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Gonadotoxic effect of tramadol administration: A prospective controlled study Gonadotoxic effect of tramadol administration: A prospective controlled study
Soliman, Tarek; Shaher, Hussein; Mohey, Ahmed; El-Shaer, Waleed; Sebaey, Ahmed
2022-01-02 00:00:00
ARAB JOURNAL OF UROLOGY 2022, VOL. 20, NO. 1, 54–60 https://doi.org/10.1080/2090598X.2021.2002634 ANDROLOGY AND SEXUAL MEDICINE: ORIGINAL ARTICLE Tarek Soliman, Hussein Shaher, Ahmed Mohey, Waleed El-Shaer and Ahmed Sebaey Department of Urology and Andrology, Benha University, Benha, Egypt ABSTRACT ARTICLE HISTORY Received 9 May 2021 Objective: To detect the possible gonadotoxic effects of tramadol dependence on seminal Accepted 8 June 2021 fluid parameters, and prolactin and testosterone hormone levels. Patients, Subjects, and Methods: There were 94 participants who were divided into KEYWORDS a tramadol-dependent group (T-group; 56 patients) and a control group (C-group; 38 healthy Tramadol; gonadotoxic; volunteers). The following variables were evaluated: testosterone level, prolactin level, erectile libido; erectile dysfunction function, libido, semen parameters, and effect of tramadol dose and dependence duration. Results: There was a significant increase in erectile dysfunction (ED) and decreased libido in the T-group vs C-group. Also, the serum testosterone level was lower in the T-group vs the C-group, while the serum prolactin level was significantly higher in the T-group vs the C-group. All semen parameters were low in the T-group except for abnormal forms, which were high. As the dose of tramadol increased there was a more negative effect on the previous parameter, while ED, libido, semen volume and concentration showed no sig- nificant changes. When comparing tramadol doses of 400–1000 mg/day to >1000 mg/day, the tramadol blood level increased with high doses, while serum testosterone level decreased when the dose increased and the prolactin level increased when the dose increased. Progressive motility of the sperm decreased and abnormal forms increased. Also increased duration of tramadol administration was also accompanied by a more negative effect on these parameters Conclusion: Tramadol administration has a negative effect on hormone levels, libido, erectile function, and semen characters. Abbreviations: ED: erectile dysfunction; EF: erectile function Opioids and tramadol as an opioid may have nega- Introduction tive effects on libido, and erectile function (EF) and Tramadol is an atypical synthetic opioid and an ejaculatory function [11,12]. Long-term use of opioids analgesic. Tramadol has two mechanisms of action may result in hypogonadism by decreasing the release through μ-opioid agonistic activity, also gamma- of GnRH, so decreasing the testosterone level and finally aminobutyric acid (GABA), noradrenaline, serotoner- affecting EF and male fertility [11,12]. gic actions it has a central action and local action The published data about the impact of chronic through increasing nitric oxide levels [1–3]; so, it is tramadol addiction on male sexual and reproduc- prescribed as pain reliever in moderate and severe tive functions are scarce. Thus, we opted to design cases [4]. the present study to investigate the effect of tra- Due to its popularity and huge use especially madol addiction on male sexual life and fertility. among youth as pain reliever, tramadol dependence has become a problem in the Egyptian community Patients, subjects, and methods [5,6]. Also a lot of people in Egypt use tramadol as a treatment for premature ejaculation, as they This was prospective controlled non-randomised study believe that tramadol has a positive impact on that enrolled 94 participants who were divided into 56 their sexual functions [7]. patients who were tramadol-dependent (T-group) and Much research has found that tramadol can pro- 38 healthy volunteers, i.e. control group (C-group). duce changes in gonadal hormone levels and These participants were among the attendants of the increase DNA damage in sperm, which affects sper- outpatient clinics, Benha University Hospital, Egypt, in matogenesis in laboratory animals such as rats [8]. the period between June 2018 and June 2019. Administration of opioid compounds at high doses The sample size was calculated with the formulas and for long periods increases reactive oxygen spe- of a two-sample test. Sampling ratio was 2:3 (N2/ cies, which can lead to DNA fragmentation of sperm N1), the power was 80%, 5% α error and CI of 95%; cells and affecting sperm motility and morphology. Calculated minimum sample size was 54 and 36 for So, it may lead to male infertility [9,10]. the T- and C-groups, respectively. CONTACT Hussein Shaher hussein.shaher@gmail.com Benha Faculty of Medicine, Benha University, Benha, Qalyubia, Egypt © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ARAB JOURNAL OF UROLOGY 55 All participants in the study were informed about those under radio- or chemotherapy. Also, patients the details of the study. And a written, well-informed dependent on mixed drugs or under hormonal treat- consent was signed by each participant. The study ment or on phosphodiesterase type 5 inhibitors were protocol was approved by the local Ethics Committee. excluded. Moreover, patients with varicocele or testi- cular tumours that may affect fertility status, patients with infertility were excluded. Inclusion criteria All participants were subjected to history taking T-group: adult males aged <40 years, dependent on including toxicological history as concentration, amount and form of tramadol received per day. tramadol only, with fulfilment of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition Duration of tramadol dependence (lifetime use of tra- (DSM V) criteria of dependence [13]. madol). Any previous treatment for dependence. Presence or absence of libido and EF were also All patients had no objections or medical diseases interfering with obtaining blood and semen samples evaluated. from them. Criteria of opioid dependence: Investigations 1. Taking the opioid in larger amounts and for Quick view tramadol test card A one-step drug of abuse rapid test: it is an in vitro longer than intended. immuno-chromatographic assay for the rapid visual 2. Wanting to cut down or quit but not being able to do it. qualitative detection of tramadol in human urine to 3. Spending a lot of time obtaining the opioid. identify positive cases who then had for tramadol their blood level investigated. 4. Craving or a strong desire to use opioids. 5. Repeatedly unable to carry out major obligations at work, school, or home due to opioid use. Semen analysis Participants were asked to give the sample in the 6. Continued use despite persistent or recurring social or interpersonal problems caused or laboratory by masturbation after avoiding ejaculation made worse by opioid use. for 72 h; and avoiding alcohol, caffeine, and drugs such as cocaine and marijuana for 5 days before the test. 7. Stopping or reducing important social, occupa- Also, patients were asked to stop any herbal or hormo- tional, or recreational activities due to opioid use. 8. Recurrent use of opioids in physically hazardous nal medications. Assessment of semen by using com- situations. puter-assisted semen analysis (CASA) and according to World Health Organization reference values for human 9. Consistent use of opioids despite acknowledg- ment of persistent or recurrent physical or psy- semen characteristics (2010) for semen volume (mL), chological difficulties from using opioids. concentration (million/mL), motility (total and progres- sive motility) and abnormal forms [14]. 10. Tolerance as defined by either a need for mark- edly increased amounts to achieve intoxication or desired effect or markedly diminished effect Testosterone and prolactin levels with continued use of the same amount (does Due to the fluctuation of testosterone levels through- not apply for diminished effect when used out the day blood samples were taken between appropriately under medical supervision). 07:00 hours and 10:00 hours to measure total serum 11. Withdrawal manifestation. testosterone and prolactin level (ng/dL) by Elecsys The presence of two to three symptoms out of Testosterone II and Elecsys Prolactin II (Roche the 11 is defined as mild. Diagnostics, Mannheim, Germany). ● The presence of four to five symptoms is defined as moderate. Erectile function ● The presence of six or more symptoms is The EF of all participants were evaluated by the vali- defined as severe dated Arabic version of the Sexual Health Inventory for Men (SHIM), which contains five questions, each of C-group: healthy adult males of the same age range them scoring from 1 to 5. A final score of 22–25 indi- with normal libido, EF, normal hormonal levels, and cated no erectile dysfunction (ED), 17–21 mild ED, 12– normal semen parameters. 16 mild-to-moderate ED, 8–11 moderate ED, and 1–7 severe ED [15]. Exclusion criteria Scrotal duplex ultrasonography Patients with chronic disease such as: diabetes, obesity Scrotal duplex ultrasonography was used to exclude (body mass index ≥30 kg/m ), bronchial asthma, hepa- varicocele and any other pathology affecting testicular tic, renal, cardiovascular, or skin diseases, cancer, and function. 56 T. SOLIMAN ET AL. In this study we classified the T-group according to and Group 2 (Table 2). Regarding the duration of dose: 400–1000 mg/day (Group 1) and >1000 mg/day intake, there was significant increase in ED, which (Group 2). We also we classified the T-group according was 8.7% in Group A vs 63.6% in Group B, and signifi - to duration of addiction to: Group (A): duration 1– cant decrease in libido, which was 13% in Group A and 4 years (Group A) and >4 years (Group B). 69.7% in Group B (Table 3). Data were expressed as a mean (standard deviation There was a significant decrease in the serum tes- [SD]) and were statistically analysed using the tosterone level in Group 1 and in Group 2, and Statistical Package for the Social Sciences (SPSS®), ver- a significant increase in the serum prolactin level sion 20 (IBM corp., Armonk, NY, USA). The independent occurred in Group 1 and in Group 2 when the tramadol Student’s t-test and chi-square test were applied when dose was increased (Table 2). There was a significant appropriate. A P < 0.05 was considered to indicate decrease in the testosterone level in Group A and statistical significance. Group B accompanied by a significant increase in the prolactin level in Group A and Group B when the duration of administration was increased (Table 3). Results There was no significant relation between trama- dol dose and both the volume of semen and the The demographic data of the participants are detailed concentration of sperm either in Group 1 or Group in Table 1, regarding age there was no significant 2. In contrast, total and progressive motility signifi - difference between The T-group and the C-group, cantly decreased as the dose of tramadol increased while for education there was a significant difference in Group 1 and in Group 2. However, increasing the between the T-group and C-group. dose of tramadol resulted in a significant increase in There was a significant difference was in ED and the abnormal forms of sperm in Group 1 and in decreased libido, which occurred respectively in Group 2 (Table 2). The semen volume, sperm con- 41.1% and 46.4% in the T-group and in 7.9% and centration, total and progressive motility revealed 13.2% in the C-group (Table 1). significant decrease when the duration of depen- Also, there was a statistically significant decrease in dence increased as shown in groups A and B, the serum testosterone level and a significant increase while the abnormal forms showed a significant in the serum prolactin level in the T-group compared increase when the duration of administration was to the C-group (Table 1). prolonged (Table 3). There was a significant decrease in seminal fluid volume, sperm concentration, total motility, and pro- gressive motility in the T-group compared to the Discussion C-group. While abnormal forms of sperm were signifi - cantly increased in the T-group compared to the The wide availability of tramadol as a pain killer for many C-group (Table 1). forms of pain either acute or chronic could be a main Regarding the dose of tramadol, when the tramadol factor for its widespread use and abuse [16,17]. Another dose was increased there was a significant increase in factor for the widespread use of tramadol is its role in ED and decrease in libido when comparing in Group 1 treatment of premature ejaculation, which may be Table 1. Comparison between the T-group and C-group according to age, education, hormone levels, and seminal parameters. Variable T-group (N = 56) C-group (N = 38) St t-test P Age, years, mean (SD) 28.52 (4.18) 28.84 (4.27) 0.37 0.72 Education, n (%) Not educated 39(69.6) 8(21.1) χ = 21.38 <0.001* Educated 17(30.4) 30(78.9) ED, n (%) Yes 23(41.1) 3(7.9) χ = 12.45 <0.001* No 33(58.9) 35(92.1) Libido, n (%) Decrease 26(46.4) 5(13.2) χ = 11.34 0.001* Normal 30(53.6) 33(86.8) Serum testosterone level, ng/dL, mean (SD) 392.32 688.29 8.71 <0.001* (118.06) (210.43) Serum prolactin level, ng/mL, mean (SD) 22.11 (3.89) 8.74 (2.01) 19.48 <0.001* Semen volume, mL, mean (SD) 1.49 (0.29) 2.04 (0.24) 9.56 <0.001* Semen concentration, million/mL, mean (SD) 14.27 (1.98) 30.84 (2.66) 34.59 <0.001* Semen total motility, %, mean (SD) 32.2 (4.08) 52.23 (3.95) 23.68 <0.001* Progressive motility, %, mean (SD) 22.83 (3.53) 39.98 (3.27) 23.82 <0.001* Abnormal forms, %, mean (SD) 52.29 (9.13) 28.37 (4.69) 14.85 <0.001* *Significant at P < 0.05. ARAB JOURNAL OF UROLOGY 57 Table 2. Comparison between effects of tramadol dose on ED, libido, hormone levels, and semen parameters. Group 1 Group 2 Dose 400–1000 mg/day Dose >1000 mg/day T-group (N = 56) (n = 36) (n = 20) St t-test P Tramadol blood level, mg, mean (SD) 415.97 (86.96) 745.95 (54.07) 15.37 <0.001* ED, n (%) Yes 5 (13.9) 18 (90.0) χ = 30.77 <0.001* No 31 (86.1) 2 (10.0) Libido, n (%) Decrease 6 (16.7) 20 (100) χ = 35.9 <0.001* Normal 30 (83.3) 0 (0.0) Serum testosterone, ng/dL, mean (SD) 451.39 (106.48) 286.0 (30.85) 6.77 <0.001* Serum prolactin, ng/mL, mean (SD) 19.69 (2.36) 26.45 (1.61) 11.38 <0.001* Semen volume, mL, mean (SD) 1.51 (0.27) 1.45 (0.33) 0.71 0.48 Semen concentration, million/mL, mean (SD) 14.43 (2.01) 13.99 (1.94) 0.81 0.42 Semen total motility, %, mean (SD) 34.53 (2.99) 28.0 (1.68) 8.98 <0.001* Semen progressive motility, %, mean (SD) 24.9 (2.48) 19.09 (1.36) 9.66 <0.001* Abnormal forms, %, mean (SD) 46.17 (4.03) 63.3 (3.6) 15.81 <0.001* *Significant at P < 0.05. considered one of the apparent causes of increased There was a significant difference between trama- magnitude of the problem among youth who believe dol-dependent patients and the controls in educa- that tramadol can improve their sexual performance tional status, as 69.6% in the T-group were [16,17]. uneducated compared with ~21.1% in the C-group. Our present study showed the effects of tramadol This finding agreed with Fawzui [22] who stated that dependence on EF, libido, seminal fluid parameters as most tramadol dependents in the Ain Shams well as testosterone and prolactin hormonal levels. It Toxicology Unit were uneducated or had a minimal was carried on 94 subjects, 56 in the T-group and 38 in educational level. the C-group. In the present study, the majority the patients (36) In the present study the selected age of the partici- in the T-group received tramadol in a dosage range pants was <40 years to exclude the ageing effect on from 400 to 1000 mg/day, with 20 subjects having semen parameters and hormonal levels, as Eskenazi a dosage of >1000 mg/day. This concurs with the et al. [18] reported significant age-related decreases Goda [23] study of 100 tramadol-dependent patients, in semen quality mostly for semen volume and sperm as he reported that 24% of his patients’ received tra- motility, and they suggested that men may became madol in dosage of <400 mg/day, 53% of them progressively less fertile as they aged. received it in a dosage range of 400–2000 mg/day, Concerning the relationship between tramadol and 23% of them received >2000 mg/day. dependence and age in the present study, the mean As regard the duration of tramadol dependence, 23 (SD) age of the T-group was 28.52 (4.18) years. This is in patients in the T-group used tramadol for 1–4 years agreement with Shadnia et al. [19], Iravani et al. [20], and 33 had used it for >4 years. Comparable results and Zabihi et al. [21] who stated that the age group of were obtained by Goda [23], as 20% of his cases used 20–45 years was the highest for drug and substance tramadol for <2 years, 44% of them used it for 2– abuse compared with other age groups. 7 years, and 36% of them used it for >7 years. Table 3. Comparison between effects of tramadol addiction duration on ED, libido, hormone levels, and semen parameters. Group A Group B Duration 1–4 years Duration >4 years T-group (N = 56) (n = 23) (n = 33) St t-test P Tramadol blood level, mg, mean (SD) 357.52 (41.71) 656.7 (121.04) 11.37 <0.001* ED, n (%) Yes 2 (8.7) 21 (63.6) χ = 16.9 <0.001* No 21 (91.3) 12 (36.4) Libido, n (%) Decrease 3 (13.0) 23 (69.7) χ = 17.49 Normal 20 (87.0) 10 (30.3) <0.001 Serum testosterone, ng/dL, mean (SD) 517.83 (69.15) 304.85 (38.17) 14.79 <0.001* Serum prolactin, ng/mL, mean (SD) 18.17 (1.4) 24.85 (2.4) 11.97 <0.001* Semen volume, mL, mean (SD) 1.79 (0.16) 1.28 (0.16) 11.82 <0.001* Semen concentration, million/mL, mean (SD) 15.83 (0.59) 13.18 (1.87) 6.55 <0.001* Semen total motility, %, mean (SD) 36.43 (1.42) 29.24 (2.3) 13.31 <0.001* Semen progressive motility, %, mean (SD) 26.57 (1.24) 20.22 (1.8) 14.64 <0.001* Abnormal forms, %, mean (SD) 43.91 (3.23) 58.12 (7.12) 8.93 <0.001* *Significant at P < 0.05. 58 T. SOLIMAN ET AL. There were significant differences in the serum tes- patients on tramadol knew that they were abnormal tosterone and prolactin levels between the T-group and dependent on the substance to allow efficient and C-group in the present study. This is compatible sex practice. The explanation of this difference could with the study done by Daniell [24], who measured the be due to the use of tramadol on demand to treat hormonal profile in 54 community-dwelling outpatient premature ejaculation but not tramadol dependence men consuming oral forms of opioids several times with regular use for >1 year [29]. daily, and he reported significant decreased levels of There was a significant increase in tramadol blood serum testosterone with increased prolactin levels, levels as the daily received dose was increased in the referring this to the disturbance of hypothalamic– present study. Similar finding observed by Deer and pituitary–gonadal axis. Testosterone was also reduced Gunn [30] who also reported that measuring tramadol due to direct inhibition of testicular testosterone blood level provides extremely valuable information, synthesis [24]. which can be used to evaluate impairment or overdose Auernhammer et al. [25] stated that opioids bind to cases. Furthermore, Cepeda et al. [31] stated that ele- specific receptors in the hypothalamus and pituitary vated or diminished tramadol blood levels could guide gland, interfering with production of corticotrophin- the clinician to select the dose and prevent overdose releasing hormone (CRH) and adrenocorticotrophic or underdose (withdrawal). hormone (ACTH), and an obstacle to the release of In the present study, it was noticed that as the dose cortisol and androgen precursors. Chan et al. [26] also and duration of tramadol increased the testosterone suggested that the lowering of the serum testosterone level decreased and prolactin level increased. This level by tramadol might result from adrenal insuffi - agrees with the result of McKim [32] who reported ciency secondary to chronic use. that changes in sex hormones levels are dependent For the seminal fluid parameters, there were signifi - on the administered dose of tramadol. cant differences in semen volume, sperm concentra- Gowing et al. [33] and Herzog et al. [34] found that tion, motility, and abnormal forms between the the influence of tramadol on testosterone and prolac- T-group and C-group in our present study. This is in tin serum levels is significantly related to its dose. agreement with Ragni et al. [27] who recorded signifi - Large doses of tramadol administration led to more cant teratozoospermia, oligospermia and diminished effects. Moreover, an animal study by El-Gaafarawi [4] sperm motility in their dependent cases. Furthermore, showed minor changes in testosterone and prolactin Ragni et al. [27] revealed abnormal semen parameters levels in rats that received 40 mg/kg tramadol after in cases of prolonged opioid administration in the form 30 days, but 80 mg/kg tramadol exerted moderate of asthenospermia (100% of cases), teratozoospermia effects at 20 and 30 days. Additionally, Yilmaz et al. and hypospermia (24%), oligospermia (17%), and they [35] reported that chronic opioid exposure may cause concluded that seminal pathology even with normal long-term endocrine disturbances in rats subcuta- hormone levels might be an early indication of opioid- neously injected with opioid (5 mg/kg) twice daily for induced gonadal dysfunction. 30 days, with further reduction in serum testosterone In the present study, a significant difference was as the duration of exposure prolonged. McKim [32] detected regarding EF and decreased libido when also stated that tramadol is known to decrease the comparing the T-group and C-group. This is consistent levels of sex hormones and this lowered hormonal with other studies that reported hypogonadism as level is thought to be a chronic outcome. a serious impact of long-term tramadol administration. In the present study, total and progressive sperm Symptoms of tramadol-induced hypogonadism motility significantly decreased as the dose of tramadol include loss of libido, infertility, fatigue, depression, increased. Also, increasing the tramadol dose resulted anxiety, loss of muscle strength and ED in men [24,27]. in an increase in abnormal forms of sperm. This is in Daniell [24] contributed the ED and decreased accordance with El-Ghawet [36] who stated that tra- libido to the subnormal sex hormone levels induced madol produced a concentration-dependent effect on by chronic tramadol administration that predispose sperm motility and abnormal forms, linking this to to a diminished quality of sexual life in his studied more cellular damage and the more oxidative stress cases. Furthermore, Katz et al. [28] reported that long- caused by higher doses of tramadol. Furthermore, term tramadol administration often induces hypogo- Omid et al. [37] found a positive correlation between nadism. This is in contrast to the results of El-Hadidy the dose and abnormal semen parameters in mice, and El-Gilany [29] who evaluated 112 tramadol- indicating that the effect of tramadol on semen quality dependent married men. They noted that the sub- is dose dependent. scales of sexual relationship, sexual self-esteem, and There was a significant relationship between the overall sexual satisfaction showed a significant dose on both ED and decreased libido in the present increase after treatment compared with before treat- study. Daniell [24] reported that ED and decreased ment. This could be explained by the fact that libido had a dose-related pattern in his study. ARAB JOURNAL OF UROLOGY 59 Additionally, Goodyear-Smith et al. [38] stated that Disclosure statement reduced libido and ED were dose-dependent effects, No potential conflict of interest was reported by the and both were improved by lowering the administered author(s). dose. The present study revealed a significant positive relationship between the duration of tramadol depen- References dence and tramadol blood level. Similarly, Fudin [39] [1] Clarot F, Goulle JP, Vaz E, et al. Fatal overdoses of found a linear relationship between blood tramadol tramadol: is benzodiazepine a risk factor of lethality? level and the period of exposure and stated that Forensic Sci Int. 2003;134(1):57–61. a duration-response can be predicted in patients with [2] Klotz U. Tramadol – the impact of its pharmacokinetic chronic tramadol toxicity. and pharmacodynamic properties on the clinical man- There was a significant negative correlation agement of pain. 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