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ORIGINAL RESEARCH—ERECTILE DYSFUNCTION Association Between Neuropathic Pain, Pregabalin Treatment, and Erectile Dysfunction Mehtap Bozkurt, MD,* Cuneyt Gocmez, MD,† Haluk Soylemez, MD,‡ Mansur Daggulli, MD,‡ Serda Em, MD,* Mehmet Yildiz, MD,* Murat Atar, MD,‡ Yasar Bozkurt, MD,‡ and Isa Ozbey, MD§ *Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Dicle University, Diyarbakir, Turkey; † Department of Neurosurgery, Faculty of Medicine, Dicle University, Diyarbakir, Turkey; ‡Department of Urology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey; §Department of Urology, Faculty of Medicine, Ataturk University, Erzurum, Turkey DOI: 10.1111/jsm.12458
ABSTRACT
Introduction. The pathophysiology of erectile dysfunction (ED) may be vasculogenic, hormonal, anatomical, neurogenic, drug-induced and/or psychogenic in origin. Neuropathic pain (NP) may facilitate ED, because it is frequently associated with anxiety, depression, and its drug, pregabalin, may also contribute ED. Aim. The objective of this study was to determine whether pregabalin treatment for patients with neuropathic pain promotes erectile dysfunction. Methods. The study sample consisted of a total of 102 male subjects that were subdivided into three groups. Group 1 patients (n = 31) had a pre-existing diagnosis of NP and was treated with 300 mg/day of pregabalin for at least 3 months. Group 2 patients (n = 34) were diagnosed with NP for at least 3 months; however, neither were they treated with pregabalin nor did they received physical therapy throughout the study. Lastly, healthy age-matched control subjects comprised group 3 (n = 37). Main Outcome Measures. Patients in all groups completed the International Index for Erectile Function (IIEF) questionnaire. Results. Mean age and mean body mass index did not differ significantly between each of the three groups. The cause of NP and the mean duration of having a diagnosis of NP did not differ significantly in groups 1 and 2. However, IIEF scores were significantly lower for group 1 when compared to group 2 in terms of erectile function, orgasmic function, overall satisfaction and total score. Yet groups 1 and 2 did not diverge significantly in the intercourse satisfaction and sexual desire scores. Overall IIEF scores for group 3 were significantly higher than those of group 2 except for mean erectile function scores. Conclusion. Taking pregabalin for the treatment of neuropathic pain poses an increased risk for developing ED in male patients. Thus, clinicians prescribing pregabalin to patients diagnosed with neuropathic pain should assess for ED before and during treatment with this medication. Bozkurt M, Gocmez C, Soylemez H, Daggulli M, Em S, Yildiz M, Atar M, Bozkurt Y, and Ozbey I. Association between neuropathic pain, pregabalin treatment, and erectile dysfunction. J Sex Med 2014;11:1816–1822. Key Words. Neuropathic Pain; Pregabalin; Erectile Dysfunction
Introduction
C
hronic pain is a significant health problem that affects one in five adults [1]. In general, pain can be classified according to etiology as J Sex Med 2014;11:1816–1822
either neuropathic or inflammatory. The pathophysiology of inflammatory pain is based on sustained nociceptor stimulation and may be observed in autoimmune diseases such as rheumatoid arthritis. In contrast, neuropathic pain (NP) © 2014 International Society for Sexual Medicine
Association Between Pregabalin and Erectile Dysfunction arises from a lesion affecting peripheral or central somatosensory pathways. NP is relatively more difficult to diagnose and treat and is primarily caused by lumbar or cervical radiculopathies, spinal cord injuries, and diabetes [2,3]. Moreover, NP is typically chronic and is frequently associated with anxiety, depression, and sleep disorders [4]. Due to the pathophysiology and symptoms often associated with NP, first line treatment strategies treat both NP and its comorbidities such as anticonvulsants and tricyclic antidepressants [5,6]. Additional treatments for NP are calcium channel ligands including pregabalin, gabapentin, and topical lidocaine [7]. Pregabalin is an anticonvulsant that has been shown to be effective in an array of randomized controlled clinical trials studying painful neuropathic conditions with central and peripheral etiologies [8]. Pregabalin is also indicated in treating psychiatric conditions such as generalized anxiety disorder, social anxiety disorder, obsessive compulsive disorder, posttraumatic stress disorder, schizophrenia, bipolar mania, and major depression [9–11]. Recent studies demonstrate that pregabalin may aid in treating alcohol withdrawal [12]. Due to the broad applications of pregabalin, including but not limited to improving anxiety and pain due to disordered sleep, it is becoming prescribed more widely [13]. Erectile dysfunction (ED) is a common disorder affecting men, and it is estimated that more than half of males between the ages of 40 to70 years suffer from it [14]. This condition is described as either a persistent or recurrent inability to have a sufficient erection for satisfactory sexual performance [15]. The pathophysiology of ED is complex and may be vasculogenic, hormonal, anatomical, neurogenic, drug-induced and/or psychogenic in origin [16]. Common medications that have ED as a side effect include antihypertensive drugs, especially diuretics; antidepressants; antiepileptics; antipsychotics; anti-androgens; and recreational substances such as alcohol, cocaine, and heroin [16,17]. The association between sexual dysfunction and older generation antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin, and primidone has long been known [18]. Whereas sexual dysfunction due to pregabalin, which may be prescribed for the treatment of partial epilepsy and neuropathic pain, has been rarely described [19]. By itself neuropathic pain may contribute to sexual dysfunction, as NP is frequently associated with anxiety and depression. Because NP facilitates ED
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Figure 1 Schema of the study design. IIEF = International Index of Erectile Function.
and pregabalin has the potential to contribute to ED as well, we aimed to investigate the effects of both NP and pregabalin use on ED in male patients. Methods
Study Sample Initially, 104 NP patients receiving care at the Physical Medicine and Rehabilitation Department of the Faculty of Medicine were selected for the participation in the study. However, 23 patients met the exclusion criteria and 16 patients refused to provide consent for participation. A total of 65 patients with NP completed the IIEF questionnaire with or without pregabalin use. In all there was a total of three groups: group 1 included patients with NP that were administered pregabalin for at least 3 months (NP + Pregabalin); group 2 was comprised of patients diagnosed with NP and were not prescribed analgesic medications including pregabalin or received any physical therapy for at least 3 months (NP); and group 3 was the control group with age, weight and height matched males without NP (control). Control subjects were composed of voluntary healthy hospital stuff. The scheme of three groups is shown on Figure 1. Diagnosis of NP NP was diagnosed based on history and physical exam, magnetic resonance imaging (MRI) and/or electromyelography testing (EMG) when indicated. The inclusion criterias for NP were: men or women with pain of at least moderate severity, a duration of at least 3 months and which could be J Sex Med 2014;11:1816–1822
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Bozkurt et al.
attributed to a peripheral nervous lesions such as cervical disc herniation (CDH), lumbar disc herniation (LDH) and peripheral nerve damage (PND). To exclude the negative effect of central nervous system on ED, central nervous lesions were excluded according to the MRI findings. LDH and CDH was diagnosed according to the region of lateral protrusion and/or extrusion on MR imaging. Patients with bulging were excluded from the study. Diagnosis of PND was based on clinical examination (e.g., hyperesthesia and dysesthesia) of affected area of peripheral nerve and EMG findings. Subject ages ranged from 25 to 60 years and every patient reported having sexual intercourse at least once or twice weekly. Individuals that met the following criteria were excluded from the study: presence of a systemic disease such as diabetes mellitus, heart disease, hypertension, etc.; genital abnormalities; psychogenic disorders; and taking medications with ED side effects. Patients in group 1 were administered 300 mg/day of pregabalin (Lyrica®; Pfizer Inc., New York) and received regular follow up to assess how well their NP was controlled. After at least 3 months of follow up appointments, group 1 patients completed the International Index for Erectile Function (IIEF) questionnaire. Patients in groups 2 and 3 completed the same questionnaire at any time during the study. Our randomized controlled study design was reviewed and approved by the human ethics committee at Dicle University.
IIEF Questionnaire IIEF is a simple questionnaire containing 15 questions that screens patients for ED [20]. This questionnaire also categorizes the degree of severity of
Table 1
ED into mild, moderate and severe. Questions 1 to 5 and 15 assess erectile function. The IIEF also has prompts regarding intercourse satisfaction (questions 6–8), orgasmic function (questions 9 and 10), sexual desire (questions 11 and 12), and overall satisfaction (questions 13 and 14). A single clinician provided all participants with a thorough explanation regarding the IIEF before completing the questionnaires. Then, all questionnaires was completed by the patients without a health professional.
Statistical Analysis Statistical analyses were performed by SPSS for Windows version 15.0 (SPSS Inc., Chicago, IL). Data are presented as the mean plus or minus one standard deviation. One-Sample KolmogorovSmirnov test was utilized to determine whether or not the data were normally distributed. Student t-test and the Mann-Whitney U-test were used to compare age, weight, height and BMI between groups. Intergroup comparisons for IIEF questionnaire results were performed by the Pearson’s chi-square test. A P value less than 0.05 was the threshold for statistical significance. Results
The means for participant age were 40.9 ± 8.5 years for group 1, 37.8 ± 9.7 years for group 2 and 37.0 ± 6.5 years for group 3. Demographics for all participants are portrayed in Table 1. No statistical differences were appreciated between all groups in terms of age, weight, height, body mass index (BMI) and educational status (P > 0.05). The most common etiology of NP for group 1 was LDH which was observed in 23 patients, while other
Descriptive group characteristics (mean ± SD)
Age, (year) Weight, (kg) Height, (cm) BMI, (kg/m2) Education, (years) Pregabalin use, (months) NP duration, (months) Etiology of NP LDH CDH PND
Group comparison P values
NP + pregabalin (Group 1, n = 31)
NP (Group 2, n = 34)
Control (Group 3, n = 37)
1–2
1–3
2–3
40.96 ± 8.57 76.32 ± 8.02 1.71 ± 0.05 26.09 ± 2.95 12.54 ± 4.32 4.94 ± 2.73 11.85 ± 3.75
37.85 ± 9.73 75.73 ± 9.96 1.72 ± 0.06 25.52 ± 3.14 11.23 ± 5.32 N/A 12.25 ± 4.64
37.08 ± 6.55 74.37 ± 10.59 1.71 ± 0.07 25.20 ± 3.12 11.64 ± 2.75 N/A N/A
0.200 0.477 0.245 0.344 0.064 — 0.282
0.085 0.392 0.619 0.223 0.124 — —
0.968 0.485 0.742 0.922 0.693 — —
22 3 6
26 3 5
N/A
0.867
—
—
NP = neuropathic pain; LDH = lumbar disc herniation; CDH = cervical disc herniation; PND = peripheral nerve damage; N/A = not available
J Sex Med 2014;11:1816–1822
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Association Between Pregabalin and Erectile Dysfunction Table 2
IIEF questionnaire total scores (mean ± SD)
Question numbers NP + pregabalin (1) NP (2) Control (3) Group comparison P values 1–2 1–3 2–3
Erectile function
Intercourse satisfaction
Orgasmic function
Sexual desire
Overall satisfaction
Total score
1, 2, 3, 4, 5, 15 20.87 ± 4.82 25.44 ± 3.23 26.78 ± 3.21
6, 7, 8 10.29 ± 2.51 10.61 ± 1.98 12.32 ± 1.71
9, 10 7.87 ± 1.74 8.67 ± 1.27 9.40 ± 1.09
11, 12 6.82 ± 1.68 7.05 ± 1.01 8.81 ± 1.19
13, 14 6.77 ± 1.76 7.70 ± 1.56 9.24 ± 1.06
All 15 52.63 ± 9.44 58.82 ± 7.58 66.56 ± 5.85
0.000 0.000 0.073
0.430 0.000 0.000
0.018 0.000 0.011
0.791 0.000 0.000
0.044 0.000 0.000
0.005 0.000 0.000
NP = neuropathic pain; IIEF = International Index of Erectile Function
causes of NP were CDH (n = 3), and PND (n = 6). In group 2, the most common cause of NP was LDH (n = 26) followed by PND (n = 5) and CDH (n = 3), which was similar to group 1 (P = 0.867). The mean duration of pregabalin treatment was 4.9 months with a range of 3–11 months for group 1 patients (Table 1). Mean duration of having a diagnosis of NP was similar between groups 1 and 2 (P = 0.282). As shown in Table 2, all IIEF questionnaire scores demonstrate a general increasing trend from group 1 to group 3. The mean total IIEF score was 52.6 ± 9.4 in group 1, 58.8 ± 7.6 in group 2, and 66.5 ± 5.8 in the control group. The greatest differences in total IIEF scores was appreciated between groups 1 and 3 (P = 0.000), and each group’s total score was significantly different from the other (P = 0.005 group 1–2, and P = 0.000 group 2–3). Mean scores to assess erectile function (questions 1–5 and 15) demonstrated an overall increase from group 1 to group 3 as follows: 20.8 ± 4.8 for group 1, 25.4 ± 3.2 for group 2, and 26.7 ± 3.2 for the control group. The NP + Pregabalin group erectile function scores differed significantly from group 1 (P = 0.000) and group 2 (P = 0.000); however, there was no significant difference between the NP and control groups (P = 0.073). Mean IIEF scores assessing intercourse satisfaction, orgasmic function, sexual desire, and overall satisfaction were significantly reduced in the NP + Pregabalin group vs. the control group (Table 2). Although, when comparing the NP + Pregabalin and NP groups, there were statistically significant differences in terms of erectile function (P = 0.000), orgasmic function (P = 0.018), and overall satisfaction (P = 0.044). No significant differences were observed in intercourse satisfaction (P = 0.430) and sexual desire (P = 0.791) between NP + Pregabalin and NP groups. Scores for all parameters except the
erectile function score differed significantly between NP and control groups. Discussion
Neuropathic pain is a type of chronic pain caused by nerve damage or a disease that targets either the peripheral or central nervous system. NP symptoms are usually greater when resting at night, but symptoms can be so severe that daily life can be affected such that patients have difficulty sleeping and eating. Due to the pervasive nature of NP, patients often experience depression and anxiety [4]. Even though it is widely understood that depression and anxiety play major roles in the pathophysiology of ED, the relationship between NP and ED has not been clearly elucidated in the scientific literature. We investigated the effect of chronic neuropathic pain (NP) on erectile function in male patients via the IIEF questionnaire. Moreover, we studied whether pregabalin, a pharmaceutical treatment for NP, exacerbated erectile dysfunction (ED) via the same assessment method. Validated psychometric questionnaires such as IIEF allow for the evaluation of several sexual function domains at baseline and after treatment with medications that may affect sexual performance. Specifically, IIEF assesses erectile function, sexual desire, orgasmic function, intercourse satisfaction, and overall satisfaction [20]. Even though ED is considered a benign disorder, it affects patient psychosocial health and may negatively impact the patient’s and sexual partner’s quality of life (QoL) [14]. The etiology of ED is multifactorial and may be due to a host of organic and/or psychogenic disorders. Previous studies have indicated that anxiety and depression, and the use of prescription antihypertensive, antidepressant and antiepileptic medications can cause ED [16,17]. Our results demonstrate that pregabalin worsens J Sex Med 2014;11:1816–1822
1820 erectile dysfunction in males with a pre-existing diagnosis of NP. Additionally, having a diagnosis of NP alone is sufficient to decrease all IIEF parameters, and our results demonstrated that this reduction was statistically significant except for the erectile function score. This finding might be due greater psychological impairments in erectile function for NP patients than for controls. Pregabalin is prescribed as an analgesic for the treatment of peripheral and central neuropathic pain [21]. It has been previously demonstrated that pregabalin has good analgesic efficacy in treating patients with neuropathic pain due to fibromyalgia, spinal cord injuries, postherpetic neuralgia, malignancy, and epilepsy [3,21–23]. Due to the wide array of indications for this medication, it is often prescribed and taken by patients. Although this relatively new drug’s efficacy in treating NP is satisfactory, it has been shown that it has negative effects on sexual function [19]. However, there is a paucity of data regarding the effects of pregabalin treatment for NP on erectile dysfunction. Indeed other antiepileptic drugs such as gabapentin and topiramate are thought to cause sexual problems via complex and poorly understood mechanisms [24,25]. Studies that reported a relationship between antiepileptic medications and ED are limited to case reports only. Of note there are isolated studies claiming that pregabalin can reverse citalopram-induced sexual dysfunction in patients with generalized anxiety disorder. Lastly, several studies have demonstrated that hyposexuality is one of the most frequent interictal problems diagnosed in epileptic patients. Several factors may contribute to the impairment of normal sexual function in patients with epilepsy including hormonal disorders, psychological problems, antiepileptic drugs and/or epilepsy itself [26,27]. It is generally understood that neuropathic disorders are commonly linked with sexual dysfunction either by nerve damage or by some other physiological cause. For determining the possible mechanism that how pregabalin cause sexual dysfunction, it must be known the central effect of the drugs in terms of neurotransmitters that may effect sexual functions. It is reported that, pregabalin decreases the release of neurotransmitters including glutamate, substance P and calcitonin gene-related peptide [28]. In another study the authors concluded that glutamate, is a potent activator of the spinal proerectile network [29]. Also, substance p is a central neurotransmitter that facilitates sexual behavior [30]. Additionally, in an experimental J Sex Med 2014;11:1816–1822
Bozkurt et al. study Bivalacqua et al. reported that calcitonin gene-related peptide restores the erectile function in rats with erectile dysfunction [31]. According to the results of studies discussed above pregabalin may act as a promoter of sexual dysfunction by effecting the central neurotransmitters which play a role in mechanism of erection and sexual behavior. For confirming these suggestions further clinical and experimental studies needed. Our study is the first controlled clinical trial describing the significance of the association between NP, treatment with pregabalin and ED. We demonstrated that mean IIEF scores for patients in the NP + Pregabalin group were lower than patients in the NP group and the control group (Table 2). Furthermore, the difference between the NP + Pregabalin and control groups was greater than the difference between NP + Pregabalin and NP groups. Specifically, the difference between the NP + Pregabalin and control groups was statistically significant for all IIEF parameters. For the NP + Pregabalin and NP groups, statistically significant differences were noted for erectile function, orgasmic function, overall satisfaction, and IIEF total score. These results reveal that NP alone impairs sexual function, and pregabalin may exacerbate ED in patients with pre-existing NP. The pathophysiology of pregabalin-induced ED is unclear and further studies must further elucidate this association, and the extent to which it affects the patient’s and partner’s QoL. On the other hand, psychological state of patients with NP did not evaluated by an objective scale, so this can be considered as a limitation of the present study. Conclusion
Our results show that pregabalin further decreases erectile function in male patients with NP. This impairment in sexual function NP patients taking pregabalin was greater than male patients with NP alone. Nevertheless, our results must be confirmed by additional randomized placebo-controlled studies with larger sample sizes before making recommendations for pregabalin dosing to limit ED. In addition, further studies should explore the pathophysiology of pregabalin-induced ED. However, we recommend that clinicians screen for ED in patients with NP before and during treatment with pregabalin using the IIEF questionnaire as it is simple to administer and to perform. Corresponding Author: Mehtap Bozkurt, MD, Department of Physical Medicine and Rehabilitation,
Association Between Pregabalin and Erectile Dysfunction University of Dicle, Diyarbakir 21280, Turkey. Tel: 00 90 412 248 80 01; Fax: 00 90 412 248 85 23; E-mail: [email protected] Conflict of Interest: The author(s) report no conflicts of interest.
Statement of Authorship
Category 1 (a) Conception and Design Mehtap Bozkurt; Cuneyt Gocmez (b) Acquisition of Data Cuneyt Gocmez; Serda Em; Mehmet Yrldrz; Mansur Daggulli (c) Analysis and Interpretation of Data Yesar Bozkurt; Haluk Soylemez
Category 2 (a) Drafting the Article Mehtap Bozkurt; Cuneyt Gocmez (b) Revising It for Intellectual Content Haluk Soylemez; Murat Atar
Category 3 (a) Final Approval of the Completed Article Iza Ozbey
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ORIGINAL RESEARCH—ERECTILE DYSFUNCTION Association Between Neuropathic Pain, Pregabalin Treatment, and Erectile Dysfunction Mehtap Bozkurt, MD,* Cuneyt Gocmez, MD,† Haluk Soylemez, MD,‡ Mansur Daggulli, MD,‡ Serda Em, MD,* Mehmet Yildiz, MD,* Murat Atar, MD,‡ Yasar Bozkurt, MD,‡ and Isa Ozbey, MD§ *Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Dicle University, Diyarbakir, Turkey; † Department of Neurosurgery, Faculty of Medicine, Dicle University, Diyarbakir, Turkey; ‡Department of Urology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey; §Department of Urology, Faculty of Medicine, Ataturk University, Erzurum, Turkey DOI: 10.1111/jsm.12458
ABSTRACT
Introduction. The pathophysiology of erectile dysfunction (ED) may be vasculogenic, hormonal, anatomical, neurogenic, drug-induced and/or psychogenic in origin. Neuropathic pain (NP) may facilitate ED, because it is frequently associated with anxiety, depression, and its drug, pregabalin, may also contribute ED. Aim. The objective of this study was to determine whether pregabalin treatment for patients with neuropathic pain promotes erectile dysfunction. Methods. The study sample consisted of a total of 102 male subjects that were subdivided into three groups. Group 1 patients (n = 31) had a pre-existing diagnosis of NP and was treated with 300 mg/day of pregabalin for at least 3 months. Group 2 patients (n = 34) were diagnosed with NP for at least 3 months; however, neither were they treated with pregabalin nor did they received physical therapy throughout the study. Lastly, healthy age-matched control subjects comprised group 3 (n = 37). Main Outcome Measures. Patients in all groups completed the International Index for Erectile Function (IIEF) questionnaire. Results. Mean age and mean body mass index did not differ significantly between each of the three groups. The cause of NP and the mean duration of having a diagnosis of NP did not differ significantly in groups 1 and 2. However, IIEF scores were significantly lower for group 1 when compared to group 2 in terms of erectile function, orgasmic function, overall satisfaction and total score. Yet groups 1 and 2 did not diverge significantly in the intercourse satisfaction and sexual desire scores. Overall IIEF scores for group 3 were significantly higher than those of group 2 except for mean erectile function scores. Conclusion. Taking pregabalin for the treatment of neuropathic pain poses an increased risk for developing ED in male patients. Thus, clinicians prescribing pregabalin to patients diagnosed with neuropathic pain should assess for ED before and during treatment with this medication. Bozkurt M, Gocmez C, Soylemez H, Daggulli M, Em S, Yildiz M, Atar M, Bozkurt Y, and Ozbey I. Association between neuropathic pain, pregabalin treatment, and erectile dysfunction. J Sex Med 2014;11:1816–1822. Key Words. Neuropathic Pain; Pregabalin; Erectile Dysfunction
Introduction
C
hronic pain is a significant health problem that affects one in five adults [1]. In general, pain can be classified according to etiology as J Sex Med 2014;11:1816–1822
either neuropathic or inflammatory. The pathophysiology of inflammatory pain is based on sustained nociceptor stimulation and may be observed in autoimmune diseases such as rheumatoid arthritis. In contrast, neuropathic pain (NP) © 2014 International Society for Sexual Medicine
Association Between Pregabalin and Erectile Dysfunction arises from a lesion affecting peripheral or central somatosensory pathways. NP is relatively more difficult to diagnose and treat and is primarily caused by lumbar or cervical radiculopathies, spinal cord injuries, and diabetes [2,3]. Moreover, NP is typically chronic and is frequently associated with anxiety, depression, and sleep disorders [4]. Due to the pathophysiology and symptoms often associated with NP, first line treatment strategies treat both NP and its comorbidities such as anticonvulsants and tricyclic antidepressants [5,6]. Additional treatments for NP are calcium channel ligands including pregabalin, gabapentin, and topical lidocaine [7]. Pregabalin is an anticonvulsant that has been shown to be effective in an array of randomized controlled clinical trials studying painful neuropathic conditions with central and peripheral etiologies [8]. Pregabalin is also indicated in treating psychiatric conditions such as generalized anxiety disorder, social anxiety disorder, obsessive compulsive disorder, posttraumatic stress disorder, schizophrenia, bipolar mania, and major depression [9–11]. Recent studies demonstrate that pregabalin may aid in treating alcohol withdrawal [12]. Due to the broad applications of pregabalin, including but not limited to improving anxiety and pain due to disordered sleep, it is becoming prescribed more widely [13]. Erectile dysfunction (ED) is a common disorder affecting men, and it is estimated that more than half of males between the ages of 40 to70 years suffer from it [14]. This condition is described as either a persistent or recurrent inability to have a sufficient erection for satisfactory sexual performance [15]. The pathophysiology of ED is complex and may be vasculogenic, hormonal, anatomical, neurogenic, drug-induced and/or psychogenic in origin [16]. Common medications that have ED as a side effect include antihypertensive drugs, especially diuretics; antidepressants; antiepileptics; antipsychotics; anti-androgens; and recreational substances such as alcohol, cocaine, and heroin [16,17]. The association between sexual dysfunction and older generation antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin, and primidone has long been known [18]. Whereas sexual dysfunction due to pregabalin, which may be prescribed for the treatment of partial epilepsy and neuropathic pain, has been rarely described [19]. By itself neuropathic pain may contribute to sexual dysfunction, as NP is frequently associated with anxiety and depression. Because NP facilitates ED
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Figure 1 Schema of the study design. IIEF = International Index of Erectile Function.
and pregabalin has the potential to contribute to ED as well, we aimed to investigate the effects of both NP and pregabalin use on ED in male patients. Methods
Study Sample Initially, 104 NP patients receiving care at the Physical Medicine and Rehabilitation Department of the Faculty of Medicine were selected for the participation in the study. However, 23 patients met the exclusion criteria and 16 patients refused to provide consent for participation. A total of 65 patients with NP completed the IIEF questionnaire with or without pregabalin use. In all there was a total of three groups: group 1 included patients with NP that were administered pregabalin for at least 3 months (NP + Pregabalin); group 2 was comprised of patients diagnosed with NP and were not prescribed analgesic medications including pregabalin or received any physical therapy for at least 3 months (NP); and group 3 was the control group with age, weight and height matched males without NP (control). Control subjects were composed of voluntary healthy hospital stuff. The scheme of three groups is shown on Figure 1. Diagnosis of NP NP was diagnosed based on history and physical exam, magnetic resonance imaging (MRI) and/or electromyelography testing (EMG) when indicated. The inclusion criterias for NP were: men or women with pain of at least moderate severity, a duration of at least 3 months and which could be J Sex Med 2014;11:1816–1822
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Bozkurt et al.
attributed to a peripheral nervous lesions such as cervical disc herniation (CDH), lumbar disc herniation (LDH) and peripheral nerve damage (PND). To exclude the negative effect of central nervous system on ED, central nervous lesions were excluded according to the MRI findings. LDH and CDH was diagnosed according to the region of lateral protrusion and/or extrusion on MR imaging. Patients with bulging were excluded from the study. Diagnosis of PND was based on clinical examination (e.g., hyperesthesia and dysesthesia) of affected area of peripheral nerve and EMG findings. Subject ages ranged from 25 to 60 years and every patient reported having sexual intercourse at least once or twice weekly. Individuals that met the following criteria were excluded from the study: presence of a systemic disease such as diabetes mellitus, heart disease, hypertension, etc.; genital abnormalities; psychogenic disorders; and taking medications with ED side effects. Patients in group 1 were administered 300 mg/day of pregabalin (Lyrica®; Pfizer Inc., New York) and received regular follow up to assess how well their NP was controlled. After at least 3 months of follow up appointments, group 1 patients completed the International Index for Erectile Function (IIEF) questionnaire. Patients in groups 2 and 3 completed the same questionnaire at any time during the study. Our randomized controlled study design was reviewed and approved by the human ethics committee at Dicle University.
IIEF Questionnaire IIEF is a simple questionnaire containing 15 questions that screens patients for ED [20]. This questionnaire also categorizes the degree of severity of
Table 1
ED into mild, moderate and severe. Questions 1 to 5 and 15 assess erectile function. The IIEF also has prompts regarding intercourse satisfaction (questions 6–8), orgasmic function (questions 9 and 10), sexual desire (questions 11 and 12), and overall satisfaction (questions 13 and 14). A single clinician provided all participants with a thorough explanation regarding the IIEF before completing the questionnaires. Then, all questionnaires was completed by the patients without a health professional.
Statistical Analysis Statistical analyses were performed by SPSS for Windows version 15.0 (SPSS Inc., Chicago, IL). Data are presented as the mean plus or minus one standard deviation. One-Sample KolmogorovSmirnov test was utilized to determine whether or not the data were normally distributed. Student t-test and the Mann-Whitney U-test were used to compare age, weight, height and BMI between groups. Intergroup comparisons for IIEF questionnaire results were performed by the Pearson’s chi-square test. A P value less than 0.05 was the threshold for statistical significance. Results
The means for participant age were 40.9 ± 8.5 years for group 1, 37.8 ± 9.7 years for group 2 and 37.0 ± 6.5 years for group 3. Demographics for all participants are portrayed in Table 1. No statistical differences were appreciated between all groups in terms of age, weight, height, body mass index (BMI) and educational status (P > 0.05). The most common etiology of NP for group 1 was LDH which was observed in 23 patients, while other
Descriptive group characteristics (mean ± SD)
Age, (year) Weight, (kg) Height, (cm) BMI, (kg/m2) Education, (years) Pregabalin use, (months) NP duration, (months) Etiology of NP LDH CDH PND
Group comparison P values
NP + pregabalin (Group 1, n = 31)
NP (Group 2, n = 34)
Control (Group 3, n = 37)
1–2
1–3
2–3
40.96 ± 8.57 76.32 ± 8.02 1.71 ± 0.05 26.09 ± 2.95 12.54 ± 4.32 4.94 ± 2.73 11.85 ± 3.75
37.85 ± 9.73 75.73 ± 9.96 1.72 ± 0.06 25.52 ± 3.14 11.23 ± 5.32 N/A 12.25 ± 4.64
37.08 ± 6.55 74.37 ± 10.59 1.71 ± 0.07 25.20 ± 3.12 11.64 ± 2.75 N/A N/A
0.200 0.477 0.245 0.344 0.064 — 0.282
0.085 0.392 0.619 0.223 0.124 — —
0.968 0.485 0.742 0.922 0.693 — —
22 3 6
26 3 5
N/A
0.867
—
—
NP = neuropathic pain; LDH = lumbar disc herniation; CDH = cervical disc herniation; PND = peripheral nerve damage; N/A = not available
J Sex Med 2014;11:1816–1822
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Association Between Pregabalin and Erectile Dysfunction Table 2
IIEF questionnaire total scores (mean ± SD)
Question numbers NP + pregabalin (1) NP (2) Control (3) Group comparison P values 1–2 1–3 2–3
Erectile function
Intercourse satisfaction
Orgasmic function
Sexual desire
Overall satisfaction
Total score
1, 2, 3, 4, 5, 15 20.87 ± 4.82 25.44 ± 3.23 26.78 ± 3.21
6, 7, 8 10.29 ± 2.51 10.61 ± 1.98 12.32 ± 1.71
9, 10 7.87 ± 1.74 8.67 ± 1.27 9.40 ± 1.09
11, 12 6.82 ± 1.68 7.05 ± 1.01 8.81 ± 1.19
13, 14 6.77 ± 1.76 7.70 ± 1.56 9.24 ± 1.06
All 15 52.63 ± 9.44 58.82 ± 7.58 66.56 ± 5.85
0.000 0.000 0.073
0.430 0.000 0.000
0.018 0.000 0.011
0.791 0.000 0.000
0.044 0.000 0.000
0.005 0.000 0.000
NP = neuropathic pain; IIEF = International Index of Erectile Function
causes of NP were CDH (n = 3), and PND (n = 6). In group 2, the most common cause of NP was LDH (n = 26) followed by PND (n = 5) and CDH (n = 3), which was similar to group 1 (P = 0.867). The mean duration of pregabalin treatment was 4.9 months with a range of 3–11 months for group 1 patients (Table 1). Mean duration of having a diagnosis of NP was similar between groups 1 and 2 (P = 0.282). As shown in Table 2, all IIEF questionnaire scores demonstrate a general increasing trend from group 1 to group 3. The mean total IIEF score was 52.6 ± 9.4 in group 1, 58.8 ± 7.6 in group 2, and 66.5 ± 5.8 in the control group. The greatest differences in total IIEF scores was appreciated between groups 1 and 3 (P = 0.000), and each group’s total score was significantly different from the other (P = 0.005 group 1–2, and P = 0.000 group 2–3). Mean scores to assess erectile function (questions 1–5 and 15) demonstrated an overall increase from group 1 to group 3 as follows: 20.8 ± 4.8 for group 1, 25.4 ± 3.2 for group 2, and 26.7 ± 3.2 for the control group. The NP + Pregabalin group erectile function scores differed significantly from group 1 (P = 0.000) and group 2 (P = 0.000); however, there was no significant difference between the NP and control groups (P = 0.073). Mean IIEF scores assessing intercourse satisfaction, orgasmic function, sexual desire, and overall satisfaction were significantly reduced in the NP + Pregabalin group vs. the control group (Table 2). Although, when comparing the NP + Pregabalin and NP groups, there were statistically significant differences in terms of erectile function (P = 0.000), orgasmic function (P = 0.018), and overall satisfaction (P = 0.044). No significant differences were observed in intercourse satisfaction (P = 0.430) and sexual desire (P = 0.791) between NP + Pregabalin and NP groups. Scores for all parameters except the
erectile function score differed significantly between NP and control groups. Discussion
Neuropathic pain is a type of chronic pain caused by nerve damage or a disease that targets either the peripheral or central nervous system. NP symptoms are usually greater when resting at night, but symptoms can be so severe that daily life can be affected such that patients have difficulty sleeping and eating. Due to the pervasive nature of NP, patients often experience depression and anxiety [4]. Even though it is widely understood that depression and anxiety play major roles in the pathophysiology of ED, the relationship between NP and ED has not been clearly elucidated in the scientific literature. We investigated the effect of chronic neuropathic pain (NP) on erectile function in male patients via the IIEF questionnaire. Moreover, we studied whether pregabalin, a pharmaceutical treatment for NP, exacerbated erectile dysfunction (ED) via the same assessment method. Validated psychometric questionnaires such as IIEF allow for the evaluation of several sexual function domains at baseline and after treatment with medications that may affect sexual performance. Specifically, IIEF assesses erectile function, sexual desire, orgasmic function, intercourse satisfaction, and overall satisfaction [20]. Even though ED is considered a benign disorder, it affects patient psychosocial health and may negatively impact the patient’s and sexual partner’s quality of life (QoL) [14]. The etiology of ED is multifactorial and may be due to a host of organic and/or psychogenic disorders. Previous studies have indicated that anxiety and depression, and the use of prescription antihypertensive, antidepressant and antiepileptic medications can cause ED [16,17]. Our results demonstrate that pregabalin worsens J Sex Med 2014;11:1816–1822
1820 erectile dysfunction in males with a pre-existing diagnosis of NP. Additionally, having a diagnosis of NP alone is sufficient to decrease all IIEF parameters, and our results demonstrated that this reduction was statistically significant except for the erectile function score. This finding might be due greater psychological impairments in erectile function for NP patients than for controls. Pregabalin is prescribed as an analgesic for the treatment of peripheral and central neuropathic pain [21]. It has been previously demonstrated that pregabalin has good analgesic efficacy in treating patients with neuropathic pain due to fibromyalgia, spinal cord injuries, postherpetic neuralgia, malignancy, and epilepsy [3,21–23]. Due to the wide array of indications for this medication, it is often prescribed and taken by patients. Although this relatively new drug’s efficacy in treating NP is satisfactory, it has been shown that it has negative effects on sexual function [19]. However, there is a paucity of data regarding the effects of pregabalin treatment for NP on erectile dysfunction. Indeed other antiepileptic drugs such as gabapentin and topiramate are thought to cause sexual problems via complex and poorly understood mechanisms [24,25]. Studies that reported a relationship between antiepileptic medications and ED are limited to case reports only. Of note there are isolated studies claiming that pregabalin can reverse citalopram-induced sexual dysfunction in patients with generalized anxiety disorder. Lastly, several studies have demonstrated that hyposexuality is one of the most frequent interictal problems diagnosed in epileptic patients. Several factors may contribute to the impairment of normal sexual function in patients with epilepsy including hormonal disorders, psychological problems, antiepileptic drugs and/or epilepsy itself [26,27]. It is generally understood that neuropathic disorders are commonly linked with sexual dysfunction either by nerve damage or by some other physiological cause. For determining the possible mechanism that how pregabalin cause sexual dysfunction, it must be known the central effect of the drugs in terms of neurotransmitters that may effect sexual functions. It is reported that, pregabalin decreases the release of neurotransmitters including glutamate, substance P and calcitonin gene-related peptide [28]. In another study the authors concluded that glutamate, is a potent activator of the spinal proerectile network [29]. Also, substance p is a central neurotransmitter that facilitates sexual behavior [30]. Additionally, in an experimental J Sex Med 2014;11:1816–1822
Bozkurt et al. study Bivalacqua et al. reported that calcitonin gene-related peptide restores the erectile function in rats with erectile dysfunction [31]. According to the results of studies discussed above pregabalin may act as a promoter of sexual dysfunction by effecting the central neurotransmitters which play a role in mechanism of erection and sexual behavior. For confirming these suggestions further clinical and experimental studies needed. Our study is the first controlled clinical trial describing the significance of the association between NP, treatment with pregabalin and ED. We demonstrated that mean IIEF scores for patients in the NP + Pregabalin group were lower than patients in the NP group and the control group (Table 2). Furthermore, the difference between the NP + Pregabalin and control groups was greater than the difference between NP + Pregabalin and NP groups. Specifically, the difference between the NP + Pregabalin and control groups was statistically significant for all IIEF parameters. For the NP + Pregabalin and NP groups, statistically significant differences were noted for erectile function, orgasmic function, overall satisfaction, and IIEF total score. These results reveal that NP alone impairs sexual function, and pregabalin may exacerbate ED in patients with pre-existing NP. The pathophysiology of pregabalin-induced ED is unclear and further studies must further elucidate this association, and the extent to which it affects the patient’s and partner’s QoL. On the other hand, psychological state of patients with NP did not evaluated by an objective scale, so this can be considered as a limitation of the present study. Conclusion
Our results show that pregabalin further decreases erectile function in male patients with NP. This impairment in sexual function NP patients taking pregabalin was greater than male patients with NP alone. Nevertheless, our results must be confirmed by additional randomized placebo-controlled studies with larger sample sizes before making recommendations for pregabalin dosing to limit ED. In addition, further studies should explore the pathophysiology of pregabalin-induced ED. However, we recommend that clinicians screen for ED in patients with NP before and during treatment with pregabalin using the IIEF questionnaire as it is simple to administer and to perform. Corresponding Author: Mehtap Bozkurt, MD, Department of Physical Medicine and Rehabilitation,
Association Between Pregabalin and Erectile Dysfunction University of Dicle, Diyarbakir 21280, Turkey. Tel: 00 90 412 248 80 01; Fax: 00 90 412 248 85 23; E-mail: [email protected] Conflict of Interest: The author(s) report no conflicts of interest.
Statement of Authorship
Category 1 (a) Conception and Design Mehtap Bozkurt; Cuneyt Gocmez (b) Acquisition of Data Cuneyt Gocmez; Serda Em; Mehmet Yrldrz; Mansur Daggulli (c) Analysis and Interpretation of Data Yesar Bozkurt; Haluk Soylemez
Category 2 (a) Drafting the Article Mehtap Bozkurt; Cuneyt Gocmez (b) Revising It for Intellectual Content Haluk Soylemez; Murat Atar
Category 3 (a) Final Approval of the Completed Article Iza Ozbey
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