|Year : 2019 | Volume
| Issue : 4 | Page : 197-203
Comparative efficacy and safety of clonazepam versus nortriptyline in restless leg syndrome among forty plus women: A prospective, open-label randomized study
Roshi1, Vishal R. Tandon1, Annil Mahajan2, Sudhaa Sharma3, Vijay Khajuria1
1 Department of Pharmacology and Therapeutic, Government Medical College, Jammu, Jammu and Kashmir, India
2 Department of General Medicine, Government Medical College, Jammu, Jammu and Kashmir, India
3 Department of Obstetrics and Gynecology, Government Medical College, Jammu, Jammu and Kashmir, India
|Date of Web Publication||26-Dec-2019|
Dr. Annil Mahajan
Department of General Medicine, Government Medical College, Jammu - 180 001, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aims and Objectives: The aim of this study is to compare the effect of clonazepam and nortriptyline on rate, frequency, and severity of restless leg syndrome (RLS) in above 40 years women suffering from RLS. Materials and Methods: A prospective, randomized, open-label comparative study was conducted at a tertiary care teaching hospital for 1 year. Restless legs syndrome (RLS) diagnosis was based on four essential clinical criteria established by the International RLS Study Group in 2003. Patients were randomized into two groups. Group 1 received tablet clonazepam 0.5 mg bedtime orally daily. Group 2 received tablet nortriptyline 25 mg bedtime orally daily. The primary efficacy endpoints by the International Restless leg Syndrome Scale (IRLS) were evaluated at 0, 4, and 8 weeks. Adverse drug events and safety assessment for vital signs such as blood pressure, pulse, heart rate, waist circumference, and body mass index were compared between two groups. Results: Effect on mean IRLSS was statistically more in clonazepam group in comparison to nortriptyline group with comparable results at 8 weeks (P < 0.001), but at 4 weeks, nortriptyline showed less improvement (P < 0.01) versus P < 0.001 in nortriptyline group. Thus, nortriptyline reported relatively more improvement on IRLSS numerically in comparison to clonazepam. Nortriptyline proved to be statistically better in improving the frequency of RLS with comparison to clonazepam, whereas the results were comparable with regard to rate and the severity of RLS. Both the groups were relatively safe and did not produce any change in biochemical parameters and were free from any serious or severe adverse events and overall, both the treatments were well tolerated. Conclusion: Both the drugs provided clinically and statistical significant effect on RLS when compared with their respective baselines. However, nortriptyline proved to be statistically better in improving the frequency of RLS in comparison to clonazepam, whereas the results were comparable with regard to rate and the severity of RLS on intergroup comparison. Both the drugs were well tolerated.
Keywords: Plus forty age, restless leg syndrome, treatment drugs, women
|How to cite this article:|
Roshi, Tandon VR, Mahajan A, Sharma S, Khajuria V. Comparative efficacy and safety of clonazepam versus nortriptyline in restless leg syndrome among forty plus women: A prospective, open-label randomized study. J Mid-life Health 2019;10:197-203
|How to cite this URL:|
Roshi, Tandon VR, Mahajan A, Sharma S, Khajuria V. Comparative efficacy and safety of clonazepam versus nortriptyline in restless leg syndrome among forty plus women: A prospective, open-label randomized study. J Mid-life Health [serial online] 2019 [cited 2022 Aug 15];10:197-203. Available from: https://www.jmidlifehealth.org/text.asp?2019/10/4/197/274010
| Introduction|| |
Restless Leg Syndrome (RLS) is a multifactorial neurological disorder defined by unpleasant leg sensations and an urge to move the legs. The International RLS Study Group has published minimal diagnostic criteria to facilitate a standardized diagnosis of this disorder purely based on symptom based.,
The mechanisms causing RLS are not fully understood. However, a dysfunction of the dopaminergic system, iron deficiency, and genetic predisposition have been postulated to be responsible for RLS., It may also be secondary to some of the causes such as pregnancy, neurologic, rheumatologic, or renal diseases, but more than 60% of cases are idiopathic in nature.,
RLS may begin at any age, but most individuals suffering are over 40 years. Some studies have shown that RLS increases with age. Majority of epidemiological studies have reported a higher prevalence of RLS among women than in men.,
Further, women are at 40% increased risk for developing insomnia compared to men resulting due to RLS. Comorbid conditions such as insomnia, excessive sleepiness, and depressive and/or anxiety symptoms have been consistently associated with RLS. Several other medical conditions have also been reported to be associated with RLS, for example, cardiovascular diseases, hypertension, diabetes, obesity along with high cholesterol, and nonspecific pain.,,,
This increase in prevalence, after the menopause may be related to metabolic and hormonal changes. Since RLS has been suggested to have linkage with all these health issues, thus, it becomes important to study the problem of RLS in this vulnerable population, i.e., plus 40 years women.
Similarly, numerous epidemiological and population-based studies exist establishing relationship between anxiety disorders and RLS, thereby suggesting role of benzodiazepines and anti-depressants in the successful and conclusive treatment of RLS. The dopamine agonists (levodopa, ropinirole, pramipexole) are considered as the first-line therapy for the treatment of moderate-to-severe RLS. Other treatment options available for RLS as per different studies are iron supplementation, opioids (tramadol, methodone), antiepileptic agents (gabapentin, carbamazepine, lamotrigine, valproate, and pregabalin), antidepressants and benzodiazepines.
Although a voluminous literature of studies is available evaluating the role of benzodiazipines (clonazepam), and antidepressant (nortriptyline),, in the treatment of RLS, to the best of our knowledge no comparative study is available comparing both of these drugs for efficacy and safety for the treatment of RLS among plus 40 years of women. Hence, the current prospective, randomized, open-label study was undertaken.
| Materials and Methods|| |
A prospective, randomized, open-label comparative study was conducted at a tertiary care teaching hospital for 1 year. The study protocol was approved by the Institutional Ethics Committee. A written informed consent was obtained from the patients fulfilling inclusion, exclusion criteria after explaining nature and purpose of the study. All principles of bioethics were followed.
- Women with any menstrual status
- Age more than 40 years and <65 years
- Legitimate consent
- Any uncomplicated comorbid condition.
- Complicated comorbid conditions
- Primary psychiatric disorder
- Allergy and intolerance to research drugs
- History of any substance dependence or abuse
- Neurological disorders
- Hypotensive akathisia
- Peripheral vascular disease/vascular claudication
- Chronic pain syndrome (lumbar and cervical)
- Sleep-related disorders
- Patients having arthritis, fibromyalgia, and varicose veins
- Patients who are on clonazepam or nortriptylinefor the last 4 weeks or more.
The restless leg syndrome was diagnosed as
RLS is a neurological sensorimotor disorder that is diagnosed based on four essential clinical criteria that were established by the International RLS Study Group in 2003.
Clinical evaluation with complete medical history, general physical and systemic examination with baseline laboratory investigations and any specialized investigation required to establish inclusion and exclusion criteria of the study was undertaken. Duration of the study was 8 weeks. Patients meeting eligibility criteria at the screening visit were randomized (by block permutation method) in 1:1 ratio into two groups to receive either clonazepam or nortriptyline.
Both the treatment arms were allowed to continue with the prescribed medicine for uncomplicated comorbid conditions.
Group 1 received tablet clonazepam 0.5 mg bed time orally daily.
Group 2 received tablet nortriptyline 25 mg bed time orally daily.
Primary end points
The primary end points efficacy evaluation was carried out at 0, 4, and 8 weeks. Assessment was carried out by the International RLS Scale. Frequency rate and severity of RLS were also compared.
Secondary end points
Secondary endpoints was monitoring of adverse drug events and safety assessment for vital signs such as blood pressure, pulse, heart rate, waist circumference, and body mass index (BMI).
International Restless Leg Syndrome Study Group rating scale (IRLSS)
The scale is developed by the International RLS Study Group. This is a pre validated and pre tested scale. This is a subjective scale assessing primary features of RLS, intensity and frequency, associated sleep problems. It has ten questions scaling from 0 to 4 with total score of 40. Scoring criteria is mild (score 1–10); moderate (score 11–20); severe (score 21–30); and very severe (score 31–40).
| Results|| |
A total of 120 patients were selected after applying the inclusion and exclusion criteria. These patients were randomized into two groups of 60 patients each. All the patients completed their follow-up in clonazepam group whereas in nortriptyline group one patient lost to follow-up without any related reason.
The baseline characteristics of the patients are shown in [Table 1], [Figure 1] and [Figure 2]. Mean age in clonazepam group was 50.35 ± 8.84 years, whereas in nortriptyline group, it was 49.42 ± 9.43 years. Urban versus rural population in clonazepam group was in the ratio of 1:1, whereas in nortriptyline group, it was 0.93:1. In clonazepam group, 39 patients (65%) were postmenopausal of which 28 patients (71.7%) had natural menopause. Mean age since menopause was 45 ± 4.06 years and mean number of years since menopause was 9.18 ± 7.59 years. In nortriptyline group, 31 patients (51.6%) were postmenopausal of which 23 patients (74.19%) had natural menopause. Mean age at menopause was 46.81 ± 4.98 years and mean number of years since menopause was 8.42 ± 7.08 years [Table 1] and [Figure 1], [Figure 2], [Figure 3], [Figure 4]. Only 28 patients (46.7%) in clonazepam group were taking calcium and Vitamin D, whereas in nortriptyline group, 29 patients (48.3%) were taking it [Table 1].
|Table 1: Demographic profile of patients in clonazepam and nortriptyline Group|
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|Figure 3: Showing comparative effect of clonazepam vs nortryptiline on mean international restless leg syndrome score|
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|Figure 4: Showing comparative effect of clonazepam vs nortryptiline on mean frequency of restless leg syndrome|
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Most common comorbidities associated in clonazepam group were hypertension in 9 patients (36%), followed by hypothyroidism gastritis and headache. In nortriptyline group, 13 patients had hypertension (46.4%) followed by gastritis and others.
Mean IRLSS in clonazepam group was 20.32 ± 8.44 at 0 week, 16.62 ± 8.5 at 4 weeks, and 13.68 ± 7.65 at 8 weeks and the difference was statistically significant in comparison to baseline P < 0.001 at 4 and 8 weeks. In nortriptyline group, the mean score was 21.78 ± 8.84 at 0 week, 17.66 ± 8.29 at 4 weeks and 14.36 ± 7.84 at 8 weeks and the difference was statistically significant with P < 0.01 at 4 weeks and P < 0.001 at 8 weeks. Difference between respective baselines of both the groups was statistically insignificant at 4 and 8 weeks [Table 2].
|Table 2: Comparative effect of clonazepam versus nortriptyline on mean international restless leg syndrome score|
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In clonazepam group, 31 patients (51.7%) had very severe rate of RLS at 0 week followed by severe, moderate, and mild, at 4 weeks, 22 patients (36.6%) had severe rate followed by moderate and mild, at 8 weeks, 24 patients (40%) had mild rate followed by moderate and severe. In nortryptiline group, 25 patients (41.6%) had very severe rate at 0 week followed by severe, 24 patients (40.7%) had severe rate and at 8 weeks, 32 patients (54.2%) had mild rate of RLS. In clonazepam group, which recorded 51.7% of the population with severe rate of RLS at 0 week left with 3.3% of the population at the end of the study with similar severity, whereas nortryptiline group recorded 41.6% of very severe rate of RLS at the start of treatment and left with no patient with such severity at the end of study. Similarly, the mild category recorded better with an increase in number at the end of the study in comparison to enrolment at the start of therapy with nortriptyline group (54.2%) in comparison to clonazepam (40%), thereby indicating that in regard to improvement in the severity of rate of RLS, nortriptyline appears numerically better than clonazepam [Table 3].
|Table 3: Comparative effect of clonazepam versus nortriptyline on rate of restless leg syndrome|
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Frequency score of RLS in clonazepam group was 2.55 ± 1.02 at 0 week, 1.98 ± 0.97 at 4 weeks, and 1.55 ± 0.93 at 8 weeks. Similarly, in nortriptyline group, mean score at 0 week was 2.03 ± 1.02, 1.57 ± 0.85 at 4 weeks and 1.23 ± 0.70 at 8 weeks. Both the drugs showed improvement at 4 and 8 weeks from their respective baseline values with P < 0.001 in nortriptyline group. However, on comparison between two groups, nortriptyline group recorded statistically better results by decreasing the frequency of RLS in comparison to clonazepam group (P < 0.01) at 4 weeks and (P < 0.05) at 8 weeks, respectively [Table 4].
|Table 4: Comparative effect of clonazepam versus nortriptyline on mean frequency of restless leg syndrome|
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At 0 week in clonazepam group, 23 (38.3%) patients had very severe RLS followed by severe, at 4 weeks, 23 (38.3%) patients had very severe RLS followed by moderate and 8 weeks, 26 (43.3%) patients had moderate RLS. In nortriptyline group, 24 patients (40%) had very severe RLS followed by moderate, at 4 weeks, 23 patients (38.3%) had severe RLS and at 8 weeks, 28 (47.4%) patients had mild rate of RLS followed by moderate. On comparison, nortriptyline proved to be better in regard to very severe category of RLS leaving no patient in this category, whereas in clonazepam group, 5% patients were in this category at 8 weeks. Similarly, 47.4% patients in nortriptyline group in mild category and 26.7% in clonazepam group at 8 weeks. Effect was comparable in complete cessation of RLS [Table 5].
|Table 5: Comparative effect of clonazepam versus nortriptyline on severity of restless leg syndrome|
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There was no clinically significant change on laboratory parameters and any vital signs such as blood pressure, pulse, heart rate, waist circumference, and BMI in both the groups.
In clonazepam group, increased sleep (50%), followed by giddiness (30%), gastritis and constipation (10%) were the adverse events. In nortriptyline group, palpitations (33.33%) were maximum followed by giddiness, gastritis, and increased sleep (16.6%). Dry mouth and anxiety was also seen in nortriptyline group (8.3%).
| Discussion|| |
The present study has shown that antidepressant (nortriptyline) have a significant improvement of the International Restless Leg Symptom Score as well as its rate, severity, and frequency in plus 40 years women.
The results are in agreement with the number of previously reported studies.,,,,,, Watson et al., 1998 in their randomized double-blind crossover trial conducted on nondepressive patients recorded comparable and significant effect on pain relief by amitriptyline and nortriptyline in a similar fashion to our study.
Gilron I et al, 2009, 2009 in their double-blind, double dummy cross over trial, concluded that combined gabapentin and nortriptyline is more efficacious than either drug given alone for such pain thereby indicating role of nortriptyline in neuropathic pain as reported by the current study.
In a meta-analysis carried out by Chou R et al, 2009 the tricyclic antidepressants have been suggested to have better pain relieving effect than gabapentin, thereby supplementing the findings of current study.
The study of Yang C et al, 2005 identically recorded a significant improvement in periodic leg movements, a component of RLS.
In a systematic review and meta-analysis of safety, efficacy, and tolerability data from randomized controlled trials of drugs used to treat postherpetic neuralgia carried out by Edelsberg JS et al, 2011 it was established that amitriptyline, capsaicin, divalproex sodium, gabapentin, morphine, nortryptiline, pregabalin, and tramadol are helpful as was reported by nortriptyline in our study on RLS.
Similar to the results of our study, Boyle J et al, 2012 in their study established that medicines such as duloxetine, amitryptiline, pregabalin, reduced pain compared to placebo, but none was superior over the other. However, the current study was carried out in plus 40 years women who were nondiabetic.
Jaracz J et al, 2015 in a randomized control trial evaluated the effect of escitalopram and nortriptyline on painful symptoms in patients of major depression and concluded that both are equally effective in amelioration of painful physical symptoms of depression.
However, depression was out of preview of current study. Although majority of studies have reported similar results to the current study favoring role of antidepressants (nortriptyline) in various forms of neuropathic pain, only few studies which reported improvement of RLS.
Newer antidepressant drugs have been proven to be of great help in neuropathic pain. There are many evidences to support the anti-noceceptive effect of antidepressant drugs in neuropathic pain or psychogenic or somatoform disorder associated pain.,,
In any case, the findings of the current study clearly establish and endorse the findings of previous studies those going in agreement in regard to beneficial effects of nortriptyline on RLS (rate, frequency, severity, and IRLSS).
Our study showed that benzodiazepines (clonazepam) have a significant improvement of the International Restless Leg Symptom Score (IRLSS) and rate, frequency, and severity of RLS among plus 40 years women. These results are in conformity with number of studies. Court and Kase 1976 it was established that clonazepam is effective in patients resistant to carbamazepine in tic douloureux (brief paroxysm of severe pain restricted to trigeminal nerve distribution).
Subsequently, evidences were provided by Montagna et al., 1984 in a preliminary double blind study on patients of RLS that clonazepam may be effective in the treatment of RLS.
Boghen et al., 1986 in their study tried to demonstrate the effect of clonazepam on patients of RLS and concluded that it is effective in improving the symptoms of RLS but not better than placebo. The current study, however, was an open labeled comparative study.
Peled R & Lavie P, 1987 in an extended dose double-blind placebo parallel group study concluded that clonazepam (0.5–2 mg bed time) is effective in the treatment of periodic leg movements during sleep and is better than placebo.
Effect of clonazepm on periodic leg movements in patients of RLS was studied by Horiguchi et al., 1992 and it was established that clonazepam (0.5–1.5 mg) decreased the total number of leg movements and number of leg movement per hour without affecting the mean intermovement interval. However, such parameter was not studied in the current study.
Antiepileptic drugs including benzodiazepines have been established to have a beneficial effect on neuropathic pain management.
Similarly, in our study, clonazepam may have affected rate, frequency, and severity in patients of RLS by any of the above mechanism directly. Besides, the well-established sedative effect of clonazepam may also have contributed indirectly in reducing the rate, severity, frequency and other parameters of RLS in plus 40 years women. However, there are some studies available in literature which are contrary to our study.,
The possible reasons for the contradictory results reported by various studies may possibly be because of different study population, varied epidemiological profile, different nature and study design, duration of the study as well as different age and gender selection criteria's followed by various studies.
| Conclusion|| |
Both the drugs provided clinically and statistically significant effect on RLS when compared to their respective baselines. However, nortriptyline proved to be statistically better in improving the frequency of RLS in comparison to clonazepam, whereas the results were comparable with regard to rate and the severity of RLS on intergroup comparison. Both the drugs were well tolerated.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]