the chest or axilla. Oxygen was continuously administered through a nasal cannula, and the vital signs were monitored throughout the procedure. Depending on the nerve involved in the lesion, body surface localization landmarks were determined, with the most painful segment located at the center and one segment extending above and below. The puncture site was centered, disinfected with a towel, and anesthetized with local infiltration of 1% lidocaine. Then, under the guidance of a CT scan, the upper one-fourth of the intervertebral foramen was used as the puncture target for the trocar needle for PRF¹⁸ (20 G, 150 mm long, and working end length of 10 mm; Fig. 2A). The needle was entered along the indicated path to a depth of no more than half of the lateral mass of the same vertebral body. After the tip of the needle was in place, a radio-frequency instrument (Baylis Medical Inc.) was used as follows (1) sensory test: voltage <0.5 V and frequency of 50 Hz; the innervated area was observed for pain, swelling, numbness, or tingling sensations and (2) motor test: voltage <0.5 V and frequency of 2 Hz; if tremors and pulsation were induced in the trunk muscle fibers, the puncture site was located near the target nerve. After determining the location of the puncture site, the temperature, time, pulse width, and frequency of PRF were set to 42 °C, 300 s, 20 ms, and 2 Hz, respectively.⁷ After completing PRF stimulation, the electrode core was withdrawn, with no aspiration of blood, gas, or fluid. Thereafter, 0.5 mL of a contrast solution (General Electric Pharmaceutical Co., Ltd., 300 mg/mL) was injected, and CT revealed no intravascular injection (Fig. 2B). After completing the PRF procedure described earlier, 5 mL of the treatment solution (100 mg of 2% lidocaine hydrochloride [Hunan Kelun Pharmaceutical Co. Ltd., 0.1 g/5 mL], 500 µg of methylcobalamin [Eisai Pharmaceutical Co. Ltd., 0.5 mg/mL] injection, 1 mL compound betamethasone [Maanshan Fengyuan Pharmaceutical Co. Ltd., 4 mg/mL] injection, and 3 mL of 30% iodohydrin [General Electric Pharmaceutical Co. Ltd., 300 mg/mL]; dilute to 15 mL with 0.9% saline) was injected into each of the affected nerve for a total of 3 ganglionic segments, based on PRF localization. Once again, CT revealed good contrast and drug diffusion, covering the pain-related neurospinal segments, and reconfirmed the absence of intravascular injection. After removing the needle, the puncture site was covered with an adjuvant. After 20 minutes of observation, no adverse reactions were observed; therefore, the patients were shifted to the ward. In group A, after completing the above mentioned treatment, 3 mL of ozone (Oxygen-Ozone Therapeutic Instrument, Shandong Zibo Yuehua Medical Instrument Co. Ltd., 40 μg/mL) was, in addition, injected into each treated nerve segment. CT revealed good ozone diffusion (Fig. 2C). After removing the needle, the puncture site was covered with excipients. After 20 minutes of observation, no adverse effects were observed; therefore, the patients were shifted to the ward.

FIGURE 2.

The needle was inserted into the upper one-fourth area of the corresponding intervertebral foramen. The CT scan verifies that the inserted needle is at the target site (A and C). Comparison of CT scan images at the end of operation between the 2 groups (B and D). The orange arrow indicates the ozone position. Puncture site indicates cervical vertebra. A and B: group B; C and D: group A. CT indicates computed tomography.

Data Collection and Follow-up

The primary outcome was the NRS scores and the incidence of clinically significant PHN. The NRS scores were recorded from 0 to 10, with 0 = no pain and 10 = the most severe pain imaginable. The NRS scores were evaluated before treatment and 1 day, 2 weeks, 4 weeks, 12 weeks, and 24 weeks after the treatment. Based on previous studies, clinically significant PHN was defined as persistent pain according to NRS with an intensity of ≥3.⁹ The proportion of clinically significant PHN at weeks 4, 12, and 24 after the end of treatment was compared using the same criteria. The secondary outcome was the average dose of gabapentin. For the purpose of analysis, the dosage of the oral drugs was converted to equivalent doses of gabapentin before treatment. The average doses of gabapentin were observed and recorded preoperation and then at 1 day, 2 weeks, 4 weeks, 12 weeks, and 24 weeks postoperation.

STATISTICAL ANALYSES

Sample Size

In our pilot study, the incidence of clinically significant PHN in the PRF combined with ozone injection group was 7.1%, and the incidence of clinically significant PHN in the PRF group was 25%, hence the difference between the incidence of clinically significant PHN in the 2 groups was 19.7%. Based on this information, we calculated that the estimated sample number was at least 63 in each group, which provided 80% power and a level of statistical significance of 0.05 (α = 0.05).

Data Analyses

All data were analyzed using SPSS 26.0 (IBM). The Shapiro-Wilk test was performed to determine whether the measurements were normally distributed. The normally distributed data were expressed as the mean ± SD, whereas non-normally distributed data were expressed as the median (quartiles). The Mann-Whitney U test or independent t test was performed for continuous variables. Furthermore, the χ² test or Fisher exact test was performed for categorical variables. Pain intensity over time was assessed using repeated measures analysis of variance. P <0.05 was considered to indicate statistical significance.

RESULTS

Patient Characteristics

In total, 218 patients were enrolled in this study, and 48 patients were excluded for the following reasons: 31 patients did not fit the inclusion criteria, 12 patients refused to participate, and 9 patients for other reasons. In groups A and B, 2 and 3 patients, respectively, were lost to follow-up. A total of 164 patients completed the operation and were analyzed statistically (Fig. 1). Nonsignificant differences were noted for the age, sex, disease duration, affected side, and presence of underlying disease before treatment between the 2 groups (Table 1).

TABLE 1.

Patients Characteristics

Variables	Group A (n = 81)	Group B (n = 83)	P
Age (y), mean±SD	62.85±10.870	65.96±11.590	0.138
Sex, n
Male	34	36	0.783
Female	47	47	—
Disease duration (d), mean±SD	16.78±9.853	17.73±9.671	0.586
Side, n
Left	38	39	0.856
Right	43	44	—
Underling disease, n
HTN	27	30	0.705
DM	5	7	—
HTN and DM	5	5	—
None	44	41	—
NRS before treatment, mean±SD	6.06±0.643	6.10±0.625	0.982

DM indicates diabetes mellitus; HTN, hypertension; NRS, Numeric Rating Scale.

Operation Related Data

Numeric Rating Scale

After treatment, the NRS scores in both groups decreased significantly (P < 0.001; Fig. 5). Furthermore, the NRS scores significantly declined at weeks 2, 4, 12, and 24 after treatment in group A when compared with that in group B (P < 0.05; Fig. 5).

FIGURE 5.

The violin plot of NRS scores in the 2 study groups. Group A: pulsed radiofrequency combined with ozone injection group. Group B: Pulsed radiofrequency group. NRS indicates Numeric Rating Scale.

The Clinically Significant Postherpetic Neuralgia

When compared with group B, the incidence of the clinically significant PHN in group A was significantly lower at 4, 12, and 24 weeks after the operation (Fig. 6).

FIGURE 6.

Comparison of the proportion of clinically valuable PHN in the 2 groups after operation. Group A: pulsed radiofrequency combined with ozone injection group. Group B: Pulsed radiofrequency group. T3: 4 weeks postoperatively. T4: 12 weeks postoperatively. T5: 24 weeks postoperatively. PHN indicates postherpetic neuralgia.

Gabapentin Consumption

After the operation, the doses of gabapentin in both groups decreased significantly (P < 0.05; Fig. 7). When compared with group B, the doses of gabapentin were significantly lower in group A at weeks 4, 12, and 24, postoperatively (P < 0.05; Fig. 7).

FIGURE 7.

Comparison of the average dose of gabapentin in the 2 groups after operation. Group A: pulsed radiofrequency combined with ozone injection group. Group B: pulsed radiofrequency group. T0: preoperation. T1: 1 day postoperatively. T2: 2 weeks postoperatively. T3: 4 weeks postoperatively. T4: 12 weeks postoperatively. T5: 24 weeks postoperatively. NRS indicates Numeric Rating Scale.

Side Effects

In both groups, there was innervation region numbness after the operation. Nevertheless, this symptom disappeared 1 to 2 months after the operation. After treatments, no bleeding or infection at the puncture site, pneumothorax, spinal cord injury, hematoma, or any other serious adverse effects were observed in both groups.

DISCUSSION

After HZ, the latent virus in the dorsal root or cranial ganglia proliferates and destroys sensory neurons, which results in altered transmembrane ion channels.¹⁹ These damaged sensory nerves generate abnormal electrical impulses that are spontaneously painful once transmitted to the spinal cord. PHN is the most common and serious complication of HZ that seriously affects the quality of life of patients and has an older onset age. Therefore, early intervention and effective quality are essential, particularly in elderly patients. Presently, there are only a few effective methods for controlling HZ-related pain. Although medications are effective during early disease onset, persisting pain and increasing medication doses and type increase the risk of side effects. As a result, several patients eventually reduce their dose or stop their medication due to intolerance to the associated side effects.

Recently, PRF has emerged as the main therapeutic measure to relieve herpetic neuralgia.^2,20 Although the exact analgesic mechanism of safe PRF remains unclear, researchers have suggested that selective long-term suppression after PRF stimulation is the primary analgesic mechanism.²¹ PRF stimulation leads to the selective and long-term inhibition of C fiber-mediated sensitization of the spinal cord, thereby decreasing the efficacy of neuronal synapses in the C fibers, which, in turn, results in delayed transmission of nociceptive signals from the peripheral nerves to the central nervous system,^21,22 thereby exerting an analgesic effect. In patients with HZ, PRF stimulation to the DRG decreases signaling to the central nervous system by modulating injured receptor fibers, thereby inhibiting severe pathologic changes in the nerves. Moreover, after PRF stimulation, microscopy revealed C, A-δ, and A-β fiber destruction in the nerve tissues.²³ C and A-δ fibers are deleterious nerve fibers, with damage to these fibers relieving pain. However, when compared with conventional radiofrequency, PRF is performed in low temperatures, has a short duration, and has a limited intensity of action. Therefore, patients often require additional treatment, and the incidence of PHN remains high. Glucocorticoids are frequently used for treating HZ neuralgia; however, they may increase the risk of infection. Furthermore, they are contraindicated for patients with diabetes and do not decrease the PHN incidence.^24,25 As a result, clinicians have been searching for more effective treatments for HZ neuralgia.

Ozone is a very strong oxidizing agent. When used in the appropriate concentration for treatment, it acts as a physiological activator, stimulating several different biological effects in the body.^25,26 Presently, ozone therapy is used to treat various diseases, including herniated intervertebral discs, arthritis, and trigeminal neuralgia.^27–29 A previous study³⁰ reported that ozone can activate the antioxidant enzyme system of the body, increase heme oxygenase-1 expression in the local microenvironment, and activate antioxidants for downstream targets through heme oxygenase-1-mediated signaling. Furthermore, ozone induces the production of high levels of superoxide dismutase and scavenges excessive free radicals, thereby regulating the antioxidant capacity of the body. Moreover, it can stimulate the patient’s body to increase the number of white blood cells, resulting in faster virus phagocytosis, and can play a role in stimulating the immune functions of some cells. In addition, the analgesic effects of ozone are well known. A local ozone injection can lead to the rapid inactivation of inflammatory factors, decrease the stimulation of sensory nerve endings through inflammatory factors, and inhibit peripheral sensitization, thereby generating an analgesic effect.¹² Ozturk et al³¹ have reported that ozone can directly stimulate sensory nerve endings, thereby inducing the activation of endorphins in the nervous system, as well as inhibiting the transmission of noxious stimuli from the periphery to the higher centers. Furthermore, by reducing oxygen, ozone therapy increases the oxygen supply in the body and improves tissue ischemia and physiological function.^32,33 Because ozone is a highly unstable atmospheric gas that rapidly decays into normal oxygen (O₂), we need to prepare ozone temporarily using a sole empty syringe and then inject it into the DRG within 15 seconds, thereby facilitating the spread of ozone in the epidural by CT. In our study, considering that there was a certain time gap between injecting the drug and ozone administration, the injected drug and ozone did not seemingly react or combine.

In the present study, patients experienced good pain relief after ozone injection with PRF treatment, and the incidence of the clinically significant PHN in group A was significantly lower than in group B after the treatment. The results indicated that the post-operation NRS scores and the doses of gabapentin were significantly lower when compared with the baseline in both groups. The NRS scores significantly declined at weeks 2, 4, 12, and 24 after treatment in group A than in group B (P < 0.05; Fig. 5). The incidence of the clinically significant PHN in group A was significantly lower at weeks 4, 12, and 24 after the operation (Fig. 6).

To ensure the maximum therapeutic effect of ozone, we used an ozone concentration of 40 ug/mL in this study (40 µg/mL of ozone was prepared by using the Oxygen-Ozone Therapeutic Instrument, Shandong Zibo Yuehua Medical Instrument Co., Ltd.). The concentration of ozone ranges from 1 to 40 µg/mL of oxygen and should not exceed 40 µg/mL.³⁴ Past studies have reported that 30 µg/mL ozone can inhibit inflammatory responses to pain-causing factors at the disease site and promote the oxygenation of local tissues, thereby decreasing nerve root ischemia and edema.^28,33 Intrathecal ozone injection should be <40 μg/mL,³⁵ and high ozone concentrations (40 to 60 μg/mL) can induce neurotoxicity.³⁶

DRG contains primary sensory afferent neurons and the location of the virus infection. Therefore, it is targeted for treatment. CT-guided ozone injection not only provides proximity to the DRG but also helps avoid the possibility of injecting drugs into the vertebral arteries and their branches. Needle insertion was primarily accomplished through the posterior upper one-fourth path of the intervertebral foramen under CT guidance (Figs. 2, 3, and 4 present the images of the puncture needle in the cervical, thoracic, and lumbar spine, respectively). Because ozone injection into the blood may not be safe, we administered a contrast agent mixture by confirming needle tip insertion and drug distribution to avoid adverse events caused by entry into the blood. In addition, these procedures ensured the safety of ozone injection.

FIGURE 3.

The needle was inserted in to the upper one-fourth area of the corresponding intervertebral foramen. The CT scan verifies that the inserted needle is at the target site (A and C). Comparison of CT scan images at the end of operation between the two groups (B and D). The orange arrow indicates the ozone position. Puncture site: thoracic vertebra. A and B: group B. C and D: group A. CT indicates computed tomography; PHN, postherpetic neuralgia.

FIGURE 4.

The needle was inserted in to the upper one-fourth area of the corresponding intervertebral foramen. The CT scan verifies that the puncture needle is at the target site (A and C). Comparison of CT scan images at the end of operation between the two groups (B and D). The orange arrow indicates the ozone position. Puncture site: lumbar vertebra. A and B: group B. C and D: group A. CT indicates computed tomography.

In summary, the results indicate that CT-guided PRF combined with ozone injection was safe and effective, and it provides patients with longer-lasting pain relief, improves efficacy and the satisfaction quotient, as well as decreases the incidence of PHN and the doses of medication. Interestingly, we observed that patients with HZ of the upper and lower extremities and concomitant muscle weakness had significant recovery after receiving PRF stimulation combined with ozone injection. Nevertheless, the reason for this phenomenon is unclear. Ozone may improve oxygen supply to the perineural tissues and physiological function. We will conduct additional studies on this phenomenon.

Limitations

Our study has some limitations that should be addressed. First, the enrolled patients belonged to a single pain management center. Second, the patients were followed up only for 6 months. Future studies should include research across multiple centers with a longer follow-up.

CONCLUSIONS

Ozone injection combined with pulsed radiofrequency therapy in the DRG was more effective in treating acute HZ neuralgia in middle-aged and elderly adults. The proposed approach provides patients with longer-lasting pain relief, decreases the incidence of PHN, and reduces the doses of medication, which ultimately improves the quality of life relative to that with PRF treatment.