Management of diabetic neuropathy with memantine: A randomized clinical trial

Abstract

Background

Diabetes patients frequently experience diabetic neuropathy (DN), a microvascular complication that significantly reduces patients’ quality of life. Memantine has demonstrated potential benefits for neuropathic pains in preclinical studies. This study aimed to assess the efficacy of memantine in the management of peripheral neuropathy in patients with type 2 diabetes mellitus (T2DM).

Method

This randomized clinical trial includes 143 diabetic patients (aged between 18 and 75 years) with a confirmed diagnosis of diabetic neuropathy. Patients were randomly assigned to receive memantine 5 mg twice daily for 1 week, followed by 10 mg twice daily plus gabapentin 300 mg daily (n = 72) or just gabapentin 300 mg daily (n = 71) for 8 weeks. The DN4 questionnaire, monofilament, tuning fork, and Tip-therm tests were used to measure neuropathy at baseline and after the 8-week intervention.

Results

The mean score of the DN4 questionnaire in the memantine group was significantly lower than the control group (p. value: .001). The number of patients with diabetic neuropathy remarkably decreased in the memantine group at the end of the study based on the performed tests (p. value: .001).

Conclusion

Memantine functions as a beneficial agent in the management of diabetic neuropathy, which would significantly improve the quality of life in diabetic patients.

Introduction

Diabetic neuropathy (DN) is one of the common consequences of type 2 diabetes mellitus (T2DM), with a prevalence of 30%–50%. ¹ DN is a painful polyneuropathy divided into peripheral and autonomic neuropathy; patients may experience one or both types simultaneously.^2,3 Due to persistent discharges in diabetic changes, excitatory amino acids and neuropeptides are released from peripheral neurons in the dorsal horn, which phosphorylates of N-methyl-D-aspartate (NMDA) receptors in postsynaptic neurons. Patients with T2DM suffer from nociception as a result of these alterations. ¹

DN is associated with decreased quality of life and increased healthcare costs in patients with diabetes. ⁴

Available guidelines have recommended several agents as first-line therapy in diabetic neuropathy, which include duloxetine, γ-aminobutyric acid analogues (gabapentin and pregabalin), tricyclic antidepressants (TCAs), and venlafaxine. ⁵ However, not all patients with DN benefit from these medications. Besides, the tolerability of these drugs and their adverse effects are further concerns.

Based on recent in vivo studies, the role of NMDA receptors has been proposed in chronic pain due to nerve damage. It has been revealed that NMDA receptor antagonists decrease the severity of nerve pain. ⁶ NMDA receptors are ion channels mediated by glutamate. Glutamate is a crucial neurotransmitter that plays a role in many neurologic pathways. The level of glutamate quickly rises to 50 times normal levels in acute injuries, which results in cell death. ⁷ Although higher levels of glutamate lead to cell injury, maintaining the physiologic concentration of glutamate is essential for memory and learning processes. ⁸ Given the role of the NMDA receptor and the central sensitization caused by increased activity of this receptor in multiple neuropathic pains, it is probable that blocking NMDA receptors may decrease the severity of pain caused by nerve damage.

After first-line therapy fails, NMDA antagonists such as ketamine, amantadine, and dextromethorphan can be considered in neuropathic pains. However, these drugs failed in clinical trials due to clinical intolerance and complete NMDA blockage. For instance, adverse effects of ketamine such as sedation, hallucinations, and mood changes, have limited the clinical applicability of this drug in the management of neuropathic pain. As non-competitive antagonists of NMDA receptors, amantadine and dextromethorphan have greater adverse effects than others. ⁴

Memantine, a by-product of adamantine, is a non-competitive NMDA antagonist with the suggested mechanism of suppressing calcium currents and regulating nerve plasticity via glutamate release.^9,10 It is approved by the FDA for Alzheimer’s disease; it is also indicated for Parkinson’s disease, spasticity, convulsions, and vascular dementia. ⁴ Memantine binds to the NMDA receptor with moderate to low affinity, which results in fewer adverse effects compared to other NMDA blockers. ⁴ Memantine surpasses other NMDA antagonists in terms of having less side effects. ¹¹

Based on the available studies, memantine has beneficial effects in reducing neuropathic pains. ¹¹

This study aims to assess the efficacy of memantine as a non-competitive NMDA antagonist in the management of neuropathic pains in patients with T2DM.

Methods/design

Patient enrollment

In this randomized unblinded clinical trial, patients were collected from the diabetes clinic of Imam Reza Hospital (main educational hospital of Tabriz University of Medical Sciences, Tabriz, Iran). A total of 500 patients with T2DM and confirmed diabetic neuropathy aged between 18 and 75 were assessed for eligibility. Exclusion criteria comprise cardiovascular diseases, uncontrolled hypertension, seizures, liver or kidney failure, pregnancy or lactation, and the presence of other neuropathies.

Intervention and follow-up

Eligible participants (n=143) were randomized (by block randomization) into memantine (n=72) and control (n=71) groups. Patients in memantine group received memantine tablets 5 mg twice daily for the first week, then titrated up to 10 mg tablet twice daily for 8 weeks. Patients in both groups received gabapentin 300 mg daily.

Baseline patient demographics as well as patients’ comorbid diseases and medications were recorded.

All the participants were assessed in terms of adherence by phone call, weekly.

Outcome measures

The endpoint of the study was neuropathy evaluation in memantine and control groups after 8-week intervention. For this purpose, Douleur Neuropathies 4 (DN4), monofilament test, tuning fork, and temperature sensation tests were performed at the baseline and 8 weeks after initiation of the intervention.

• 1. Douleur Neuropathique 4 (DN4): DN4—a questionnaire for screening neuropathic pain—includes 10 questions plus physical examinations. The questions assess the severity and type of neuropathic pain [13].

• 2. Tip-therm: This device has two sides with different temperatures, both of which are touched by the patients’ feet. Patients who notice a temperature difference are considered positive, and patients who do not notice a temperature difference are considered negative [14].

• 3. Tunning fork test: This test is performed with a 128 tuning fork over the big toe and medial malleolus. Examiner hit the fork gently against the palm so that vibration could be felt for 10 to 15 seconds. Patients will be asked initially and after 5 seconds whether they perceived vibration. Patients who sensed vibration are scored as normal (positive), and patients who were unable to sense vibrations are considered abnormal (negative) [15].

• 4. Monofilament sensation test: This test is performed by Semmes—Weinstein 5.07 monofilament at points on the patients’ feet. In this method, the monofilament was applied until it bent and held for one second. Patients were asked to state the time interval during which the stimulus was felt. For each foot, the experiment is repeated twice. If the patient can feel the string in the sole, it is considered positive which means that the severity of neuropathy is lower. Moreover, the test is considered negative if the patient does not feel it [16].

Sample size

The sample size was calculated based on the DN4 score as the primary outcome. In order to make between-group comparisons, considering the difference of two points for the average DN4 score in the two groups as an important and clinically meaningful difference, and considering the standard deviation equal to three for the DN4 score obtained from the pilot study, type 1 error =0.05, power of 90%, and using the sample size formula for the independent t-test, the sample size for each group was estimated at 49 patients.

Randomization

In this study, we used a block randomization strategy for random allocation. The size of the blocks was 4. Given a block size of 4, there were six possible ways to equally assign participants to a block. Allocation was performed by randomly selecting one of the orderings and assigning the next block of participants to study groups according to the specified sequence.

Statistical analysis

The data were analyzed using SPSS (SPSS Inc., Chicago, Ilinoise, U.S.A.) version 22 software. Data were described as mean, SD for continuous variables, and number (percent) for categorical variables. Within-group comparisons for each group were done with a paired t-test, and between-group comparisons for baseline and final continuous variables were performed with an independent t-test. Categorical data were compared between two groups by the Chi-squared test. The evaluation of the final effect of the intervention on continuous outcomes by adjusting for their baseline values was done by the analysis of Covariance. P-values less than or equal to .05 were considered statistically significant.

Standard protocol approval, registration, and patients’ consent

The trial was registered in the Iranian Registry of Clinical Trials (registry number: IRCT20180404039187N5). The study protocol was approved by the local Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1398.232). All patients were informed about the trial and provided written informed consent prior to the study initiation.

Results

In this study, 500 patients were assessed for eligibility, of whom 143 were enrolled. Patients were assigned to memantine (n = 72) and the control groups (n = 71). Forty patients discontinued the study during the follow-up period. Therefore, 103 patients were analyzed (Figure 1). The baseline demographic and clinical characteristics of 103 patients are summarized in Table 1. The mean age of patients was 55.8 ± 7.4 and 54.67 ± 5.3 years in the memantine and control groups, respectively.

Figure 1.

Consort diagram of the study.

Table 1.

Baseline demographic and clinical characteristics of patients in both groups.

Parameters	Memantine (n = 49)	Control (n = 54)	p-value
Gender (female %)	35 (71.4%)	29 (53.7%)	.064
Age (year)	55.8 ± 7.4	54.67 ± 5.3	.09
Comorbidities
Renal disorders	13 (26.5%)	17 (31.5%)	.58
Hyperlipidemia	26 (53.1%)	40 (74.1%)	.03
BPH	2 (4.1%)	7 (13.1%)	.16
IHD	8 (16.1%)	20 (37%)	.02
Medications
Metformin	36 (66.7%)	44 (81.4%)	.06
Insulin	18 (33.3%)	15 (27.7%)	.8
Antihypertensive agent	49 (100%)	54 (100%)	1
Statin	49 (100%)	54 (100%)	1
Aspirin	46 (93.8)	50 (92.5%)	1

Data were described as mean ± standard deviation (SD) or number (%). BPH: benign prostatic hyperplasia; IHD: ischemic heart disease. p-value ≤ .05 is significant.

With a few exceptions, the two study groups were well-balanced for baseline parameters (p-value > .05). There was a significant difference between the groups in terms of the DN4 questionnaire score at baseline (p-value = .03), presence of ischemic heart disease (IHD) (p-value = .02), and presence of hyperlipidemia (p-value = .03). In the final analysis, data were adjusted based on gender, hyperlipidemia, IHD, and DN4 questionnaire score at baseline.

Between-group comparisons of neuropathy assessments are summarized in Table 2. The mean score in the DN4 score questionnaire at baseline was 9.1 ± 0.96 and 8.3 ± 1.34 in the memantine and control groups, respectively (p-value = .03). After the intervention and adjustment based on the baseline scores, the DN4 score was 2.68 ± 1.65 and 8.25 ± 1.8 in the memantine and control groups, respectively (p-value < .001).

Table 2.

Between-group comparison of neuropathy assessment at baseline and after 8 week intervention.

Neuropathy assessment	Memantine (n = 49)	Control (n = 54)	p-value*	p-value**
DN4 score
Pre-intervention	9.1 ± 0.96	8.3 ± 1.34	.03	<.001
Post-intervention	2.68 ± 1.65	8.25 ± 1.8	<.001
Tunning fork test
Pre-intervention	9 (18.4%)	14 (25%)	.35	<.001
Post-intervention	41 (83.7%)	12 (22.2%)	<.001
Monofilament test
Pre-intervention	7 (13%)	5 (10.2%)	.66	<.001
Post-intervention	43 (87.8%)	7 (13%)	<.001
Tiptherm test
Pre-intervention	16 (29.6%)	11 (22.4%)	.4	<.001
Post-intervention	43 (87.8%)	17 (31.5%)	<.001

Data were described as mean ± standard deviation or number (%). DN4: douleur neuropathique 4. p-value* and p-value** are represented as p-values before and after adjustment based on confounding variables, respectively. p-value ≤ .05 is significant.

At baseline, the results of the tunning fork test were positive in 18.4% and 25% of the patients in the memantine and control groups, respectively (p-value = .35). After the intervention, the results were positive in 83.7% and 22.2% of the patients in the memantine and control groups, respectively (p-value < .001). Moreover, the baseline Monofilament test was positive in 13% and 10.2% of the patients in the memantine and control groups, respectively (p-value = .66). After the intervention, 87.8% and 13% of the patients were positive for this test in the memantine and control groups, respectively (p-value < .001). At baseline, temperature discrimination was found in 29.6% and 22.4% of the patients in the memantine and control groups, respectively (p-value = .4). Overall, 87.8% and 31.5% of the patients could discriminate temperature after the intervention in the memantine and control groups, respectively (p-value < .001).

Discussion

DN is a frequent complication of diabetes, with a prevalence estimation of 6%–51%, and it is the most common type of neuropathy. ¹² Poor glucose control is the most important precipitating factor for DN in patients with diabetes. Complications of DN such as pain, foot ulceration, and amputation necessitate a safe agent for the management of DN in patients with T2DM.

Among NMDA antagonists, memantine is a promising agent that outweighs others due to its clinical tolerability and fewer adverse effects. ⁴ However, it has been assumed that only the prophylactic use of NMDA antagonists will demonstrate a neuroprotective effect. ¹³

In this study, we aimed to evaluate the effectiveness of memantine in the treatment of DN in patients with T2DM. To the best of our knowledge, this is the first study that has evaluated the efficacy of memantine in combination with gabapentin for the treatment of DN. Based on the results of our study, use of memantine significantly improved DN in patients with T2DM.

The efficacy of memantine for the prevention and treatment of neuropathic pains has been reported in various clinical studies.

In 2016, Morel et al. studied the efficacy of memantine in the prevention of post-mastectomy pain in 40 patients. ¹⁴ Patients in the intervention arm (n =20) of this pilot study received memantine 5-20 mg daily for 2 weeks prior to mastectomy surgery for a total of 4 weeks. The intensity of pain was evaluated on a numerical rating scale (0–10) 3 months after mastectomy surgery. Based on the results, memantine significantly decreased the severity of post-mastectomy pain (5% vs 30% in the placebo group) and decreased analgesic requirements in patients. ¹⁴ The mentioned study supports our idea regarding the beneficial effect of memantine in neuropathic pains; however, in our study, memantine demonstrated a beneficial effect in a prolonged period of treatment (8 weeks) compared to the mentioned study (4 weeks). Moreover, our study is focused on the treatment of neuropathic pains rather than prevention.

A randomized clinical trial was carried out on 40 female patients to evaluate the preventive effect of memantine on docetaxel-induced peripheral neuropathy in patients with breast cancer. Twenty patients received memantine 20 mg for the first eight weeks of chemotherapy, and 20 patients did not receive any medication for pain management.‏ The results of this study showed that prophylactic use of memantine was beneficial in the prevention of docetaxel-induced neuropathy. ¹⁵

Shaseb et al. carried out a randomized clinical trial to evaluate the efficacy of memantine in 16 patients with subacute herpetic neuralgia. ¹⁶ In this study, memantine (5 mg twice daily for a week and then titrated up to 10 mg twice daily) in combination with gabapentin (300 mg daily) reduced patients’ pain scores compared with patients who received just gabapentin (300 mg daily) for 8 weeks. However, six patients in the memantine group reported dizziness.

The findings of our study were inconsistent with some of the previous works. The use of memantine 10–20 mg/day for 5 weeks did not relieve post herpetic neuralgia in 24 affected patients. ¹⁷ Another study carried out by Nikolajsen et al. failed to demonstrate the nociceptive property of memantine (5–20 mg/day for 5 weeks) in reducing post-surgery or post-amputation neuropathic pain in 19 patients. ¹⁸

Controversy over the results of memantine studies in reducing neuropathic pains can be due to various reasons, including the assessment methods, sample sizes, different doses of memantine, duration of the study, and coexistence of other types of neuropathies.

In conclusion, concomitant use of memantine with gabapentin reduced the severity of diabetic neuropathy in T2DM patients.

Limitations

Due to some limitations, the results of the present study should be interpreted with caution. First, our study has a pilot nature; therefore, further studies with larger sample sizes are necessitated. Second, in this study, we tried to consider factors such as patients’ medications and comorbidities to get more accurate results; however, other confounding factors such as patients’ glycemic profile, weight, etc., could be considered in the final analysis too.

ORCID iD

Elnaz Shaseb https://orcid.org/0000-0001-7931-4632