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<p class="ltrs-br-ltr-br-title"><span class="bold">Tramadol-Induced Hypomania and Serotonin Syndrome</span></p>

<p class="ltrs-br-ltr-br-body-text"><span class="semibold">To the Editor:</span> Tramadol, a centrally acting synthetic opioid analgesic, has at least 2 complementary mechanisms of action. It binds to μ-opioid receptors and is a weak inhibitor of reuptake of norepinephrine and serotonin.<span class="htm-cite"><a href="#ref1">1</a></span> Tramadol shares many characteristics with venlafaxine. The drugs are structurally similar, and both cause serotonergic and noradrenergic inhibition.<span class="htm-cite"><a href="#ref2">2</a></span> Tramadol has antidepressant-like properties,<span class="htm-cite"><a href="#ref3">3</a></span> while venlafaxine on the other hand is efficacious in the long-term treatment of chronic pain with associated major depressive disorder.<span class="htm-cite"><a href="#ref4">4</a></span> Both drugs have been implicated in the induction of mania.<span class="htm-cite"><a href="#ref5">5–7</a></span> This case report describes a woman with bipolar II disorder and comorbid fibromyalgia who developed hypomania and serotonin syndrome 2 days after taking tramadol.</p>

<p class="ltrs-br-ltr-br-body-text"> </p>

<p class="ltrs-br-ltr-br-body-text"><span class="semibold-ital">Case report.</span> Ms A was a 63-year-old woman with a history of bipolar II disorder since her early 20s for which she had required several psychiatric hospitalizations. Her mood stabilized on the combination of lithium 600 mg and quetiapine 300 mg, and there were no recurrences of depression or hypomania for at least 15 months prior to the index hypomanic episode (<span class="italic">DSM-5</span>). However, she continued to struggle with symptoms of fibromyalgia. After failing to respond to pregabalin, she was prescribed tramadol 100 mg daily for fibromyalgia. Within 48 hours of taking tramadol, she began to feel agitated, had twitching of her muscles, and had muscle incoordination. Despite that she was not getting much sleep, she did not feel tired. She felt euphoric and thought her brain was working overtime. She had difficulty expressing herself due to thoughts “popping” into her head.</p>

<p class="ltrs-br-ltr-br-body-text">Within 2 days of stopping tramadol and putting lithium on hold, the symptoms of hypomania (euphoria, decreased sleep requirement, increased energy, and racing thoughts) and serotonin syndrome (agitation, twitching muscles, and muscle incoordination) resolved. When assessed at our clinic a couple days later, she was alert, oriented, and able to provide a detailed and coherent account of the psychiatric and physical symptoms she experienced over the past few days. Ms A confirmed that she had been taking the prescribed medications as directed. She denied having had any symptoms suggestive of lithium toxicity such as diarrhea, vomiting, stomach pains, dizziness, hand tremor, or slurred speech. Her most recent serum lithium level checked a month before initiation of tramadol was 0.81 mmol/L. When repeated a day after the onset of adverse reactions, her lithium level was <<span class="thinspace"> </span>0.4 mmol/L.</p>

<p class="ltrs-br-ltr-br-body-text"> </p>

<p class="ltrs-br-ltr-br-body-text"><span class="callout"><a href="#" onclick="createFigure('t1'); return false;">Table 1</a></span> lists case reports of tramadol-induced mania. Tramadol dose ranged from 100 mg to 400 mg daily. Tramadol was used alone in 4 cases, in combination with an antidepressant in 3 cases, and with lithium in 1 case. Patients developed symptoms of mania and serotonin syndrome <a id="_idTextAnchor000"></a>within 1 month. Symptoms were severe enough to require psychiatric hospitalization in 5 cases.</p>

<div id="figure-2"> <a href="#" onclick="createFigure('t1'); return false;"><img src="16l01975t1.gif" alt="Table 1" id="t1" border="0" /></a>

<p class="click-to-enlarge">Click figure to enlarge</p>

</div>

<p class="ltrs-br-ltr-br-body-text">Given the timing of symptom onset, improvement following the discontinuation of tramadol, and lack of alternate explanation, it was concluded that tramadol was the probable cause of symptoms of hypomania and serotonin syndrome. A score of 7 on the Naranjo scale also indicated a probable relationship between tramadol and the adverse reactions.<span class="htm-cite"><a href="#ref12">12</a></span> Clinical drug information<span class="htm-cite"><a href="#ref13">13</a></span> does not list mania as a side effect of tramadol but acknowledges that 7% to 14% of individuals can have symptoms of central nervous stimulation.</p>

<p class="ltrs-br-ltr-br-body-text">Contrary to reports that lithium provides protection against the occurrence of tramadol-induced mania, our patient experienced hypomania in spite of lithium use for several years. It is highly likely that early recognition of symptoms, correct diagnosis, discontinuation of tramadol, and temporary suspension of lithium<span class="htm-cite"><a href="#ref10">10</a></span> played a role in the quick resolution of adverse reactions. Our case highlights the importance of inquiring about personal history of bipolar disorder in individuals with depression and fibromyalgia who are being considered for a trial of tramadol.<span class="htm-cite"><a href="#ref14">14</a></span></p>

<p class="references_references-heading"><span class="smallcaps">References</span></p>

<p class="references-references-text-1-9"><a name="ref1"></a><span class="htm-ref"> 1. </span>Grond S, Sablotzki A. Clinical pharmacology of tramadol. <span class="italic">Clin </span><span class="italic">Pharmacokinet</span>. 2004;43(13):879–923. <a href="

<p class="references-references-text-1-9"><a name="ref2"></a><span class="htm-ref"> 2. </span>Reeves RR, Cox SK. Similar effects of tramadol and venlafaxine in major depressive disorder. <span class="italic">South Med J</span>. 2008;101(2):193–195. <a href="

<p class="references-references-text-1-9"><a name="ref3"></a>3.<span class="htm-ref"> </span>Yalcin I, Aksu F, Bodard S, et al. Antidepressant-like effect of tramadol in the unpredictable chronic mild stress procedure: possible involvement of the noradrenergic system. <span class="italic">Be</span><span class="italic">hav Pharmacol</span>. 2007;18(7):623–631. <a href="

<p class="references-references-text-1-9"><a name="ref4"></a><span class="htm-ref"> 4. </span>Bradley RH, Barkin RL, Jerome J, et al. Efficacy of venlafaxine for the long term treatment of chronic pain with associated major depressive disorder. <span class="italic">Am J Ther</span>. 2003;10(5):318–323. <a href="

<p class="references-references-text-1-9"><a name="ref5"></a><span class="htm-ref"> 5. </span>Ceylan D, Kaçar M, Ulaş H. Manic episodes associated with tramadol: a case report. <span class="italic">J Clin Ps</span><span class="italic">ychopharmacol</span>. 2015;35(1):111–113. <a href="

<p class="references-references-text-1-9"><a name="ref6"></a><span class="htm-ref"> 6. </span>Ansermot N, Chocron O, Herrera F, et al. Severe manic episode associated with tramadol in a patient with recurrent depressive disorder. <span class="italic">J Cl</span><span class="italic">in Psychopharmacol</span>. 2015;35(2):203–204. <a href="

<p class="references-references-text-1-9"><a name="ref7"></a><span class="htm-ref"> 7. </span>Jagadheesan K, Sandil R, Ram D. Venlafaxine-induced mania. <span class="italic">Indi</span><span class="italic">an J Psychiatry</span>. 2001;43(4):357–359. <a href="

<p class="references-references-text-1-9"><a name="ref8"></a><span class="htm-ref"> 8. </span>Gonzalez-Pinto A, Imaz H, De Heredia JL, et al. Mania and tramadol-fluoxetine combination. <span class="italic">Am J Psychiatry</span>. 2001;158(6):964–965. <a href="

<p class="references-references-text-1-9"><a name="ref9"></a>9<span class="htm-ref">. </span>Chen KJ, Lu ML, Shen WW. Tramadol-related psychosis in a patient with bipolar I disorder. <span class="italic">Acta Ne</span><span class="italic">uropsychiatr</span>. 2015;27(2):126–128. <a href="

<p class="references-references-text-10-99"><a name="ref10"></a>10. Oronsky B, Martin R. Intolerance to tramadol may herald bipolar disease. <span class="italic">Internet J Fa</span><span class="italic">m Pract</span>. 2007;6(2).</p>

<p class="references-references-text-10-99"><a name="ref11"></a>11. John AP, Koloth R. Severe serotonin toxicity and manic switch induced by combined use of tramadol and paroxetine. <span class="italic">Au</span><span class="italic">st N Z J Psychiatry</span>. 2007;41(2):192–193. <a href="

<p class="references-references-text-10-99"><a name="ref12"></a>12. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. <span class="italic">C</span><span class="italic">lin Pharmacol Ther</span>. 1981;30(2):239–245. <a href="

<p class="references-references-text-10-99"><a name="ref13"></a>13. Lexi-Comp, Inc (Lexi-Drugs) [computer program]. Lexi-Comp, Inc. <a href="

<p class="references-references-text-10-99"><a name="ref14"></a>14. Russell IJ, Kamin M, Bennett RM, et al. Efficacy of tramadol in treatment of pain in fibromyalgia. <span class="italic">J Clin Rheumatol</span>. 2000;6(5):250–257. <a href="

<p class="ltrs-br-ltr-br-author"><span class="bold">Verinder Sharma, MB, BS, FRCP(C)</span><span class="superscript">a</span></p>

<p class="ltrs-br-ltr-br-author"><a href="

<p class="end-matter"><span class="superscript">a</span>Parkwood Institute, Mental Health Care Bldg, London, Ontario, Canada</p>

<p class="end-matter"><span class="bold-italic">Potential conflicts of interest:</span> <span class="semibold">Dr Sharma</span> has received grant support from, participated on scientific advisory boards for, or served on the speakers’ bureaus of AstraZeneca, Bristol-Myers Squibb, Cephalon, Elan Pharmaceuticals, Eli Lilly, Janssen, Lundbeck, Neurocrine Biosciences, Pfizer, Servier, and The Stanley Medical Research Institute.</p>

<p class="end-matter"><span class="bold-italic">Funding/support: </span>None.</p>

<p class="end-matter"><span class="bold-italic">Acknowledgments:</span> Shannon Brauen, BA, M.Cl.Sc.O.T., of Parkwood Institute is thanked for her contribution to the preparation of the manuscript. Ms Brauen has no conflicts of interest.</p>

<p class="end-matter"><span class="bold-italic">Published online:</span> December 15, 2016.</p>

<p class="end-matter"><span class="italic">Prim Care Companion CNS Disord 2016;18(6):</span><span class="doi italic">doi:10.4088/PCC.16l01975</span></p>

<p class="end-matter"><span class="italic">© Copyright 2016 Physicians Postgraduate Press, Inc.</span></p>

</div>

This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions. Tramadol-Induced Hypomania and Serotonin Syndrome To the Editor: Tramadol, a centrally acting synthetic opioid analgesic, has at least 2 complementary mechanisms of action. It binds to μ-opioid receptors and is a weak inhibitor of reuptake of norepinephrine and serotonin. 1 2 3 4 5–7 Case report. Ms A was a 63-year-old woman with a history of bipolar II disorder since her early 20s for which she had required several psychiatric hospitalizations. Her mood stabilized on the combination of lithium 600 mg and quetiapine 300 mg, and there were no recurrences of depression or hypomania for at least 15 months prior to the index hypomanic episode ( DSM-5 ). However, she continued to struggle with symptoms of fibromyalgia. After failing to respond to pregabalin, she was prescribed tramadol 100 mg daily for fibromyalgia. Within 48 hours of taking tramadol, she began to feel agitated, had twitching of her muscles, and had muscle incoordination. Despite that she was not getting much sleep, she did not feel tired. She felt euphoric and thought her brain was working overtime. She had difficulty expressing herself due to thoughts “popping” into her head. Within 2 days of stopping tramadol and putting lithium on hold, the symptoms of hypomania (euphoria, decreased sleep requirement, increased energy, and racing thoughts) and serotonin syndrome (agitation, twitching muscles, and muscle incoordination) resolved. When assessed at our clinic a couple days later, she was alert, oriented, and able to provide a detailed and coherent account of the psychiatric and physical symptoms she experienced over the past few days. Ms A confirmed that she had been taking the prescribed medications as directed. She denied having had any symptoms suggestive of lithium toxicity such as diarrhea, vomiting, stomach pains, dizziness, hand tremor, or slurred speech. Her most recent serum lithium level checked a month before initiation of tramadol was 0.81 mmol/L. When repeated a day after the onset of adverse reactions, her lithium level was < 0.4 mmol/L. Table 1 within 1 month. Symptoms were severe enough to require psychiatric hospitalization in 5 cases. Click figure to enlarge Given the timing of symptom onset, improvement following the discontinuation of tramadol, and lack of alternate explanation, it was concluded that tramadol was the probable cause of symptoms of hypomania and serotonin syndrome. A score of 7 on the Naranjo scale also indicated a probable relationship between tramadol and the adverse reactions. 12 13 Contrary to reports that lithium provides protection against the occurrence of tramadol-induced mania, our patient experienced hypomania in spite of lithium use for several years. It is highly likely that early recognition of symptoms, correct diagnosis, discontinuation of tramadol, and temporary suspension of lithium 10 14 References 1. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet . 2004;43(13):879–923. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15509185&dopt=Abstract "> PubMed http://dx.doi.org/10.2165/00003088-200443130-00004 "> doi:10.2165/00003 088-200443130-00004 2. Reeves RR, Cox SK. Similar effects of tramadol and venlafaxine in major depressive disorder. South Med J . 2008;101(2):193–195. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=18364623&dopt=Abstract "> PubMed http://dx.doi.org/10.1097/SMJ.0b013e3181616e66 "> doi:10.1097/SMJ. 0b013e3181616e66 3. Yalcin I, Aksu F, Bodard S, et al. Antidepressant-like effect of tramadol in the unpredictable chronic mild stress procedure: possible involvement of the noradrenergic system. Be hav Pharmacol . 2007;18(7):623–631. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17912046&dopt=Abstract "> PubMed http://dx.doi.org/10.1097/FBP.0b013e3282eff109 "> doi:10.1097/FBP.0b 013e3282eff109 4. Bradley RH, Barkin RL, Jerome J, et al. Efficacy of venlafaxine for the long term treatment of chronic pain with associated major depressive disorder. Am J Ther . 2003;10(5):318–323. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12975715&dopt=Abstract "> PubMed http://dx.doi.org/10.1097/00045391-200309000-00003 "> doi:10.1097/00 045391-200309000-000 03 5. Ceylan D, Kaçar M, Ulaş H. Manic episodes associated with tramadol: a case report. J Clin Ps ychopharmacol . 2015;35(1):111–113. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=25357197&dopt=Abstract "> PubMed http://dx.doi.org/10.1097/JCP.0000000000000231 "> doi:10.1097/JCP.00 00000000000231 6. Ansermot N, Chocron O, Herrera F, et al. Severe manic episode associated with tramadol in a patient with recurrent depressive disorder. J Cl in Psychopharmacol . 2015;35(2):203–204. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=25627074&dopt=Abstract "> PubMed http://dx.doi.org/10.1097/JCP.0000000000000275 "> doi:10.1097/J CP.0000000000000275 7. Jagadheesan K, Sandil R, Ram D. Venlafaxine-induced mania. Indi an J Psychiatry . 2001;43(4):357–359. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=21407889&dopt=Abstract "> PubMed 8. Gonzalez-Pinto A, Imaz H, De Heredia JL, et al. Mania and tramadol-fluoxetine combination. Am J Psychiatry . 2001;158(6):964–965. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11384912&dopt=Abstract "> PubMed http://dx.doi.org/10.1176/appi.ajp.158.6.964-a "> doi:10.1176/app i.ajp.158.6.964-a 9 . Chen KJ, Lu ML, Shen WW. Tramadol-related psychosis in a patient with bipolar I disorder. Acta Ne uropsychiatr . 2015;27(2):126–128. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=25603153&dopt=Abstract "> PubMed http://dx.doi.org/10.1017/neu.2014.45 "> doi:10.1017/neu.2014.45 10. Oronsky B, Martin R. Intolerance to tramadol may herald bipolar disease. Internet J Fa m Pract . 2007;6(2). 11. John AP, Koloth R. Severe serotonin toxicity and manic switch induced by combined use of tramadol and paroxetine. Au st N Z J Psychiatry . 2007;41(2):192–193. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17484083&dopt=Abstract "> PubMed 12. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. C lin Pharmacol Ther . 1981;30(2):239–245. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7249508&dopt=Abstract "> PubMed http://dx.doi.org/10.1038/clpt.1981.154 "> doi:10.1038/c lpt.1981.154 13. Lexi-Comp, Inc (Lexi-Drugs) [computer program]. Lexi-Comp, Inc. http://online.lexi.com/action/home " target="_blank"> http://online.lexi.com/action/home 14. Russell IJ, Kamin M, Bennett RM, et al. Efficacy of tramadol in treatment of pain in fibromyalgia. J Clin Rheumatol . 2000;6(5):250–257. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19078481&dopt=Abstract "> PubMed http://dx.doi.org/10.1097/00124743-200010000-00004 "> doi:10.1097/0 0124743-200010000-00 004 Verinder Sharma, MB, BS, FRCP(C) a mailto:vsharma@uwo.ca "> vsharma@uwo.ca a Parkwood Institute, Mental Health Care Bldg, London, Ontario, Canada Potential conflicts of interest: Dr Sharma has received grant support from, participated on scientific advisory boards for, or served on the speakers’ bureaus of AstraZeneca, Bristol-Myers Squibb, Cephalon, Elan Pharmaceuticals, Eli Lilly, Janssen, Lundbeck, Neurocrine Biosciences, Pfizer, Servier, and The Stanley Medical Research Institute. Funding/support: None. Acknowledgments: Shannon Brauen, BA, M.Cl.Sc.O.T., of Parkwood Institute is thanked for her contribution to the preparation of the manuscript. Ms Brauen has no conflicts of interest. Published online: December 15, 2016. Prim Care Companion CNS Disord 2016;18(6): doi:10.4088/PCC.16l01975 © Copyright 2016 Physicians Postgraduate Press, Inc. 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