Pregabalin in the Treatment of Peripheral and Central Chronic Neuropathic Pain

Abstract

Background:

Pregabalin is a first-line therapy of pain with additional positive effects on the states of depression and anxiety that often occur in patients with chronic pain, thus improving their quality of life.

Objective:

The aim of this study was to demonstrate the efficacy of pregabalin in reducing neuropathic pain and improving quality of life in patients with peripheral and central chronic neuropathic pain in Bosnia and Herzegovina. Also, the aim was to monitor the safety of therapy with pregabalin.

Methods:

The study included patients with neuropathic pain lasting more than 3 months. Based on the underlying disease, patients were divided into 5 groups: DM–patients with diabetes mellitus, M–patients after stroke, D–patients with lower back pain, MS–patients with multiple sclerosis, and P group–patients with spinal cord injury. During the baseline visit, the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) was used to assess neuropathic pain. During two follow-up visits (1.5 and 3 months after baseline), the 36-Item Short-Form Health Survey (SF 36) was used to assess the effectiveness of therapy on quality of life. The safety of the treatment was evaluated by monitoring the incidence of adverse drug reactions.

Results:

The study included 125 patients. During treatment with pregabalin, there was a statistically significant reduction in pain intensity in the DM, M, D and MS groups. In group P, the decrease in pain intensity was not statistically significant (p = 0.070). There was a significant improvement in different parameters of the quality of life in all analyzed groups, with the most prominent effects in the DM group. The effectiveness of treatment was rated as “good” and “very good” in more than 70% of subjects in each group. The expected side effects of treatment were recorded in 27.1% of patients in the DM group, in 20.0% in the M group and in 22.2% in the MS group. Unexpected side effects of treatment were observed in one patient (2.1%) in the DM group. Assessment of tolerability of the applied treatment showed “good” and “very good” response in 68.7% of patients in DM group, 73.3% in M group, 74.5% in D group, 88.9% in MS group and 85.8% in P group.

Conclusion:

Pregabalin is a safe and effective drug in treatment of neuropathic pain of different etiology.

1. BACKGROUND

According to the widely accepted definition given by the International Association for the Study of Pain (IASP), pain is an unpleasant sensory and emotional experience associated with, or resembling that it is associated with, actual or potential tissue damage (1). The basic biological role of pain is to protect the organism from further damage, and this protective mechanism is the strongest immediately after the injury, it lasts for a while, and then, with the healing, it stops. As neuropathic pain is the result of a change in the functioning, chemistry or structure of nerve cells, its purpose is to alert the body to the condition due to which it is present. The first description of neuropathic pain in medical literature was given by Ambroise Paré (1510–1590). Causes of peripheral neuropathic pain are diabetes mellitus, herpes zoster infection, radiculopathy, paraneoplastic syndrome, chemotherapy, limb amputations, alcohol consumption, HIV, and trauma. Examples of central neuropathic pain are poststroke pain, multiple sclerosis, Parkinson’s disease, spinal cord injury pain, and syringomyelia (2,3,4). The most common forms of neuropathic pain are diabetic polyneuropathy, postherpetic neuralgia, trigeminal neuralgia, neuropathic pain in patients who experienced stroke or in patients with multiple sclerosis, pain due to spinal cord injury, and pain after surgery. In Europe, the prevalence of chronic pain in the general population ranges from 32% to 48%, while the prevalence of chronic pain with a predominantly neuropathic component is between 7% and 8% (5). The prevalence of patients with lower back pain is 9.4%, of which as many as 37% develop neuropathic pain of central origin (4). Central neuropathic pain often affects patients after cerebrovascular insult. It is estimated that about 3% of the world’s population survives a stroke, of which 8% develop central neuropathic pain (5). According to research by Osterberg et al. central pain has 23.6%, nociceptive pain in 20.9%, trigeminal neuralgia 4.9% and spasticity pain in 1% of patients with multiple sclerosis. Unlike nociceptive pain, which is stabbing and sharp in nature, neuropathic pain is mostly spontaneous (painful symptoms are not caused by stimuli), burning, radiating–pain like an electric shock or a needle prick (2,7,8). Neuropathic pain is also an evoked pain (caused by stimuli, sensory hypersensitivity). Evoked pain includes mechanical hypersensitivity (mechanical allodynia) and hypersensitivity to heat and cold (thermal allodynia) (2).

It is estimated that in Bosnia and Herzegovina about 7 – 8% of the total population suffers from various forms of neuropathic pain, with peripheral or central etiology (over 250,000 people) (2). An epidemiological study of multiple sclerosis, disease associated with significant neuropathic pain, in the Federation of Bosnia and Herzegovina, published in 2002, showed a prevalence of 27.3 / 100,000 inhabitants (6). Neuropathic pain has a proven negative effect on the quality of life, physical functioning, and emotional state of the patient. Also, it is the cause of increasing existing and generating new significant costs in the community (3,9,10). Neuropathic pain is insufficiently diagnosed in primary and secondary health care, which is the reason why patients are often not treated (2). Also, very often patients are prescribed inadequate therapy (analgesics, nonsteroidal antirheumatic drugs). In the treatment of neuropathic pain, pharmacotherapy is the “gold standard” (2). According to the European Federation of Neurological Societies (EFNS) guidelines for the treatment of neuropathic pain, pregabalin is recommended for first-line treatment (11, 12). In addition to its effect on pain, pregabalin also has a positive effect on the state of depression and anxiety that often occurs in patients with chronic pain, thus improving their quality of life (12).

In Bosnia and Herzegovina no previous studies were conducted to evaluate efficacy of pregabalin in reducing neuropathic pain.

2. OBJECTIVE

The aim of this study was to demonstrate the efficacy of pregabalin in reducing neuropathic pain and improving quality of life in patients with peripheral and central chronic neuropathic pain in Bosnia and Herzegovina. Also, the aim was to monitor the safety of therapy with pregabalin.

3. PATIENTS AND METHODS

The study was designed as an observational, non-interventional cohort study to analyze the efficacy and tolerability of pregabalin in the treatment of peripheral and central chronic neuropathic pain. The study was conducted at 13 investigational centers in Bosnia and Herzegovina.

Participants

The study included patients of both genders, aged 18 to 65 years, who met the inclusion criteria: neuropathic pain lasting more than 3 months (chronic neuropathic pain), patients not receiving other therapies for neuropathic pain, and patients who were on stable therapy of the underlying disease/injury (diabetes mellitus, post-stroke condition, dorsalgia, multiple sclerosis, spinal cord injury). Patients who showed hypersensitivity to the components of the drug, patients with impaired renal function, patients using antiepileptics, patients using pregabalin due to other indications/comorbidities (epilepsy, generalized anxiety disorder), as well as pregnant and lactating women, were not included in the study. Withdrawal criteria were: worsening of the underlying disease, serious side effects requiring discontinuation of study therapy, a disease requiring hospitalization for the duration of the study, use of drugs that may mask the study drug activity, and cessation of patient cooperation.

Patients were divided into 5 groups based on the underlying disease: DM–patients with diabetes mellitus, M–patients after stroke, D–patients with lower back pain, MS–patients with multiple sclerosis, and P group–patients with spinal cord injury. Treatment efficacy was measured in all five groups.

Patients used pregabalin (Epiron^®) in the form of capsules of 75 mg and 150 mg manufactured by Bosnalijek d.d. and were monitored for 3 months.

Procedure and ethical considerations

The study was approved by the Agency for medicinal products and medical devices of Bosnia and Herzegovina. The Helsinki Declaration from 1975 and its amendments from 1983 were followed in all procedures. Before any procedure started, each participant signed informed consent form.

Measures

During the study, baseline and two control visits were performed. During the baseline visit, the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) was used to assess neuropathic pain. The first control visit was one and a half months after the start of therapy and the second control visit 3 months after the start of treatment using pregabalin. During follow-up visits, the 36-Item Short-Form Health Survey (SF 36) was used to assess the effectiveness of therapy on quality of life.

The safety of the treatment was evaluated by monitoring the incidence of adverse drug reactions with the assessment of the association between drug administration and the occurrence of adverse reactions (definite, probable, possible, unlikely, unclassified and cannot be classified).

Statistical analysis

Statistical data analysis was performed using the Statistical Package for Social Sciences (SPSS), version 13.0. The results of the study were presented as the arithmetic mean (X) and standard deviation (SD) for the variables that followed the normal distribution, or as the median and interquartile range for the variables that did not follow the normal distribution and as absolute and relative numbers. The student t-test for independent samples or the Mann Whitney U test, depending on whether the distribution of data was normal or not, was used to compare the mean values of the continuous variables. The normal distribution of data was verified by the Kolmogorov-Smirnov test. The chi-square test or Fisher test was used to compare the frequencies of categorical variables. To analyze the significance of the difference in the variables measured at time intervals, Analysis of Variance (ANOVA) for repeated measurements or Student t-test for dependent samples was used for the variables with a normal distribution. Friedman and the Wilcoxon Signed Rank Test were used if the variables did not follow normal distribution. Accepted statistical significance was set at p <0.05.

4. RESULTS

The study included 125 patients, 45.6% women and 51.2% men. The mean age was 55.9 ± 12.7 years. There were 48 patients in the DM group, 15 patients in the M group, 44 patients in the D group, 9 patients in the MS group, and 7 patients in the P group.

At the baseline visit, a high number of patients had symptoms of pain that were described as discomfort, sensitivity to touch, and changes in skin temperature (Table 1).

Table 1: LANSS pain scale. DM–patients with diabetes mellitus, M–patients after stroke, D–patients with lower back pain, MS–patients with multiple sclerosis, and P group–patients with spinal cord injury marrow.

		Groups
		DM		M		D		MS		P
		No	Yes	No	Yes	No	Yes	No	Yes	No	Yes
Do you feel pain as unusual, unpleasant sensations on the skin? These sensations can be described by words such as tingling, numbness, stinging with a needle.	N	1	47	2	13	1	43	0	9	0	7
	%	2.1	97.9	13.3	86.7	2.3	97.7	0.0	100.0	0.0	100.0
Does your pain make the skin in the painful area look different from normal? This kind of skin looks mottled, red or pink.	N	22	26	15	0	33	11	7	2	6	1
	%	45.8	54.2	100.0	0.0	75.0	25.0	77.8	22.2	85.7	14.3
Does the pain make you feel that the affected skin is more sensitive to touch? These phenomena are described as discomfort when smoothing the skin or are described as pain when wearing tight clothing.	N	4	44	3	12	14	30	1	8	2	5
	%	8.3	91.7	20.0	80.0	31.8	68.2	11.1	88.9	28.6	71.4
Does the pain appear suddenly, without any stimulus in the form of phenomena that can be described as electric shock, tearing or cracking?	N	14	34	6	9	13	31	1	8	1	6
	%	29.2	70.8	40.0	60.0	29.5	70.5	11.1	88.9	14.3	85.7
Do you feel pain as a change in skin temperature in the painful area? These sensations can be described as burning or burning.	N	4	44	6	9	17	27	4	5	3	4
	%	8.3	91.7	40.0	60.0	38.6	61.4	44.4	55.6	42.9	57.1

During treatment with pregabalin, there was a statistically significant reduction in pain intensity in the DM, M, D and MS groups. However, in group P, the decrease in pain intensity was not statistically significant (p = 0.070). The results are shown in Table 2.

Table 2. Mean values of pain intensity in all groups at the beginning and end of the study. DM–patients with diabetes mellitus, M–patients after stroke, D–patients with lower back pain, MS–patients with multiple sclerosis, and P group–patients with spinal cord injury marrow.

Group	At the beggining of the study	At the end of the study	P value
DM	4.3 ± 1.7	2.1 ± 1.5	< 0.001
M	4.1 ± 2.0	2.3 ± 1.7	0.047
D	5.0 ± 2.2	2.3 ± 1.3	< 0.001
MS	5.4 ± 2.0	2.0 ± 1.3	0.003
P	6.7 ± 1.2	2.3 ± 2.1	0.070

There was a significant improvement in different parameters of the quality of life in all analyzed groups, with the most prominent effects in the DM group resulting in better general health, less difficulty in daily work, less pain and better emotional well-being. Changes in quality of life at the second and third examinations are shown in Table 3.

Table 3. Average sum of answers to questions from the SF-36 questionnaire for the second and third visits. DM–patients with diabetes mellitus, M–patients after stroke, D–patients with lower back pain, MS–patients with multiple sclerosis, and P group–patients with spinal cord injury marrow, * p <0.05.

Parameter	Visit	DM	M	D	MS	P
Physical functioning	Second	3.2	2.4	3.3	2.7	1.0
	Third	3.6	3.1*	3.7*	3.8	4.0
Role limitations due to physical health	Second	3.0	2.8	3.3	2.4	2.0
	Third	3.9*	3.3*	3.9*	3.9	3.0*
Role limitations due to emotional problems	Second	3.2	3.0	3.6	2.9	2.3
	Third	4.4*	3.7	4.4*	4.0	3.0
Energy/fatigue	Second	3.0	3.0	3.4	3.0	3.0
	Third	3.8	3.6	3.8*	4.0	2.7
Emotional well-being	Second	3.2	2.9	3.7	3.3	2.7
	Third	4.3*	3.7	4.3*	4.0*	3.0
Social functioning	Second	3.2	2.4	3.5	2.6	2.0
	Third	3.9	3.3	4.2*	3.9*	3.0
Pain	Second	2.8	2.2	3.0	2.1	2.0
	Third	4.2*	3.0	4.1*	4.0	3.3
General health	Second	2.5	2.7	2.8	1.7	1.7
	Third	3.7*	3.7	3.8*	3.1	3.0

The effectiveness of treatment was rated as “good” and “very good” in 70.4% of subjects in DM group, in 73.3% in M group, in 74.5% in D group, in 77.7% in MS group and in 71.5% in P group.

The expected side effects of treatment were recorded in 27.1% of patients in the DM group, in 20.0% in the M group and in 22.2% in the MS group. Unexpected side effects of treatment were observed in one patient (2.1%) in the DM group.

Assessment of tolerability of the applied treatment showed “good” and “very good” response in 68.7% of patients in DM group, 73.3% in M group, 74.5% in D group, 88.9% in MS group and 85.8% in P group.

5. DISCUSSION

This study confirmed the efficacy and safety of pregabalin in treatment of neuropathic pain. Neuropathic pain is a health problem of multidimensional and chronic nature, which represents a diagnostic and therapeutic challenge and deserves the same attention as any other chronic disease. Pain therapists agree that neuropathic pain is not easy to treat. Common analgesics such as acetylsalicylic acid, paracetamol, and antirheumatic drugs are not effective in treating this pain. In recent decades, the recognition of neuropathic pain within various diseases has significantly improved, and several new drugs have been discovered and synthesized. The European Federation of Neurological Societies (EFNS) has systematized and published the results of all these studies, in the form of a guide with recommendations for the pharmacological treatment of neuropathic pain. According to these recommendations, it is extremely important to treat neuropathic pain precisely, which means according to the cause, i.e. the disease that led to it, in order to act on the presumed mechanisms of pain.

Prolonged and excruciating pain causes sleep and mood disorders, often depression. Due to pain, the social functioning of these patients is impaired, which often leads to impaired family and business functioning (13).

Since non-opioid and opioid analgesics work poorly, according to the guidelines for the treatment of neuropathic pain, drugs from the group of antiepileptics, gabapentinoids type, are used, which in the case of neuropathic pain also have analgesic properties, so they stop or modulate the transmission of painful stimuli to the brain. Today, pregabalin, which belongs to the group of antiepileptics, has been successfully established in the treatment of pain of non-inflammatory origin (11).

Pregabalin was introduced in 2004 as a more potent successor to the antiepileptic drug gabapentin. It is a structural analogue of the gamma-aminobutyric acid inhibitor neurotransmitter (GABA). Pregabalin binds to the alpha-2-delta subunit of calcium channels by reducing the release of several excitatory neurotransmitters of activated nociceptors, thus blocking the onset of hyperalgesia and central sensitization (14).

Although there are three other subtypes of α2δ subunits, biochemical studies have shown that pregabalin and gabapentin bind exclusively to type 1 and 2 α2δ subunits on neurons. The binding of pregabalin reduces the entry of calcium into nerve endings and thus reduces the release of excitatory neurotransmitters glutamate and substance P (14, 15). It is considered that the reduced release of neurotransmitters from the brain and spinal cord is the mechanism on which the analgesic, anxiolytic and anticonvulsant action of pregabalin is based.

Evidence-based medicine (level of evidence A) recommends pregabalin, which acts to reduce presynaptic neurotransmitter release, for the treatment of neuropathic pain (16). Its effectiveness has been demonstrated in studies in diabetic neuropathy, postherpetic neuralgia, spinal cord and inferior alveolar nerve injuries (15). The results of our study showed that pregabalin treatment resulted in a significant reduction in pain intensity in patients with diabetes mellitus, and to an improvement in quality of life.

Pregabalin is the first drug approved by the US Food and Drug Administration (FDA) in the treatment of diabetic neuropathy and trigeminal neuralgia (11). Clinical trials that lasted up to 12 weeks, showed a reduction in both peripheral and central neuropathic pain during the first week of treatment and was maintained throughout treatment (15). This study showed that pregabalin led to a statistically significant reduction in neuropathic pain in patients with diabetes mellitus, in patients after stroke, in patients with lower back pain, and in patients with multiple sclerosis.

Pregabalin at a dose of 300 to 600 mg per day leads to a significant reduction in neuropathic pain in patients with diabetes mellitus, to the improvement of the weekly score for monitoring sleep disturbances, to the improvement of the subjective feeling of numbness, pain, and paresthesia with excellent tolerability and transient mild side effects (17). In another study, pregabalin in the dose range of 300 mg to 600 mg per day also significantly reduced pain in patients with peripheral diabetic neuropathy, with 46% of patients who responded positively receiving 300 mg pregabalin per day and 48% of patients receiving 600 mg pregabalin per day compared with 18% of patients receiving placebo. Pregabalin showed its effect after the first seven days of treatment while maintaining the effect for a period of 5 weeks of the study (18). In this study, statistically significant results were achieved on the third visit, after 3 months of pregabalin treatment. In patients diagnosed with lower back pain with a neuropathic component, pregabalin has been shown to be an effective drug in reducing pain, improving function, and improving general health status after 8 weeks of therapy (19). Pregabalin is the preferred therapy in the treatment of neuropathic pain in elderly patients due to its low potential to interact with other drugs (20,21). The efficacy rate of pregabalin in the treatment of neuropathic pain in elderly patients with chronic back pain was 73.3% (19). Pregabalin is also effective in the treatment of central neuropathic pain with the added effect of sleep improvement and anxiety reduction. It is estimated that neuropathic pain occurs in 8% of patients after stroke, in 25% of patients with multiple sclerosis, and in 40% of patients with spinal cord injury (19). In patients with spinal cord injury, pregabalin in the dosing regimen of ascending titration with a gradual increase in dose to 300 mg twice daily for a period of 9 weeks led to a reduction in neuropathic pain. Similar results have been reported in patients after stroke who used the Visually Analogous Scale (VAS) scale to assess neuropathic pain (22). In this study, the efficacy of the treatment was rated as “good” and “very good” in 73.3% of patients after stroke. Taking into consideration the fact that the presence of neuropathic pain reduces work activity, social functioning, sleep, and overall quality of life, data from studies conducted with pregabalin have shown that reducing neuropathic pain in patients improves daily functioning, reduces sleep-related disorders, improves the quality of life and daily functioning. This study showed that in all patients there was an improvement in certain segments of quality of life that were monitored. The best improvement in quality-of-life parameters was observed in patients who had dorsalgia (in whom there was an improvement in all quality of life parameters that were monitored), then in patients who had diabetes (in whom there was an improvement in more than half of the monitored parameters quality of life, in 5 parameters out of a total of 8). In patients after stroke, a significant improvement was observed in performing normal physical activities and daily work. In patients with multiple sclerosis an increase in mean values was observed in the impact of health status, i.e. neuropathy on social activities where there was an improvement. In patients with spinal cord injury an improvement was observed in performing daily activities outside the home, where there was an increase in the mean value on the third visit. After more than a decade of worldwide experience with pregabalin, the available evidence from clinical trials conducted worldwide has shown that pregabalin is an effective and well-tolerated drug in the treatment of neuropathic pain. In addition to clinically proven efficacy, a good safety profile with excellent tolerability is the reason why pregabalin is the most common drug of first therapeutic choice in the treatment of neuropathic pain of various etiologies (23).

6. CONCLUSION

Pregabalin is a safe and effective drug in treatment of neuropathic pain of different etiology.

Declaration of patient consent:

The authors certify that they have obtained all appropriate patient consent forms.

Author’s contribution:

BP and MM have made a substantial contribution to the conception and design of the work and have made a substantial contribution to the analysis and interpretation of data for the work. All authors critically revised article for important intellectual content. All authors gave final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflicts of interest:

None declared.

Financial support and sponsorship:

Bosnalijek d.d.