|Year : 2018 | Volume
| Issue : 2 | Page : 63-67
Randomized study to compare the effect of pregabalin with fixed-drug combination of pregabalin and methylcobalamin in the patients of postherpetic neuralgia
Asmita Jha, Karjigi Siddalingappa, Kallappa Herakal, Karan Malhotra
Department of DVL, Navodaya Medical College Hospital and Research Centre, Raichur, Karnataka, India
|Date of Web Publication||31-Aug-2018|
Dr. Asmita Jha
Department of DVL, Navodaya Medical College Hospital and Research Centre, Raichur, Karnataka
Source of Support: None, Conflict of Interest: None
Aim: To know the effect of adding methylcobalamin to pregabalin in patients of postherpetic neuralgia (PHN) and also to compare the side effects of pregabalin alone and fixed-drug combination (FDC) of pregabalin and methylcobalamin. Materials and Methods: This was a multicenter randomized 10-month prospective study. A total of 90 patients with PHN (age and sex matched) were included. Baseline pain intensity was measured on a 10-point visual analog scale (VAS) score. Patients were randomized into two groups. Group A patients received pregabalin (75 mg) 12th hourly, whereas Group B patients were given FDC of pregabalin (75 mg) along with methylcobalamin (750 μg) 12th hourly. Thereafter, patients were assessed for the pain score at 4, 8, and 12 weeks after initiation of the treatment. The frequency and severity of adverse events were assessed. Results: Before starting medication, the average VAS score of Group A and Group B was 6.86 and 6.97, respectively. Post-medication average VAS score of Group A and Group B was found out to be 2.95 and 3.11, respectively. A significant reduction in VAS scores of both the groups was observed when compared to their respective baseline VAS scores (P < 0.001). But post-medication VAS scores of both the groups were not statistically significant (P = 0.58). Side effects such as dizziness and somnolence were observed in both the groups. This was also found out to be not statistically significant when side effects of both the groups were compared (P = 0.52). Conclusion: The result of our study shows minimal statistical difference between pregabalin alone and the FDC of pregabalin with methylcobalamin for the treatment of PHN. Patients showed improvement in pain with minimal side effects such as somnolence and dizziness in both the groups.
Keywords: Methylcobalamin, postherpetic neuralgia, pregabalin
|How to cite this article:|
Jha A, Siddalingappa K, Herakal K, Malhotra K. Randomized study to compare the effect of pregabalin with fixed-drug combination of pregabalin and methylcobalamin in the patients of postherpetic neuralgia. Indian J Pain 2018;32:63-7
|How to cite this URL:|
Jha A, Siddalingappa K, Herakal K, Malhotra K. Randomized study to compare the effect of pregabalin with fixed-drug combination of pregabalin and methylcobalamin in the patients of postherpetic neuralgia. Indian J Pain [serial online] 2018 [cited 2019 Jun 16];32:63-7. Available from: http://www.indianjpain.org/text.asp?2018/32/2/63/240278
| Introduction|| |
Herpes zoster (HZ) or shingles is a result of reactivation of the varicella-zoster virus (VZV), the same virus that causes chicken pox. After the acute varicella infection (i.e., chicken pox in childhood), the virus lies dormant for decades in sensory nerve ganglia, usually involving the lumbar, thoracic, and trigeminal ganglia. HZ results when dormant VZV in these nerves is reactivated, possibly secondary to a decline in specific cell-mediated immunity to VZV with aging and/or immunosuppression. The majority of cases of HZ are seen in older adults with incidence increasing sharply at around 50 years of age and doubling by the age of 80 years., Neither gender, race, nor ethnicity appear to be risk factors for HZ. It is estimated that 5%–20% of those with HZ go on to develop postherpetic neuralgia (PHN).
PHN is defined in the literature as the pain that persists for more than 1–6 months after rash resolution.,, PHN pain is often severe, unrelenting, and exhausting. Patients may develop insomnia, weight loss, chronic fatigue, and an inability to perform daily activities.
Successful management of PHN can be complicated and challenging as no definitive treatment algorithm is available for patients with PHN. In recent years, a number of published guidelines have been proposed for the treatment of neuropathic pain in general.,, These recommendations are essentially based on the evidence of efficacy from randomized controlled trials of pharmacologic therapies; there is a lack of clinical trials directly comparing efficacy and safety of one pharmacotherapy versus another. These guidelines uniformly recommend tricyclic antidepressants (TCAs) and anticonvulsants as first-line therapeutic options for treating neuropathic pain.
Pregabalin has been used as the first-line management for PHN. Pregabalin has efficacy similar to that of TCA but poses lower risk of serious side effects. Methylcobalamin has also been tried to treat PHN. But limited published data are available on the fixed-drug combination (FDC) of pregabalin and methylcobalamin in immediate-release or as a sustained-release formulation.
| Materials and Methods|| |
A total of 90 immunocompetent patients with PHN were included in our study, comparing pregabalin alone and pregabalin with methylcobalamin for the treatment of PHN.
Inclusion criteria included patients aged 40 years and above, patients with pain present for more than 3 months after healing of the zoster rash, patients not on treatment for any other ailment, and patients willing to participate in the study.
Exclusion criteria included hypersensitivity to gabapentinoids, other causes of neuropathy, systemic disease including hepatic or renal system, and smoking or alcohol abuse.
Patients who gave the informed and written consent underwent a routine physical and hematological examination. Their baseline pain scores (visual analog scale [VAS] score) were noted down. They were then randomly divided into two groups: Group A and Group B with 45 cases in each group. Group A was treated with pregabalin (75 mg) twice a day and Group B was given pregabalin (75 mg) twice a day along with methylcobalamin (750 μg).
Patients were assessed at 4, 8, and 12 weeks after starting the medication. At each visit, they were assessed for the improvement in pain (with the help of VAS score) and adverse events. At the 12th week, they underwent a routine physical and hematological examination.
Pain was assessed subjectively on the basis of VAS. A VAS is a measurement instrument, which tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. It is used in epidemiologic and clinical research to measure the intensity or frequency of various symptoms such as pain. It is a straight horizontal line measuring 10 cm. Oriented from left (worst) to the right (best), the patients were asked to mark the point that they feel represents their perception of current state. Using a ruler, the score is determined by measuring the distance (in millimeters) on the 10-cm line between the “no pain” anchor and the patient's mark, providing a range of scores from 0–100. A higher score indicates greater pain intensity. On the basis of distribution of pain VAS scores in postsurgical patients who described their postoperative pain intensity as none, mild, moderate, or severe, the following cut points on the pain VAS scores have been recommended: no pain (0–4 mm), mild pain (5–44 mm), moderate pain (45–74 mm), and severe pain (75–100 mm).
| Statistical Analysis|| |
Results on continuous measurements were presented as mean ± standard deviation and results on categorical measurements were presented as number (percentage). Student's t-test (two tailed, independent) was used to find the significance of study parameters on continuous scale between two groups and Chi-square/Fisher's exact test was used to find the significance of study parameters on categorical scale between two or more groups.
The statistical software namely (GraphPad Software (2016), California, US) was used for the analysis of the data and (Microsoft Word and Excel (2013), India) were used to generate graphs, tables, and so on. The data obtained in this study were analyzed using unpaired t-test, which gives a P value. A P value <0.05 was considered as statistically significant.
| Results|| |
No statistically significant differences were observed in the distribution of sex and age between both the treatment groups [Table 1]. Similarly, no statistically significant differences were reported in the duration of PHN in both the groups [Table 2].
No statistical difference was found in the baseline pain score of both the groups (P = 0.73) [Table 3] [Figure 1].
A significant reduction was observed in VAS score of both the groups when compared to their respective baseline VAS scores (P < 0.001).
However, post-medication VAS scores of both the groups were not statistically significant (P = 0.58).
Side effects were seen in both the groups [Figure 2], but no statistically significant difference was observed in both the groups (P = 0.52) [Table 4].
| Discussion|| |
PHN is a complex neuropathic pain condition in which the pain is the direct consequence of the response to peripheral nerve damage sustained during the HZ attack. The risk factors are advancing age, severe prodromal pain, severe pain during the active attack, severe rash, and immunosuppression.
Pain is the major symptom of HZ, and pain resolves spontaneously in most of the patients. But in 10%–15% of patients, there is pain that persists after the characteristic rash disappears. In some patients, this pain might continue for years. PHN is often characterized by a combination of throbbing or burning pain, intermittent sharp pains, and altered sensory perception, including paresthesia and allodynia.
The pathophysiology of pain is considered to be injury to the dorsal root ganglia and dorsal horn as well as injury to the peripheral nerves. Presence of pain before rash eruption, rash severity, and inflammation and fever are all thought to have an effect on PHN severity.
It is estimated that more than 50% of patients with PHN have sleep disturbances and about 25% report a decrease in socialization. Eventually, it was found that the patients with PHN have depression.
Pregabalin is a structural analog of gamma-aminobutyric acid. It acts by presynaptic binding to the α-2-λ subunit of voltage-gated calcium channels that are widely distributed in spinal cord and brain. This mechanism leads to the inhibition of excitatory neurotransmitters (glutamate, substance P, and calcitonin) release. Pregabalin has a better fat solubility and more favorable transmission in blood–brain barrier when compared to gabapentin. It also has a better pharmacokinetic property; less hepatic metabolism lowers the drug interaction chances. It is considered as one of the first-line drugs for the treatment of neuropathic pain. Reported evidence suggests that pregabalin is effective for both central and peripheral neuropathic pain and that it achieves rapid pain reduction. Pain reduction can be achieved as early as the 1st week after initiating the treatment with improvement that is dose related from 150 to 600 mg/day. Pregabalin has also been shown to have a beneficial effect on sleep and mood disturbances.
The common side effects observed with pregabalin are somnolence, dizziness, edema, dry mouth, blurred vision, weight gain, and difficulty in concentrating.
Methylcobalamin is an essential element in the synthesis of the myelin sheath and in the maintenance of nerve function. The myelin sheath provides insulation to the nerve and aids in the proper and rapid conduction of impulses along the nerve. Methylcobalamin has an important role in the regeneration of myelin sheath and helps to restore the function of the nerve in neuropathy. According to few studies, patients with PHN had a low level of vitamin B12 along with few other vitamins, and also the reduced level increased the risk of neuralgia.
A few limited published data are available on the FDC of pregabalin and methylcobalamin as immediate-release or sustained-release formulation. The objective of this study was to see if there is any advantage of adding methylcobalamin to pregabalin in the patients of PHN.
In our study, it was found that there was a significant reduction in pain score in both the groups. Side effects were also seen in both the groups. Various studies have been carried out showing the efficacy of pregabalin in PHN and other neuropathic pains.
In a study conducted by Dongre and Swamy, it was shown that FDC of sustained-release pregabalin (75–150 mg) and methylcobalamin (1200 μg) reduced the neuropathic pain by VAS score of 72.3% with few side effects such as giddiness, sedation, dizziness, drowsiness, and nausea.
According to Goodman and Brett, gabapentinoids are just an alternative to opioids to relieve pain.
Another study conducted by Caram-Salas and Reyes-García showed that the use of cyanocobalamin (0.75–6 mg/kg) with dexamethasone (32 mg/kg) reduced the intensity of allodynia to 68%.
A case control study conducted in Taiwan showed a significant reduction in vitamin B12, vitamin C, zinc, and calcium in patients with PHN, and supplementing the patients with these helped in pain reduction.
However, there is a scarcity of clinical data on the efficacy and safety of these FDCs of pregabalin and methylcobalamin. The previously published PRECISE (PREgabalin Combination In Several Endpoints) study reported that a FDC of pregabalin immediate release and methylcobalamin was effective and well tolerated in Indian patients with various neuropathies and orthopedic conditions. In a recently published report, Prabhoo et al. reported the efficacy and tolerability of the FDC of pregabalin and methylcobalamin in neuropathic pain.
| Conclusion|| |
The result of our study shows minimal statistical difference between the combination of pregabalin with methylcobalamin and pregabalin alone for the treatment of PHN. Patients showed improvement in pain with minimal side effects such as somnolence and dizziness in both the groups.
The limitation of our study was the small sample size and the need to be further evaluated with a larger study group.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]