Clinical observations on selective dorsal root ganglion pulsed radiofrequency lesioning combined with gabapentin in the treatment of postherpetic neuralgia
Keywords: Gabapentin, inflammatory response, pulsed radiofrequency, postherpetic neuralgia, T-cell immunity
Herpes zoster (HZ) is transmitted by the varicella zoster virus through the airways, via the pharyngeal lymphoid tissue, into the body. The virus then replicates and rapidly spreads to circulating T lymphocytes, eventually being distributed along damaged sensory nerves of the skin, and involves the dorsal root ganglion or the trigeminal ganglion. When the host immune function is compromised, the virus triggers an opportunistic activation and causes a clinically- defined pain. The acute phase continues for 3 weeks and is often associated with severe, spontaneous and induced pain. After symptomatic treatment, such as antiviral medications and immunity enhancement agents, are administered, 70–90% of the patients can completely recover from this infection without any sequelae being present. However, 9–35% of patients, after the recovery of their lesions, may develop postherpetic neuralgia (PHN). The main risk factors for the occurrence of PHN include an advanced age, the presence of severe pain, and the occurrence of a severe herpes infection. The occurrence of PHN is characterized by neuropathic pain. It has an incidence rate of 500,000 new cases each year. This incidence is second only to the overall incidence of lower back pain and diabetic neuropathy. Acyclovir has a significant antiviral effect and can significantly improve the patient's symptoms, shorten the course of the disease, and improve the prognosis in the acute phase of PHN. However, the overall rate of benefit from the neuralgic pain due to acyclovir alone is only in the range of 50–75%, as assessed during clinical observation. There is no definitive methodology for achieving cure from PHN at present, and the traditionally administered analgesics have a very poor effect in ameliorating its symptomatology. Gabapentin and pregabalin are the first-line drugs for PHN. Gabapentin acts on the voltage-gated calcium channel α2δ subunits, reducing calcium influx into the cells and inhibiting the peripheral nociceptor substance P and glutamate release, thereby relieving pain. Selective dorsal root ganglion pulsed radiofrequency uses low-frequency pulse currents to inhibit nerve impulse conduction, thus relieving and controlling the pain. However, the underlying mechanisms are not clear. Therefore, this study aimed to analyze the clinical effects and possible therapeutic mechanisms of tandem radiofrequency and gabapentin therapy utilized for the treatment of PHN.
One hundred and sixteen patients first diagnosed with PHN, who were admitted to the Second Affiliated Hospital of Kunming Medical University between January 2013 and January 2016, were included in this study. The inclusion criteria included: (1) an age range between 18–70 years; (2) the symptoms and history consistent with the diagnosis of PHN, which included an initial infection by HZ and/or the presence of pain that excluded the association of nervousness, anxiety or impairment of cognition in the patient; (3) the complete cure of the rash related to HZ infection, and without the persisting symptoms of local or systemic infection; (3) the pure unilateral involvement of the trigeminal nerve; (4) the neuralgic pain could not be alleviated with the routine medication, and was seriously affecting the patient's life and activities of daily living; and (5) the patient exhibited a good treatment compliance, his/her comprehensive clinical data was available, and an informed consent could be procured. The exclusion criteria included: (1) The presence of diabetic neuropathy, the occurrence of pain due to the presence of a tumor or previously sustained trauma, or the presence of any other unequivocal source of pain or discomfort; (2) the presence of a low immunity in the patient, due to the continued recent use of glucocorticoids or cytotoxic drugs or autoimmune diseases; and/or, (3) the prior application of other sympathetic nervous system inhibiting treatments such as tricyclic antidepressants, opioids or narcotics.
The patients were divided into the control and the observation groups using the random number table method. Each group consisted of 58 individuals. The control group had 29 male and 29 female subjects, with a mean age of 46.7 ± 12.3 years. The average course of the clinical manifestations of herpes zoster virus clinical affliction in this group was of 41.2 ± 8.5 days; the lesions were located in the chest in 32 cases, in the face and neck in 16 cases, and in the lumbosacral region in 10 cases. The observation group had 32 male and 26 female patients, who had a mean age of 48.5 ± 14.6 years. This group presented with an average course of clinical manifestations of herpes virus affliction for 45.6 ± 9.7 days, and 35 cases had lesions located in the chest region, 9 cases in the face and neck region, and 14 cases in the lumbosacral region. The baseline data of the two groups were comparable.
The control group was orally treated with gabapentin capsules (trade name: Neurontin, Pfizer Pharma GmbH, Berlin, Germany, 100 mg × 30 s), 2400 mg/d, tid. At the same time, the control group patients received antiviral medications (such as acyclovir), a reasonable rest and diet, a moderate amount of exercise, and techniques to develop an adequate emotional adjustment, etc. The observation group received all of the above mentioned treatments, as well as radiofrequency therapy.
Radiofrequency was performed as follows: A supine position was assumed by the patient for an operation on the face, and a prone position for an operation on the neck or thoracolumbar regions, respectively. A needle was inserted with the guidance of a 16-slice spiral computed tomographic (CT) imaging (3 mm slice thickness, with the conventional plain scan positioning; General Electric, Boston) using the position of the intervertebral foramen in the corresponding spinal cord segments to select the best puncture point. The distance between the needle point and the midline, as well as the angle, and the depth of the needle were measured. The corresponding position on the body surface was marked. If the dorsal ganglion manifesting the pain involved more than three segments, the three segments corresponding to the most intense pain were selected. Using the 22G radiofrequency puncture needle under local anesthesia, a cervical section up to a length of 10 cm, and, a thoracolumbar section up to a length of 15 cm was made; and, the bare end of the needle measured approximately 5 mm. The needle was slowly inserted along the preset puncture path with timely adjustments based upon the CT guidance. The tip was positioned at the posterior one-third of the intervertebral foramen, from the external aspect, and it was ensured that no liquid effluent could be withdrawn. Thereafter, about 0.5 mL of the contrast agent, Ultravist 370, was injected into the puncture point. The absence of leakage of the contrast agent confirmed the correct puncture location. The motor nerves were tested at a frequency of 2 Hz, with no local muscle spasm induced within 1 V. The sensory nerves were tested at a frequency of 50 Hz and at an amplitude not greater than 0.4 V, until a pain sensation similar to that occurring during the manifesting of the clinical symptoms was induced. The treatment protocol was as follows: 0.5 mL 2% lidocaine was injected into the dorsal root ganglion as an infiltration anesthesia and radiofrequency lesioning for pain treatment was started utilizing the PMG-230 Baylis machine (Baylis Medical Company Inc., Canada). After 5 minutes of the infiltration of the local anesthetic, the radiofrequency treatment was performed utilizing the following parameters: a frequency of 2 Hz, a pulse width of 20 ms, and the temperature being maintained at 42°C. The treatment was continued for two cycles (of 120 s each) at an interval of 15 s.
The degree of pain persisting and the complications that occurred were compared at 1, 2, and 4 weeks before and after the performance of the radiofrequency lesioning. The immune index used was the estimation of T-lymphocyte subset percentages. The inflammatory indices that were tested included the serum interleukin (IL)-6, C-reactive protein (CRP), and tumor necrosis factor (TNF)-α levels. The total follow-up duration was 6 months, and the effective treatment rate was compared between the subjects and control groups after this period. The visual analog scale (VAS) was used to evaluate pain. It ranges from 0 to 10 points, with higher scores indicating more severe pain. The complications assessed included the drug-related sleepiness, any allergies or gastrointestinal discomfort produced, the occurrence of radiofrequency-related pain exacerbation, as well as the occurrence of local infection, and/or nerve damage. The CD4+ and CD8+ cell levels, and the CD4+/CD8+ ratio in the peripheral blood were detected by flow cytometry. Levels of inflammatory indices were detected by enzyme-linked immunosorbent assay (ELISA) [the reagents were purchased from Jiangsu Beyotime Biotechnology Co., Ltd]. The results of treatment were graded as: Cured, markedly effective, effective, and ineffective. The cured status was marked by the presence of complete pain relief and the absence of complications until the end of the follow-up period; the markedly effective status was defined as at least 70% incidence of reduced pain, as determined by the Visual Analog Scale (VAS) score, with no rebound occurrence of pain, and no complications being seen; the effective status was marked by a 50–69% reduction in the VAS score, with no rebound occurrence of pain, and no complications being observed. If a patient did not meet any of these criteria, the treatment was considered as being ineffective.
The statistical analysis software (SAS 7.0) was used for data analysis. Quantitative data followed normal distributions and were expressed as mean ± standard deviation. t-Tests were used for comparisons between the two groups. Data at different time-points within the same group were analyzed by variance analysis of repeated measures. Qualitative data were expressed as percentage (%), with comparisons being made using the χ2 test. Grade data were evaluated using a nonparametric rank-sum test. Tests were bilateral, with P < 0.05 being considered as a statistically significant result.
Pain visual analog scale and complications
The observation group had a significantly lower VAS score than the control group at 1, 2, and 4 weeks after treatment (P ≤ 0.05) [Table 1]. Neither group showed severe complications.
After treatment, the percentage of CD4+ cells and the CD4+/CD8+ ratio in the observation group increased gradually, while the percentage of CD8+ cells decreased (P ≤ 0.05). No significant improvement was observed in the control group (P > 0.05) [Table 2].
Interleukin (IL)-6, C-reactive protein (CRP), and tumor necrosis factor (TNF)-α levels were significantly lower in the observation group than in the control group at 1, 2, and 4 weeks after the treatment [Table 3].
Total effective rate
Both the total effective rate and the effectiveness of treatment were greater in the observation group when compared to the control group (P ≤ 0.05) [Table 4].
The pathogenesis of HZ and PHN involves viral implantation in the sensory ganglion. This is followed by the activation, replication, and proliferation of the virus, leading to skin tissue damage, including local hemorrhage, demyelination, axonal degeneration, and the occurrence of apoptosis as well as necrosis of the sensory nerve fibers and supporting cells. This process triggers peripheral and central hyperalgesia, causing intense pain. The pathological characteristics of the condition include the occurrence of neuronal hemorrhagic necrosis of the dorsal root ganglion, eosinophilic inclusion body formation within the satellite cells, and the occurrence of peripheral nerve fiber demyelination. The surface sensory nerve injury often shows bilateral asymmetry, with the motor nerves in corresponding segments of the spinal cord being involved. Skin biopsies suggest an abnormal increase in the levels of the nociceptive marker, calcitonin gene-related peptide, in sensory neurons. The fast conductive, thick, myelinated nerve fibers continue to decrease, while the numbers of nociceptive, afferent and fine fibers are relatively increased. The thick and thin nerve fibers are disproportionate, eventually leading to the mismatch of afferent signals related to pain, which may be the critical basis for the occurrence of PHN.
Gabapentin is a relatively newer antiepileptic drug, which has achieved relatively good clinical results in the treatment of PHN. The drug has a short half-life with the peak absorption occurring 3–4 h after its administration. It rarely binds with plasma proteins, and has a weak competition or antagonism with other drugs. The maximum safe dose is stated to be in the range of 1800–3600 mg/d. Its main side effects include dizziness, drowsiness, peripheral edema, and ataxia. Factors contributing to the insufficient application of the medication in clinical practice include: A decreased treatment compliance as a result of the mandatory requirement of three doses per day; the slow intravenous infusion rate which extends the treatment time; and, the restriction of the main absorption site to the upper small intestine. Gabapentin sustained-release tablets (Enacarbil) and gastrointestinal absorption-delayed gabapentin further improve the clinical application rates and the effects of its treatment. Kim et al., have suggested that selective dorsal root ganglion pulsed radiofrequency lesioning increases the clinical benefit related to pain control, thus, shortening the course of treatment, improving the quality of life, and reducing the use of analgesic drugs. A subsequent study confirmed that pulsed radiofrequency currents can induce biological effects on the stability of cell morphology, as well as in bringing about the regulation of synaptic and pain signal transmission. An animal model has shown that following the administration of a continuous pulse current on the rat cervical ganglion, the light microscopy has shown only a small amount of intracellular modifications, that include the expansion of the endoplasmic reticulum pool and the occurrence of a mild edema, with the presence of significant cell damage. Clinical pulse radiofrequency treatment also did not lead to an obvious occurrence of hyperalgesia, paresthesia, or any other complications.
According to our study, the VAS score was significantly lower in the observation group than in the control group after treatment. Furthermore, the CD4+ cell percentage as well as the CD4+/CD8+ ratio gradually increased in the peripheral blood, while the CD8+ percentage decreased. Levels of IL-6, CRP, and TNF-α were significantly lower in the observation group than the control group, and the total treatment effectiveness was superior in the observation group. These results suggest that radiofrequency in combination with gabapentin is safe and efficacious in the treatment of PHN. Furthermore, these results indicate that the observed therapeutic improvement may be related to the enhancement of T-cell immunity and the inhibition of inflammatory reaction. The T-cell immune status is closely related to virus activation, the induction of neuronal and nerve fiber inflammatory response, and apoptosis. The hypo-immunity induced as a result of a decrease in the number and function of peripherally circulating T-cells in PHN patients is associated with a greater disease severity and a graver prognosis, with the immune function improving after the initiation of treatment. An abnormal increase in the levels of the inflammatory factors, IL-6, CRP, and TNF-α, in the peripheral circulation and cerebrospinal fluid of patients suffering from PHN may be associated with the generation and activation of central pain-inducing neurotransmitters, glycine and galectin-3., Neuropathic glycine transporter (GlyT2) inhibitors acting on the spinal cord can significantly reduce the intensity of acute and chronic herpes zoster neuralgia. Intrathecal injection of galectin-3 antibody to the galectin-3 knockout mice can also significantly reduce the incidence of PHN.
The present study has demonstrated that radiofrequency lesioning combined with gabapentin in the treatment of PHN has a good safety profile and is efficacious. The beneficial effects of this treatment may be related to an increased T-cell immunity and an inhibited inflammatory response.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]