Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 9764  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (638 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

  In this Article
 »  Abstract
 »  Materials and Me...
 » Results
 » Discussion
 » Conclusion
 »  References
 »  Article Tables

 Article Access Statistics
    PDF Downloaded35    
    Comments [Add]    
    Cited by others 1    

Recommend this journal


Table of Contents    
Year : 2018  |  Volume : 66  |  Issue : 6  |  Page : 1706-1710

Clinical observations on selective dorsal root ganglion pulsed radiofrequency lesioning combined with gabapentin in the treatment of postherpetic neuralgia

1 Department of Pain Management, The Second Affiliated Hospital of Kunming Medical University, Yunnan, People's Republic of China
2 Department of Anesthesiology and Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China

Date of Web Publication28-Nov-2018

Correspondence Address:
Dr. Xiaofeng He
No. 374 Dianmian Road, Kuming, Yunnan 650101
People's Republic of China
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.246245

Rights and Permissions

 » Abstract 

Background: This study investigated the clinical effects of selective dorsal root ganglion pulsed radiofrequency lesioning in combination with oral administration of gabapentin in the treatment of postherpetic neuralgia (PHN).
Material and Methods: One hundred and sixteen consecutive cases of initially diagnosed patients with PHN were randomly divided into the control and the observation groups, with each group consisting of 58 patients. The control group was treated with oral gabapentin (2400 mg/d, tid), while the observation group received gabapentin and pulsed radiofrequency lesioing of the dorsal root ganglion. The clinical efficacy of both the regimens was compared after a follow up period of 6 months.
Results: The observation group had a significantly lower score on the visual analog scale than the control group (P ≤ 0.05, with no significant complications occurring in both the groups) at a 1, 2, and 4 week posttreatment duration. The percentage of cluster of differentiation (CD) 4+ cells and the CD4+/CD8+ ratio increased gradually, while the percentage of CD8 + cells decreased in the observation group (P ≤ 0.05). No significant alterations were observed in the control group (P > 0.05). The observation group had significantly lower serum interleukin-6, C-reactive protein, and tumor necrosis factor-α levels than the control group (P < 0.05) at 1, 2, and 4 weeks after the treatment was instituted. The observation group also demonstrated a superior total effective rate and efficiency than the control group (P ≤ 0.05).
Conclusion: Our study demonstrated that radiofrequency combined with gabapentin in the treatment of PHN has a good safety and efficacy profile. The effects of this treatment may be related to an increased T-cell immunity and an inhibited inflammatory response.

Keywords: Gabapentin, inflammatory response, pulsed radiofrequency, postherpetic neuralgia, T-cell immunity
Key Message: Selective dorsal root ganglion pulsed radiofrequency lesioning uses low-frequency pulse currents to inhibit nerve impulse conduction, thus alleviating the pain or controlling its intensity. On utilizing a tandem treatment of radiofrequency lesioning of dorsal root ganglion and gabapentin for the treatment of post-herpetic neuralgia (PHN), an efficacious response was obtained with a good safety profile. The beneficial effects of this treatment may be related to an increased T-cell immunity and an inhibited inflammatory response.

How to cite this article:
Huang Y, Luo F, He X. Clinical observations on selective dorsal root ganglion pulsed radiofrequency lesioning combined with gabapentin in the treatment of postherpetic neuralgia. Neurol India 2018;66:1706-10

How to cite this URL:
Huang Y, Luo F, He X. Clinical observations on selective dorsal root ganglion pulsed radiofrequency lesioning combined with gabapentin in the treatment of postherpetic neuralgia. Neurol India [serial online] 2018 [cited 2022 May 26];66:1706-10. Available from: https://www.neurologyindia.com/text.asp?2018/66/6/1706/246245

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).[1] 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.[2] 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.[3] 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.[4] 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.[5] Selective dorsal root ganglion pulsed radiofrequency uses low-frequency pulse currents to inhibit nerve impulse conduction, thus relieving and controlling the pain.[6] 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.

 » Materials and Methods Top

Patient data

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.

Treatment methodology

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.

Observation indices

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.

Statistical analysis

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.

 » Results Top

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.
Table 1: Pain visual analog scale (VAS) and complications in the control and observation groups

Click here to view

Immune index

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].
Table 2: Immune index

Click here to view

Inflammatory indices

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].
Table 3: Inflammatory indices

Click here to view

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].
Table 4: Total effective rate [case (%)]

Click here to view

 » Discussion Top

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.[7] 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.[8] The surface sensory nerve injury often shows bilateral asymmetry, with the motor nerves in corresponding segments of the spinal cord being involved.[9] Skin biopsies suggest an abnormal increase in the levels of the nociceptive marker, calcitonin gene-related peptide, in sensory neurons.[10] 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.[11]

Gabapentin is a relatively newer antiepileptic drug, which has achieved relatively good clinical results in the treatment of PHN.[12] 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[13] 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.[14] Kim et al.,[15] 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[16] 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.[17] 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.[18] 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.[19] 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.[20],[21] Neuropathic glycine transporter (GlyT2) inhibitors acting on the spinal cord can significantly reduce the intensity of acute and chronic herpes zoster neuralgia.[22] Intrathecal injection of galectin-3 antibody to the galectin-3 knockout mice can also significantly reduce the incidence of PHN.[23]

 » Conclusion Top

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.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

Cui JZ, Zhang XB, Zhu P, Zhao ZB, Geng ZS, Zhang YH, et al. Effect of repetitive intracutaneous injections with local anesthetics and steroids for acute thoracic herpes zoster and incidence of postherpetic neuralgia. Pain Med 2017;18:1566-72.  Back to cited text no. 1
Hadley GR, Gayle JA, Ripoll J, Jones MR, Argoff CE, Kaye RJ, et al. Post-herpetic neuralgia: A review. Curr Pain Headache Rep 2016;20:17.  Back to cited text no. 2
Ortiz-Covarrubias A. Measurement of the burden, resources use and health costs associated with herpes zoster and post-herpetic neuralgia in Mexico. Master study. Value Health 2015;18:A870.  Back to cited text no. 3
Lee EG, Lee HJ, Hyun DJ, Min K, Kim DH, Yoon MS. Efficacy of low dose gabapentin in acute herpes zoster for preventing postherpetic neuralgia: A prospective controlled study. Dermatol Ther 2016;29:184-90.  Back to cited text no. 4
Thomas BM, Farquhar-Smith P. Gabapentin enacarbil extended release for the treatment of postherpetic neuralgia in adults. Ther Clin Risk Manag 2013;9:469-75.  Back to cited text no. 5
Dworkin RH, O'Connor AB, Kent J, Mackey SC, Raja SN, Stacey BR, et al. Interventional management of neuropathic pain: NeuPSIG recommendations. Pain 2013;154:2249-61.  Back to cited text no. 6
Gershon AA, Gershon MD, Breuer J, Levin MJ, Oaklander AL, Griffiths PD. Advances in the understanding of the pathogenesis and epidemiology of herpes zoster. J Clin Virol 2010;48:S2-7.  Back to cited text no. 7
Opstelten W, McElhaney J, Weinberger B, Oaklander AL, Johnson RW. The impact of varicella zoster virus: Chronic pain. J Clin Virol 2010;48:S8-13.  Back to cited text no. 8
Truini A, Galeotti F, Haanpaa M, Zucchi R, Albanesi A, Biasiotta A, et al. Pathophysiology of pain in postherpetic neuralgia: A clinical and neurophysiological study. Pain 2008;140:405-10.  Back to cited text no. 9
Guedon JM, Yee MB, Zhang M, Harvey SA, Goins WF, Kinchington PR. Neuronal changes induced by varicella zoster virus in a rat model of postherpetic neuralgia. Virology 2015;482:167-80.  Back to cited text no. 10
Kinchington PR, Goins WF. Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models. J Neurovirol 2011;17:590-9.  Back to cited text no. 11
Meng FY, Zhang LC, Liu Y, Pan LH, Zhu M, Li CL, et al. Efficacy and safety of gabapentin for treatment of postherpetic neuralgia: A meta-analysis of randomized controlled trials. Minerva Anestesiol 2014;80:556-67.  Back to cited text no. 12
Kanodia SK, Seth AK, Dixit AM. Dose related efficacy of gabapentin in acute herpetic neuralgia among geriatric patients. Indian J Dermatol 2012;57:362-5.  Back to cited text no. 13
[PUBMED]  [Full text]  
Rauck RL, Irving GA, Wallace MS, Vanhove GF, Sweeney M. Once-daily gastroretentive gabapentin for postherpetic neuralgia: Integrated efficacy, time to onset of pain relief and safety analyses of data from two phase 3, multicenter, randomized, double-blind, placebo-controlled studies. J Pain Symptom Manage 2013;46:219-28.  Back to cited text no. 14
Kim YH, Lee CJ, Lee SC, Huh J, Nahm FS, Kim HZ, et al. Effect of pulsed radiofrequency for postherpetic neuralgia. Acta Anaesthesiol Scand 2008;52:1140-3.  Back to cited text no. 15
Nicholas HL, Chua KC, Vissers ME. Pulsed radiofrequency treatment in interventional pain management: Mechanisms and potential indications—a review. Acta Neurochir 2011;153:763-71.  Back to cited text no. 16
Protasoni M, Requzzoni M, Sanqiorqi S, Reverberi C, Borsani E, Rodella LF, et al. Pulsed radiofrequency effects on the lumbar ganglion of the rat dorsal root: A morphological light and transmission electron microscopy study at acute stage. Eur Spine J 2009;18:473-8.  Back to cited text no. 17
Bhandage S, Kurki M, Hosur V, Sukhija P, Bajoria A. A little-known relationship between immune recovery syndrome and herpes zoster. J Korean Assoc Oral Maxillofac Surg 2016;42:169-72.  Back to cited text no. 18
Shirane R, Tang H, Hayashi K, Okuno Y, Iso H, Asada H, et al. Relationship between cell-mediated immunity to Varicella-Zoster virus and aging in subjects from the community-based Shozu Herpes Zoster study. J Med Virol 2017;89:313-7.  Back to cited text no. 19
Nishikawa Y, Sasaki A, Kuraishi Y. Blockade of glycine transporter (GlyT) 2, but not GlyT1, ameliorates dynamic and static mechanical allodynia in mice with herpetic or postherpetic pain. J Pharmacol Sci 2010;112:352-60.  Back to cited text no. 20
Kuraishi Y. A memoir of my research on pain and analgesia for 39 years. Yakugaku Zasshi 2014;134:1125-42.  Back to cited text no. 21
Wallace MS, Rowbotham MC, Katz NP, Dworkin RH, Dotson RM, Galer BS, et al. A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology 2002;59:1694-700.  Back to cited text no. 22
Takasaki I, Taniguchi K, Komatsu F, Sasaki A, Andoh T, Nojima H, et al. Contribution of spinal galectin-3 to acute herpetic allodynia in mice. Pain 2012;153:585-92.  Back to cited text no. 23


  [Table 1], [Table 2], [Table 3], [Table 4]

This article has been cited by
1 Safety of Conventional and Pulsed Radiofrequency Lesions of the Dorsal Root Entry Zone Complex (DREZC) for Interventional Pain Management: A Systematic Review
Mila Pastrak, Ognjen Visnjevac, Tanja Visnjevac, Frederick Ma, Alaa Abd-Elsayed
Pain and Therapy. 2022;
[Pubmed] | [DOI]


Print this article  Email this article
Online since 20th March '04
Published by Wolters Kluwer - Medknow