532789
research-article2014
AOPXXX10.1177/1060028014532789Annals of PharmacotherapyHsu et al
Article
Rapid Management of Trigeminal Neuralgia and Comorbid Major Depressive Disorder With Duloxetine: A Case Report
Annals of Pharmacotherapy 1–3 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014532789 aop.sagepub.com
Chung-Chih Hsu, MD1, Chun-Wei Chang, MD, PhD1, Chia-Ho Peng, MD1, and Chih-Sung Liang, MD1,2
Abstract Objective: To describe a case of a patient diagnosed with major depressive disorder whose trigeminal neuralgia was unexpectedly but rapidly and efficiently responsive to duloxetine. Case Summary: A 37-year-old woman was diagnosed with trigeminal neuralgia, and the initial treatment with carbamazepine 800 mg/d did not improve her pain. In the following 3 years, she was poorly responsive to the combination therapy with several medications, including carbamazepine, valproate, baclofen, diclofenac, and acetaminophen. The repeated gamma knife radiosurgery still did not relieve her symptoms. She developed clinically significant depressive symptoms, and a diagnosis of major depressive disorder was made. Duloxetine 30 mg/d was initiated for the management of depression, with the dose gradually increased to 60 mg/d. Unexpectedly, at the dose of 60 mg/d, the patient reported remarkable relief in her trigeminal neuralgia within the first week. Her depressed mood gradually improved in the following 3 weeks. At the 4-year follow-up, she was gradually tapered off her medications, and her depression and trigeminal neuralgia were well managed on duloxetine 60 mg/d and carbamazepine 600 mg/d. Discussion: The mechanisms may be related to duloxetine’s ability to modulate norepinephrine and serotonin and antagonize N-methyl-d-aspartate (NMDA) receptors. The ignition hypothesis is a proposed etiology of trigeminal neuralgia, in that any individual hyperexcitable neuron can spread its discharge quickly to activate the entire population of neurons. We suggest that duloxetine exerts desynchronizing effects through its NMDA antagonism, modulating the hyperexcitable state of the trigeminal afferents. Conclusions: Duloxetine may be an adjuvant in treatment-resistant trigeminal neuralgia. Keywords trigeminal neuralgia, depression, duloxetine, NMDA receptor, desynchronization
Introduction Trigeminal neuralgia, a neuropathic pain syndrome, is considered one of the most painful conditions experienced by people and is characterized by a severe, almost exclusively unilateral, neuropathic pain located within the distribution of the trigeminal nerve. Its relapsing-remitting and excruciating characteristics can severely and negatively affect the quality of life and increase the risk of depression in affected people.1 A variety of medications have been shown to effectively treat neuropathic pain,2 but 30% of patients still experience pain after appropriate treatment strategies.2 Combinations of 2 or more drugs with different mechanisms of action may be considered in these remaining patients.2 The American Academy of Neurology and the European Federation of Neurological Societies (AANEFNS) guidelines suggest that only carbamazepine and oxcarbazepine are established as effective for pain control in the management of trigeminal neuralgia.3
Historically, antidepressant medications have been used in the management of trigeminal neuralgia, such as tricyclic antidepressants and serotonin-noradrenaline reuptake inhibitors; however, according to the AAN-EFNS guidelines,3 the efficacy is inconclusive. Duloxetine is a serotonin-noradrenaline reuptake inhibitor that also has approval for the management of diabetic peripheral neuropathic pain,4 and preliminary data from an open-label trial provide evidence supporting its benefit for treating trigeminal 1
Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC 2 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC Corresponding Author: Chih-Sung Liang, Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, No. 60, Xinmin Rd, Beitou District, Taipei City 11243, Taiwan, ROC. Email: [email protected]
Downloaded from aop.sagepub.com at UNIVERSITY OF BRIGHTON on June 10, 2014
2
Annals of Pharmacotherapy
neuralgia.5 There are no studies examining whether these beneficial results could be obtained in individuals with both depression and trigeminal neuralgia. A case of a patient diagnosed with depression whose trigeminal neuralgia was unexpectedly but rapidly and efficiently responsive to duloxetine is reported here. The analgesic effect of duloxetine was found to precede its antidepressant effect. To our knowledge, this is the first report demonstrating the efficacy of duloxetine for treating both depression and trigeminal neuralgia. In addition to the modulation of norepinephrine and serotonin, we provide another point of view about the pain-relieving mechanisms of duloxetine to rapidly improve trigeminal neuralgia.
trigeminal neuralgia within the first week. The significant improvement was also evident by her score, which changed from 10 to 6, on the Pain Intensity Numerical Rating Scale (NRS), where 0 indicates no pain and 10 indicates the worst pain. In the following 3 weeks, her depressed mood gradually improved, and her Clinical Global Impressions (CGI) Severity Scale score changed from 6 to 3. In the following 4 years, the patient was followed up at our outpatient clinic, and her depression and trigeminal neuralgia were well managed on duloxetine 60 mg/d and carbamazepine 600 mg/d. Moreover, she was able to resume her job.
Case Report
The patient did not have a previous history of mood, personality, and somatoform disorders, and her clinically significant depressive symptoms developed after becoming refractory to the medications and radiosurgical intervention for trigeminal neuralgia. We observed a rapid onset of the analgesic effect of duloxetine 60 mg/d for trigeminal neuralgia, and this analgesic effect clearly preceded its antidepressant effect. The improvement in both the trigeminal neuralgia and depression is supported by our observations and changes in the Pain Intensity NRS and the CGI Severity Scale. In brief, this case adds to the literature supporting the view that duloxetine 60 mg/d could effectively manage the cooccurrence of trigeminal neuralgia and major depressive disorder. Duloxetine has been well documented to alleviate diabetic neuropathy,4,6,7 and the improvement could be observed as early as 1 week after duloxetine treatment. Our observations that duloxetine exerted its analgesic effect in trigeminal neuralgia within days seemingly correspond to its reported efficacy in diabetic neuropathy. The mechanisms of duloxetine in pain relief have been associated with the descending inhibition with the modulation of the synaptic availability of norepinephrine and serotonin.8,9 Strong evidence derived from path analysis suggests that this analgesic effect comes directly from duloxetine itself rather than its indirect antidepressant effect.10 However, pain is a complex experience, which consists of the physiological responses of the nociceptive system and the processing of that information in the emotion-related brain network.10 Thus, the pain relief gained from duloxetine may be partially related to some of the pain caused by the depression itself. In addition to duloxetine’s relatively balanced mode of action on norepinephrine and serotonin,10 we suggest that the rapid analgesic effect of duloxetine is related to its ability to antagonize N-methyl-d-aspartate (NMDA) receptors and impede the l-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, according to preliminary evidence from animal research.11 Evidence indicates that both NMDA receptors and NO are involved in the development of neuropathic pain.12-14 NMDA receptor blocking agents, such as ketamine and dextromethorphan, have been suggested to offer a novel approach to
A 37-year-old woman with no previous psychiatric history suffered from paroxysmal, shooting right facial pain over the third branch of the right trigeminal nerve. Each episode of pain usually persisted up to 1 minute, with attacks occurring throughout the day, particularly in the evening. Trigeminal neuralgia was diagnosed, and carbamazepine was administered, with the dose gradually titrated up to 800 mg/d. However, only a slight improvement in pain was reported. In the 3 years following the initial diagnosis of trigeminal neuralgia, a variety of medications were added, including valproate, baclofen, diclofenac, and acetaminophen, but the pain remained refractory to these medications. The patient was then transferred to a medical center for magnetic resonance imaging (MRI) of the brain, which revealed a small vessel impinging on the nerve root entry zone of the trigeminal nerve on the right side, with welldemonstrated bilateral fifth nerves and excluded right trigeminal neuroma. The patient underwent gamma knife stereotactic radiosurgery with a dose of 90 Gy, which did not relieve her pain. Another brain MRI performed 1 year later revealed a focal enhancement at the cisternal portion of the right trigeminal nerve, which was compatible with a radiation effect from the previous gamma knife radiosurgery. A second gamma knife radiosurgery was performed with a dose of 85 Gy. Unfortunately, the patient still complained of intolerable pain and declined another operational intervention suggested by her treating neurologist. When the patient was 40 years of age, she developed a clinically significant depressed mood, with loss of interest and a low activity level, became easily distracted, and developed suicidal ideation. During this time, she also quit her job as a result of occupational, social, and interpersonal dysfunction that occurred secondary to her depressive symptoms. She was then referred to our outpatient clinic, where she was diagnosed with major depressive disorder. Duloxetine 30 mg/d was initiated for the management of depression, with the dose gradually increased to 60 mg/d over the next month. Unexpectedly, at the dose of 60 mg/d, the patient reported remarkable relief in her
Discussion
Downloaded from aop.sagepub.com at UNIVERSITY OF BRIGHTON on June 10, 2014
3
Hsu et al the treatment of neuropathic pain, but there are some inconsistencies among study results.15 The blockade of NO is reported to reverse the mechanical allodynia and thermal hyperalgesia in rats in a rapid manner.16 As a result, we suggest that the inhibition of NMDA receptors and NO-cGMP synthesis contributes to the analgesic effect of duloxetine. On the other hand, the ignition hypothesis is a proposed etiology of trigeminal neuralgia.17 It postulates that any individual hyperexcitable neuron can spread its discharge quickly to activate the entire population of neurons, causing synchronized after-discharge activity that is associated with paroxysmal lancinating pain. Given that glutamate could synchronize the neuronal activity through NMDA receptors18 and NMDA antagonism has been demonstrated to disrupt the synchronization of action potential firing in animal studies,19 the mechanisms through which duloxetine effectively manages trigeminal neuralgia might be related to its desynchronization property. This hypothesis warrants further investigation. According to the revised EFNS guidelines,20 tricyclic antidepressants, gabapentin, and pregabalin are indicated as first-line treatment for various neuropathic pain conditions; however, in the management of trigeminal neuralgia, carbamazepine and oxcarbazepine are confirmed as first-line therapy. The revised guidelines now recommend duloxetine as first-line therapy in painful diabetic polyneuropathies. Interestingly, a recent study examining the efficacy of duloxetine monotherapy in trigeminal neuralgia showed a promising result.5 Our case report provides evidence supporting the management of both trigeminal neuropathic pain and depression with duloxetine. Our patient failed to respond to several medications, but her trigeminal neuralgia was significantly relieved after adding duloxetine 60 mg/d as an adjuvant to carbamazepine 600 mg/d. The analgesic effect of duloxetine appears to precede its antidepressant effect. Moreover, duloxetine may exert desynchronizing effects through its NMDA antagonism, which can modulate the hyperexcitable state of the trigeminal afferents. Further studies investigating the combination therapy of carbamazepine and duloxetine for treating trigeminal neuralgia are encouraged. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Macianskyte D, Januzis G, Kubilius R, Adomaitiene V, Sciupokas A. Associations between chronic pain and depressive symptoms in patients with trigeminal neuralgia. Medicina (Kaunas). 2011;47:386-392. 2. Vranken JH. Mechanisms and treatment of neuropathic pain. Cent Nerv Syst Agents Med Chem. 2009;9:71-78.
3. Cruccu G, Gronseth G, Alksne J, et al. AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol. 2008;15:1013-1028. 4. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;(1):CD007115. 5. Anand KS, Dhikav V, Prasad A, Shewtengna. Efficacy, safety and tolerability of duloxetine in idiopathic trigeminal neuralgia. J Indian Med Assoc. 2011;109:264-266. 6. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005;116:109-118. 7. Kajdasz DK, Iyengar S, Desaiah D, et al. Duloxetine for the management of diabetic peripheral neuropathic pain: evidence-based findings from post hoc analysis of three multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. Clin Ther. 2007;29(suppl):2536-2546. 8. Bymaster FP, Lee TC, Knadler MP, Detke MJ, Iyengar S. The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des. 2005;11:1475-1493. 9. Verdu B, Decosterd I, Buclin T, Stiefel F, Berney A. Antidepressants for the treatment of chronic pain. Drugs. 2008;68:2611-2632. 10. Perahia DG, Pritchett YL, Desaiah D, Raskin J. Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect? Int Clin Psychopharmacol. 2006;21:311-317. 11. Zomkowski AD, Engel D, Cunha MP, Gabilan NH, Rodrigues AL. The role of the NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of duloxetine in the forced swimming test. Pharmacol Biochem Behav. 2012;103:408-417. 12. Calabrese F, Guidotti G, Molteni R, Racagni G, Mancini M, Riva MA. Stress-induced changes of hippocampal NMDA receptors: modulation by duloxetine treatment. PLoS One. 2012;7:e37916. 13. Levy D, Zochodne DW. NO pain: potential roles of nitric oxide in neuropathic pain. Pain Pract. 2004;4:11-18. 14. Wu LJ, Zhuo M. Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. Neurotherapeutics. 2009;6:693-702. 15. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in cancer pain management. Oncologist. 2004;9:571-591. 16. Levy D, Tal M, Hoke A, Zochodne DW. Transient action of the endothelial constitutive nitric oxide synthase (ecNOS) mediates the development of thermal hypersensitivity following peripheral nerve injury. Eur J Neurosci. 2000;12:23232332. 17. Devor M, Amir R, Rappaport ZH. Pathophysiology of trigeminal neuralgia: the ignition hypothesis. Clin J Pain. 2002;18:4-13. 18. Angulo MC, Kozlov AS, Charpak S, Audinat E. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J Neurosci. 2004;24:6920-6927. 19. Molina LA, Skelin I, Gruber AJ. Acute NMDA receptor antagonism disrupts synchronization of action potential firing in rat prefrontal cortex. PLoS One. 2014;9:e85842. 20. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17:1113-1123.
Downloaded from aop.sagepub.com at UNIVERSITY OF BRIGHTON on June 10, 2014
research-article2014
AOPXXX10.1177/1060028014532789Annals of PharmacotherapyHsu et al
Article
Rapid Management of Trigeminal Neuralgia and Comorbid Major Depressive Disorder With Duloxetine: A Case Report
Annals of Pharmacotherapy 1–3 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014532789 aop.sagepub.com
Chung-Chih Hsu, MD1, Chun-Wei Chang, MD, PhD1, Chia-Ho Peng, MD1, and Chih-Sung Liang, MD1,2
Abstract Objective: To describe a case of a patient diagnosed with major depressive disorder whose trigeminal neuralgia was unexpectedly but rapidly and efficiently responsive to duloxetine. Case Summary: A 37-year-old woman was diagnosed with trigeminal neuralgia, and the initial treatment with carbamazepine 800 mg/d did not improve her pain. In the following 3 years, she was poorly responsive to the combination therapy with several medications, including carbamazepine, valproate, baclofen, diclofenac, and acetaminophen. The repeated gamma knife radiosurgery still did not relieve her symptoms. She developed clinically significant depressive symptoms, and a diagnosis of major depressive disorder was made. Duloxetine 30 mg/d was initiated for the management of depression, with the dose gradually increased to 60 mg/d. Unexpectedly, at the dose of 60 mg/d, the patient reported remarkable relief in her trigeminal neuralgia within the first week. Her depressed mood gradually improved in the following 3 weeks. At the 4-year follow-up, she was gradually tapered off her medications, and her depression and trigeminal neuralgia were well managed on duloxetine 60 mg/d and carbamazepine 600 mg/d. Discussion: The mechanisms may be related to duloxetine’s ability to modulate norepinephrine and serotonin and antagonize N-methyl-d-aspartate (NMDA) receptors. The ignition hypothesis is a proposed etiology of trigeminal neuralgia, in that any individual hyperexcitable neuron can spread its discharge quickly to activate the entire population of neurons. We suggest that duloxetine exerts desynchronizing effects through its NMDA antagonism, modulating the hyperexcitable state of the trigeminal afferents. Conclusions: Duloxetine may be an adjuvant in treatment-resistant trigeminal neuralgia. Keywords trigeminal neuralgia, depression, duloxetine, NMDA receptor, desynchronization
Introduction Trigeminal neuralgia, a neuropathic pain syndrome, is considered one of the most painful conditions experienced by people and is characterized by a severe, almost exclusively unilateral, neuropathic pain located within the distribution of the trigeminal nerve. Its relapsing-remitting and excruciating characteristics can severely and negatively affect the quality of life and increase the risk of depression in affected people.1 A variety of medications have been shown to effectively treat neuropathic pain,2 but 30% of patients still experience pain after appropriate treatment strategies.2 Combinations of 2 or more drugs with different mechanisms of action may be considered in these remaining patients.2 The American Academy of Neurology and the European Federation of Neurological Societies (AANEFNS) guidelines suggest that only carbamazepine and oxcarbazepine are established as effective for pain control in the management of trigeminal neuralgia.3
Historically, antidepressant medications have been used in the management of trigeminal neuralgia, such as tricyclic antidepressants and serotonin-noradrenaline reuptake inhibitors; however, according to the AAN-EFNS guidelines,3 the efficacy is inconclusive. Duloxetine is a serotonin-noradrenaline reuptake inhibitor that also has approval for the management of diabetic peripheral neuropathic pain,4 and preliminary data from an open-label trial provide evidence supporting its benefit for treating trigeminal 1
Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC 2 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC Corresponding Author: Chih-Sung Liang, Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, No. 60, Xinmin Rd, Beitou District, Taipei City 11243, Taiwan, ROC. Email: [email protected]
Downloaded from aop.sagepub.com at UNIVERSITY OF BRIGHTON on June 10, 2014
2
Annals of Pharmacotherapy
neuralgia.5 There are no studies examining whether these beneficial results could be obtained in individuals with both depression and trigeminal neuralgia. A case of a patient diagnosed with depression whose trigeminal neuralgia was unexpectedly but rapidly and efficiently responsive to duloxetine is reported here. The analgesic effect of duloxetine was found to precede its antidepressant effect. To our knowledge, this is the first report demonstrating the efficacy of duloxetine for treating both depression and trigeminal neuralgia. In addition to the modulation of norepinephrine and serotonin, we provide another point of view about the pain-relieving mechanisms of duloxetine to rapidly improve trigeminal neuralgia.
trigeminal neuralgia within the first week. The significant improvement was also evident by her score, which changed from 10 to 6, on the Pain Intensity Numerical Rating Scale (NRS), where 0 indicates no pain and 10 indicates the worst pain. In the following 3 weeks, her depressed mood gradually improved, and her Clinical Global Impressions (CGI) Severity Scale score changed from 6 to 3. In the following 4 years, the patient was followed up at our outpatient clinic, and her depression and trigeminal neuralgia were well managed on duloxetine 60 mg/d and carbamazepine 600 mg/d. Moreover, she was able to resume her job.
Case Report
The patient did not have a previous history of mood, personality, and somatoform disorders, and her clinically significant depressive symptoms developed after becoming refractory to the medications and radiosurgical intervention for trigeminal neuralgia. We observed a rapid onset of the analgesic effect of duloxetine 60 mg/d for trigeminal neuralgia, and this analgesic effect clearly preceded its antidepressant effect. The improvement in both the trigeminal neuralgia and depression is supported by our observations and changes in the Pain Intensity NRS and the CGI Severity Scale. In brief, this case adds to the literature supporting the view that duloxetine 60 mg/d could effectively manage the cooccurrence of trigeminal neuralgia and major depressive disorder. Duloxetine has been well documented to alleviate diabetic neuropathy,4,6,7 and the improvement could be observed as early as 1 week after duloxetine treatment. Our observations that duloxetine exerted its analgesic effect in trigeminal neuralgia within days seemingly correspond to its reported efficacy in diabetic neuropathy. The mechanisms of duloxetine in pain relief have been associated with the descending inhibition with the modulation of the synaptic availability of norepinephrine and serotonin.8,9 Strong evidence derived from path analysis suggests that this analgesic effect comes directly from duloxetine itself rather than its indirect antidepressant effect.10 However, pain is a complex experience, which consists of the physiological responses of the nociceptive system and the processing of that information in the emotion-related brain network.10 Thus, the pain relief gained from duloxetine may be partially related to some of the pain caused by the depression itself. In addition to duloxetine’s relatively balanced mode of action on norepinephrine and serotonin,10 we suggest that the rapid analgesic effect of duloxetine is related to its ability to antagonize N-methyl-d-aspartate (NMDA) receptors and impede the l-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, according to preliminary evidence from animal research.11 Evidence indicates that both NMDA receptors and NO are involved in the development of neuropathic pain.12-14 NMDA receptor blocking agents, such as ketamine and dextromethorphan, have been suggested to offer a novel approach to
A 37-year-old woman with no previous psychiatric history suffered from paroxysmal, shooting right facial pain over the third branch of the right trigeminal nerve. Each episode of pain usually persisted up to 1 minute, with attacks occurring throughout the day, particularly in the evening. Trigeminal neuralgia was diagnosed, and carbamazepine was administered, with the dose gradually titrated up to 800 mg/d. However, only a slight improvement in pain was reported. In the 3 years following the initial diagnosis of trigeminal neuralgia, a variety of medications were added, including valproate, baclofen, diclofenac, and acetaminophen, but the pain remained refractory to these medications. The patient was then transferred to a medical center for magnetic resonance imaging (MRI) of the brain, which revealed a small vessel impinging on the nerve root entry zone of the trigeminal nerve on the right side, with welldemonstrated bilateral fifth nerves and excluded right trigeminal neuroma. The patient underwent gamma knife stereotactic radiosurgery with a dose of 90 Gy, which did not relieve her pain. Another brain MRI performed 1 year later revealed a focal enhancement at the cisternal portion of the right trigeminal nerve, which was compatible with a radiation effect from the previous gamma knife radiosurgery. A second gamma knife radiosurgery was performed with a dose of 85 Gy. Unfortunately, the patient still complained of intolerable pain and declined another operational intervention suggested by her treating neurologist. When the patient was 40 years of age, she developed a clinically significant depressed mood, with loss of interest and a low activity level, became easily distracted, and developed suicidal ideation. During this time, she also quit her job as a result of occupational, social, and interpersonal dysfunction that occurred secondary to her depressive symptoms. She was then referred to our outpatient clinic, where she was diagnosed with major depressive disorder. Duloxetine 30 mg/d was initiated for the management of depression, with the dose gradually increased to 60 mg/d over the next month. Unexpectedly, at the dose of 60 mg/d, the patient reported remarkable relief in her
Discussion
Downloaded from aop.sagepub.com at UNIVERSITY OF BRIGHTON on June 10, 2014
3
Hsu et al the treatment of neuropathic pain, but there are some inconsistencies among study results.15 The blockade of NO is reported to reverse the mechanical allodynia and thermal hyperalgesia in rats in a rapid manner.16 As a result, we suggest that the inhibition of NMDA receptors and NO-cGMP synthesis contributes to the analgesic effect of duloxetine. On the other hand, the ignition hypothesis is a proposed etiology of trigeminal neuralgia.17 It postulates that any individual hyperexcitable neuron can spread its discharge quickly to activate the entire population of neurons, causing synchronized after-discharge activity that is associated with paroxysmal lancinating pain. Given that glutamate could synchronize the neuronal activity through NMDA receptors18 and NMDA antagonism has been demonstrated to disrupt the synchronization of action potential firing in animal studies,19 the mechanisms through which duloxetine effectively manages trigeminal neuralgia might be related to its desynchronization property. This hypothesis warrants further investigation. According to the revised EFNS guidelines,20 tricyclic antidepressants, gabapentin, and pregabalin are indicated as first-line treatment for various neuropathic pain conditions; however, in the management of trigeminal neuralgia, carbamazepine and oxcarbazepine are confirmed as first-line therapy. The revised guidelines now recommend duloxetine as first-line therapy in painful diabetic polyneuropathies. Interestingly, a recent study examining the efficacy of duloxetine monotherapy in trigeminal neuralgia showed a promising result.5 Our case report provides evidence supporting the management of both trigeminal neuropathic pain and depression with duloxetine. Our patient failed to respond to several medications, but her trigeminal neuralgia was significantly relieved after adding duloxetine 60 mg/d as an adjuvant to carbamazepine 600 mg/d. The analgesic effect of duloxetine appears to precede its antidepressant effect. Moreover, duloxetine may exert desynchronizing effects through its NMDA antagonism, which can modulate the hyperexcitable state of the trigeminal afferents. Further studies investigating the combination therapy of carbamazepine and duloxetine for treating trigeminal neuralgia are encouraged. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Macianskyte D, Januzis G, Kubilius R, Adomaitiene V, Sciupokas A. Associations between chronic pain and depressive symptoms in patients with trigeminal neuralgia. Medicina (Kaunas). 2011;47:386-392. 2. Vranken JH. Mechanisms and treatment of neuropathic pain. Cent Nerv Syst Agents Med Chem. 2009;9:71-78.
3. Cruccu G, Gronseth G, Alksne J, et al. AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol. 2008;15:1013-1028. 4. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;(1):CD007115. 5. Anand KS, Dhikav V, Prasad A, Shewtengna. Efficacy, safety and tolerability of duloxetine in idiopathic trigeminal neuralgia. J Indian Med Assoc. 2011;109:264-266. 6. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005;116:109-118. 7. Kajdasz DK, Iyengar S, Desaiah D, et al. Duloxetine for the management of diabetic peripheral neuropathic pain: evidence-based findings from post hoc analysis of three multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. Clin Ther. 2007;29(suppl):2536-2546. 8. Bymaster FP, Lee TC, Knadler MP, Detke MJ, Iyengar S. The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des. 2005;11:1475-1493. 9. Verdu B, Decosterd I, Buclin T, Stiefel F, Berney A. Antidepressants for the treatment of chronic pain. Drugs. 2008;68:2611-2632. 10. Perahia DG, Pritchett YL, Desaiah D, Raskin J. Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect? Int Clin Psychopharmacol. 2006;21:311-317. 11. Zomkowski AD, Engel D, Cunha MP, Gabilan NH, Rodrigues AL. The role of the NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of duloxetine in the forced swimming test. Pharmacol Biochem Behav. 2012;103:408-417. 12. Calabrese F, Guidotti G, Molteni R, Racagni G, Mancini M, Riva MA. Stress-induced changes of hippocampal NMDA receptors: modulation by duloxetine treatment. PLoS One. 2012;7:e37916. 13. Levy D, Zochodne DW. NO pain: potential roles of nitric oxide in neuropathic pain. Pain Pract. 2004;4:11-18. 14. Wu LJ, Zhuo M. Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. Neurotherapeutics. 2009;6:693-702. 15. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in cancer pain management. Oncologist. 2004;9:571-591. 16. Levy D, Tal M, Hoke A, Zochodne DW. Transient action of the endothelial constitutive nitric oxide synthase (ecNOS) mediates the development of thermal hypersensitivity following peripheral nerve injury. Eur J Neurosci. 2000;12:23232332. 17. Devor M, Amir R, Rappaport ZH. Pathophysiology of trigeminal neuralgia: the ignition hypothesis. Clin J Pain. 2002;18:4-13. 18. Angulo MC, Kozlov AS, Charpak S, Audinat E. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J Neurosci. 2004;24:6920-6927. 19. Molina LA, Skelin I, Gruber AJ. Acute NMDA receptor antagonism disrupts synchronization of action potential firing in rat prefrontal cortex. PLoS One. 2014;9:e85842. 20. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17:1113-1123.
Downloaded from aop.sagepub.com at UNIVERSITY OF BRIGHTON on June 10, 2014
