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Priapism associated with pregabalin
Journal Pre-proofs PRIAPISM ASSOCIATED WITH PREGABALIN Yusuf Karancı PII: DOI: Reference:
S0735-6757(19)30766-1 https://doi.org/10.1016/j.ajem.2019.11.027 YAJEM 158604
To appear in:
American Journal of Emergency Medicine
Received Date: Revised Date: Accepted Date:
30 October 2019 14 November 2019 14 November 2019
Please cite this article as: Y. Karancı, PRIAPISM ASSOCIATED WITH PREGABALIN, American Journal of Emergency Medicine (2019), doi: https://doi.org/10.1016/j.ajem.2019.11.027
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Inc.
PRIAPISM ASSOCIATED WITH PREGABALIN Running Title: Priapism associated with pregabalin Yusuf Karancı1 1
Health Science University, Antalya Training and Research Hospital, Department of Emergency Medicine, Antalya, Turkey
Address for correspondence: Yusuf K.., MD, Health Science University Antalya Training And Research Hospital, Kazım Karabekir Street postal zip code: 07100, Muratpaşa, Antalya, Turkey.
Phone:
+905067507825,
Fax:
+902422494487
mail
adres:
[email protected] Yusuf KARANCI: https://orcid.org/0000-0003-0230-2187
PRIAPISM ASSOCIATED WITH PREGABALIN
Abstract Priapism is defined as a prolonged erection of the penis for at least 4 hours without sexual stimulation. It may occur in all age groups. Drugs are the most common cause in adults. A 64year-old male patient was admitted to the emergency department with painful erection that had lasted for 2 days without sexual stimulation. Our patient had used pregabalin for around 1 year due to neuropathic pain. The dose of the drug was increased as his pain scaled up
recently. Approximately 30cc of dark blood was drained from the corpus cavernosum with an 18 Gauge needle in the emergency department. Cavernous blood aspiration and irrigation resulted in significant recovery and relief. We present this report of priapism associated with pregabalin as it is a rare case with insufficient number of studies in the literature. Key words: Priapism; pregabalin; emergency 1. Introduction Priapism is defined as a prolonged erection of the penis for at least 4 hours without sexual stimulation. Priapism affects quality of life, sexual function and physical health negatively. Although rare, it may occur in all age groups and is more common in patients with sickle cell anemia. There are three types of priapism: ischemic, non-ischemic and recurrent. Ischemic priapism is more common [1]. Penile erection begins with the smooth muscle relaxation of the cavernosal tissue and arteries, leading to increased blood inflow and decreased venous outflow. Corpora cavernosum is clogged due to blood accumulation resulting in a continuous painful erection [2]. The underlying cause has not been described in most cases (primary or idiopathic priapism), but some of them presented with specific medications and diseases (secondary priapism). Drug use is the most common cause in adults, particularly intracavernous injections accounting for 25 percent of the cases [3]. In our case, the patient had been using pregabalin for 1 year due to neuropathic pain and applied to the emergency department following the occurence of priapism due to increased dose of pregabalin. We present this report of priapism associated with pregabalin as it is a rare case with insufficient number of studies in the literature.
2. Case
A 64-year-old male patient was admitted to the emergency department with painful erection that had lasted for 2 days without sexual stimulation. His history revealed that he had been using 75 mg pregabalin twice a day for neuropathic pain for 1 year. However, the dose of pregabalin was increased to 300 mg twice a day by the physical therapist by whom the patient was examined due to the continious neuropathic pain he had experienced for the last 4 days. Painful erections started after increasing the drug dosage and had not regressed for 2 days. He applied to our emergency department about 36 hours after his complaints started. Approximately 30cc of dark blood was drained from the corpus cavernosum with an 18 Gauge needle in the emergency department. The patient did not have any previous history of priapism, hemoglobinopathy, cancer or any other neurological diseases except for a cerebrovascular event he experienced 2 years ago. The patient did not have a history of perineal injury, drug allergy, previous surgery, alcohol or substance use. Other than pregabalin, he used 100 mg of coraspin daily. The color of the penis was normal on examination. There was no bruising, ecchymosis, trauma and prosthesis. He had a rigid, erectile, sensitive penis. The glans penis was soft. Anal tone and rectal touch appeared normal. Neurological examination revealed 3/5 motor loss on the left (previously). Other systemic examinations were normal. Complete blood count, electrolytes, kidney and liver function tests were within normal limits. Cavernous blood aspiration and irrigation resulted in significant recovery and relief (Fig. 1). No new attack of priapism occured at 6-hour follow-up. Thereafter, the patient was discharged 2 days later with the suggestion of outpatient follow-up. He was advised to stop using pregabalin. No new attack of priapism was observed on the second day. At 1 month follow-up, the patient did not report any other attack of priapism.
3. Discussion
Pregabalin is chemically related to gabapentin and has multiple simultaneous mechanisms of action, such as gabapentin. It binds to the alpha-2-delta subunits of voltagegated calcium channels and reduces calcium transfer to other cells [4]. Pregabalin is also a presynaptic inhibitor of the release of many excitatory neurotransmitters including glutamate, noradrenaline, and substance P. Neuronal excitability appears to be inhibited as a result of the effect of pregabalin [5]. Pregabalin is used for the treatment of focal seizures, diabetic peripheral neuropathy, postherpetic neuralgia and various neuropathic pains. Pregabalin is excreted from the kidneys and is not metabolized in the liver. It has an elimination life of about 6 hours. It is not expected to interact pharmacokinetically with other drugs as it does not bind to plasma proteins [6]. Priapism most frequently occurs as a side effect of drugs. These generally include intracavernous injections, antipsychotics, antidepressants, cocaine and alcohol. Some studies have demonstrated that adrenergic α receptor blockers are also associated with priapism because of its effect on cavernous smooth muscles [7-9]. The first case of priapism, which was thought to be associated with pregabalin, was published in 2014 [10]. A case of priapism associated with increased pregabalin dose has been presented in this report for the first time. A randomized clinical trial showed that increased dose of pregabalin resulted in a clear dose-related increase in efficacy as well as an increase in the incidence of many adverse events in the treatment of neuropathic pain. The most common adverse events were dizziness, drowsiness and peripheral edema [11]. Pregabalin-induced priapism can be explained by 2 different mechanisms. Pregabalin reduces intracellular free cytosolic calcium levels by inhibiting voltage-gated calcium channels, which can induce penile erection by loosening cavernous smooth muscles. The other way is that pregabalin affects the voltage-gated calcium
channels of the adrenergic nerves, which leads to a reduction in the release of intracellular calcium stores, thereby inducing erection by relaxation of the cavernous smooth muscles [7].
4. Conclusion Pregabalin is commonly prescribed by physical therapists and neurologists. Although priapism is rarely seen, it still bears some risk, so we recommend that patients should be informed accordingly. Conflict of interest None. Sources of support None.
References [1] Johnson MJ, Kristinsson S, Ralph O, Chiriaco G, Ralph D. The surgical management of ischaemic priapism. Int J Impot Res. 2019. https://doi: 10.1038/s41443-019-0197-9. [2] Mishra K, Loeb A, Bukavina L, Baumgarten A, Beilan J, Mendez M, et al. Management of Priapism:
A
Contemporary
Review.
Sex
Med
Rev.
2019.
https://doi:
10.1016/j.sxmr.2019.01.001. [3] Burnett AL, Bivalacqua TJ. Priapism: current principles and practice. Urol Clin North Am 2007; 34:631. [4] Morano A, Palleria C, Citraro R, Nesci V, De Caro C, Giallonardo AT, et al. Immediate and controlled-release pregabalin for the treatment of epilepsy. Expert Rev Neurother. 2019. https://doi.org/10.1080/14737175.2019.1681265. [5] Lauria-Horner BA, Pohl RB. Pregabalin: a new anxiolytic. Expert Opin Investig Drugs 2003;12:663.
[6] Bockbrader HN, Burger P, Knapp L. Pregabalin effect on steady-state pharmacokinetics of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, and tiagabine. Epilepsia 2011; 52:405. [7] Leu TF. Physiology of Penile Erection and Pathophysiology of Erectile Dysfunction. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, editors. Campbell-Walsh Urology. 9th ed. Philadelphia. Saunders Elsevier; 2007. p. 718-49. [8] Spagnul SJ, Cabral PH, Verndl DO, Glina S. Adrenergic α-blockers: An infrequent and overlooked cause of priapism. Int J Impot Res 2011;23:95-8. [9] Marconi M, Pavez P, San Francisco I, Narvaez P. Priapism induced by use of tamsulosin: A case report and review of the literature. Arch Ital Urol Androl. 2019;2;91. [10]
Alsulihem
AA, Rabah
DM.
Priapism associated
with pregabalin.
Urol
Ann. 2014;6(4):366-8. [11] Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses. Diabetes Care 2008; 31:1448.
S0735-6757(19)30766-1 https://doi.org/10.1016/j.ajem.2019.11.027 YAJEM 158604
To appear in:
American Journal of Emergency Medicine
Received Date: Revised Date: Accepted Date:
30 October 2019 14 November 2019 14 November 2019
Please cite this article as: Y. Karancı, PRIAPISM ASSOCIATED WITH PREGABALIN, American Journal of Emergency Medicine (2019), doi: https://doi.org/10.1016/j.ajem.2019.11.027
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Inc.
PRIAPISM ASSOCIATED WITH PREGABALIN Running Title: Priapism associated with pregabalin Yusuf Karancı1 1
Health Science University, Antalya Training and Research Hospital, Department of Emergency Medicine, Antalya, Turkey
Address for correspondence: Yusuf K.., MD, Health Science University Antalya Training And Research Hospital, Kazım Karabekir Street postal zip code: 07100, Muratpaşa, Antalya, Turkey.
Phone:
+905067507825,
Fax:
+902422494487
adres:
[email protected] Yusuf KARANCI: https://orcid.org/0000-0003-0230-2187
PRIAPISM ASSOCIATED WITH PREGABALIN
Abstract Priapism is defined as a prolonged erection of the penis for at least 4 hours without sexual stimulation. It may occur in all age groups. Drugs are the most common cause in adults. A 64year-old male patient was admitted to the emergency department with painful erection that had lasted for 2 days without sexual stimulation. Our patient had used pregabalin for around 1 year due to neuropathic pain. The dose of the drug was increased as his pain scaled up
recently. Approximately 30cc of dark blood was drained from the corpus cavernosum with an 18 Gauge needle in the emergency department. Cavernous blood aspiration and irrigation resulted in significant recovery and relief. We present this report of priapism associated with pregabalin as it is a rare case with insufficient number of studies in the literature. Key words: Priapism; pregabalin; emergency 1. Introduction Priapism is defined as a prolonged erection of the penis for at least 4 hours without sexual stimulation. Priapism affects quality of life, sexual function and physical health negatively. Although rare, it may occur in all age groups and is more common in patients with sickle cell anemia. There are three types of priapism: ischemic, non-ischemic and recurrent. Ischemic priapism is more common [1]. Penile erection begins with the smooth muscle relaxation of the cavernosal tissue and arteries, leading to increased blood inflow and decreased venous outflow. Corpora cavernosum is clogged due to blood accumulation resulting in a continuous painful erection [2]. The underlying cause has not been described in most cases (primary or idiopathic priapism), but some of them presented with specific medications and diseases (secondary priapism). Drug use is the most common cause in adults, particularly intracavernous injections accounting for 25 percent of the cases [3]. In our case, the patient had been using pregabalin for 1 year due to neuropathic pain and applied to the emergency department following the occurence of priapism due to increased dose of pregabalin. We present this report of priapism associated with pregabalin as it is a rare case with insufficient number of studies in the literature.
2. Case
A 64-year-old male patient was admitted to the emergency department with painful erection that had lasted for 2 days without sexual stimulation. His history revealed that he had been using 75 mg pregabalin twice a day for neuropathic pain for 1 year. However, the dose of pregabalin was increased to 300 mg twice a day by the physical therapist by whom the patient was examined due to the continious neuropathic pain he had experienced for the last 4 days. Painful erections started after increasing the drug dosage and had not regressed for 2 days. He applied to our emergency department about 36 hours after his complaints started. Approximately 30cc of dark blood was drained from the corpus cavernosum with an 18 Gauge needle in the emergency department. The patient did not have any previous history of priapism, hemoglobinopathy, cancer or any other neurological diseases except for a cerebrovascular event he experienced 2 years ago. The patient did not have a history of perineal injury, drug allergy, previous surgery, alcohol or substance use. Other than pregabalin, he used 100 mg of coraspin daily. The color of the penis was normal on examination. There was no bruising, ecchymosis, trauma and prosthesis. He had a rigid, erectile, sensitive penis. The glans penis was soft. Anal tone and rectal touch appeared normal. Neurological examination revealed 3/5 motor loss on the left (previously). Other systemic examinations were normal. Complete blood count, electrolytes, kidney and liver function tests were within normal limits. Cavernous blood aspiration and irrigation resulted in significant recovery and relief (Fig. 1). No new attack of priapism occured at 6-hour follow-up. Thereafter, the patient was discharged 2 days later with the suggestion of outpatient follow-up. He was advised to stop using pregabalin. No new attack of priapism was observed on the second day. At 1 month follow-up, the patient did not report any other attack of priapism.
3. Discussion
Pregabalin is chemically related to gabapentin and has multiple simultaneous mechanisms of action, such as gabapentin. It binds to the alpha-2-delta subunits of voltagegated calcium channels and reduces calcium transfer to other cells [4]. Pregabalin is also a presynaptic inhibitor of the release of many excitatory neurotransmitters including glutamate, noradrenaline, and substance P. Neuronal excitability appears to be inhibited as a result of the effect of pregabalin [5]. Pregabalin is used for the treatment of focal seizures, diabetic peripheral neuropathy, postherpetic neuralgia and various neuropathic pains. Pregabalin is excreted from the kidneys and is not metabolized in the liver. It has an elimination life of about 6 hours. It is not expected to interact pharmacokinetically with other drugs as it does not bind to plasma proteins [6]. Priapism most frequently occurs as a side effect of drugs. These generally include intracavernous injections, antipsychotics, antidepressants, cocaine and alcohol. Some studies have demonstrated that adrenergic α receptor blockers are also associated with priapism because of its effect on cavernous smooth muscles [7-9]. The first case of priapism, which was thought to be associated with pregabalin, was published in 2014 [10]. A case of priapism associated with increased pregabalin dose has been presented in this report for the first time. A randomized clinical trial showed that increased dose of pregabalin resulted in a clear dose-related increase in efficacy as well as an increase in the incidence of many adverse events in the treatment of neuropathic pain. The most common adverse events were dizziness, drowsiness and peripheral edema [11]. Pregabalin-induced priapism can be explained by 2 different mechanisms. Pregabalin reduces intracellular free cytosolic calcium levels by inhibiting voltage-gated calcium channels, which can induce penile erection by loosening cavernous smooth muscles. The other way is that pregabalin affects the voltage-gated calcium
channels of the adrenergic nerves, which leads to a reduction in the release of intracellular calcium stores, thereby inducing erection by relaxation of the cavernous smooth muscles [7].
4. Conclusion Pregabalin is commonly prescribed by physical therapists and neurologists. Although priapism is rarely seen, it still bears some risk, so we recommend that patients should be informed accordingly. Conflict of interest None. Sources of support None.
References [1] Johnson MJ, Kristinsson S, Ralph O, Chiriaco G, Ralph D. The surgical management of ischaemic priapism. Int J Impot Res. 2019. https://doi: 10.1038/s41443-019-0197-9. [2] Mishra K, Loeb A, Bukavina L, Baumgarten A, Beilan J, Mendez M, et al. Management of Priapism:
A
Contemporary
Review.
Sex
Med
Rev.
2019.
https://doi:
10.1016/j.sxmr.2019.01.001. [3] Burnett AL, Bivalacqua TJ. Priapism: current principles and practice. Urol Clin North Am 2007; 34:631. [4] Morano A, Palleria C, Citraro R, Nesci V, De Caro C, Giallonardo AT, et al. Immediate and controlled-release pregabalin for the treatment of epilepsy. Expert Rev Neurother. 2019. https://doi.org/10.1080/14737175.2019.1681265. [5] Lauria-Horner BA, Pohl RB. Pregabalin: a new anxiolytic. Expert Opin Investig Drugs 2003;12:663.
[6] Bockbrader HN, Burger P, Knapp L. Pregabalin effect on steady-state pharmacokinetics of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, and tiagabine. Epilepsia 2011; 52:405. [7] Leu TF. Physiology of Penile Erection and Pathophysiology of Erectile Dysfunction. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, editors. Campbell-Walsh Urology. 9th ed. Philadelphia. Saunders Elsevier; 2007. p. 718-49. [8] Spagnul SJ, Cabral PH, Verndl DO, Glina S. Adrenergic α-blockers: An infrequent and overlooked cause of priapism. Int J Impot Res 2011;23:95-8. [9] Marconi M, Pavez P, San Francisco I, Narvaez P. Priapism induced by use of tamsulosin: A case report and review of the literature. Arch Ital Urol Androl. 2019;2;91. [10]
Alsulihem
AA, Rabah
DM.
Priapism associated
with pregabalin.
Urol
Ann. 2014;6(4):366-8. [11] Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses. Diabetes Care 2008; 31:1448.