Cases That Test Your Skills Epileptic and depressed Magdalena Romanowicz, MD, and John Michael Bostwick, MD Ms. R, age 33, seeks treatment for worsening depression after her How would you epilepsy diagnosis 1 year ago. She has a history of bulimia and handle this case? Visit CurrentPsychiatry.com ongoing anxiety and chronic pain. How would you manage her? to input your answers and see how your colleagues responded CASE New-onset seizures What is the most likely explanation for Ms. R’s Ms. R, age 33, is referred by her neurologist worsening depressive symptoms? for treatment of depressive symptoms that a) major depressive disorder (MDD) second- have intensified after she was diagnosed with ary to a general medical condition epilepsy 1 year ago. She has a history of buli- b) MDD, recurrent mia and ongoing anxiety and depression. She c) chronic pain disorder also has long-standing neuropathic pain in d) somatoform disorder her left lateral shin and ankle that started after e) substance-induced mood disorder her foot was amputated in a lawn mower ac- cident at age 5. Ms. R says she didn’t take pain The authors’ observations medication until age 24, when her pain spe- Tramadol, a centrally acting synthetic an- cialist prescribed tramadol, 300 to 400 mg/d, algesic, consists of 2 enantiomers that act which she continues to take. as weak agonists at µ-opioid receptors Ms. R’s first seizure occurred 1 year ago. while also inhibiting serotonin and norepi- Despite trials of several antiepileptics, her nephrine reuptake.1 Euphoria associated seizures persist; she is taking lamotrigine, 200 with µ receptor activation often is consid- mg/d, when she presents for treatment. She ered a “high.” Most abused opioids are has no history of brain injuries or strokes to prototypical µ agonists. When opioids are explain her epilepsy. An MRI and 3 electroen- injected or inhaled, drug levels in the brain cephalograms show no signs of focal, poten- rise rapidly, causing a “rush”—a brief, in- tially epileptogenic lesions. tense, pleasurable sensation—followed by Ms. R reports worsening depressive a longer-lasting high. Tolerance and physi- symptoms—particularly impaired attention cal dependence occur when opioids are and concentration—over several months that used chronically. interfere with her housekeeping and ability to Despite tramadol’s µ-opioid activity, finish simple tasks at work. She says she drinks the FDA approved it as an unscheduled alcohol occasionally, but denies substance analgesic in 1994 based on several human abuse. We initiate venlafaxine, titrated to studies.2 Experience with tramadol has 300 mg/d, because Ms. R has a history of confirmed it has low abuse potential, yet intolerable side effects with fluoxetine (gastrointestinal distress) and citalopram Dr. Romanowicz is a Child and Adolescent Psychiatry Fellow, Stanford University, Stanford, CA. Dr. Bostwick is Professor of Current Psychiatry (weight gain). Psychiatry, Mayo Clinic, Rochester, MN. Vol. 11, No. 5 45 Cases That Test Your Skills Table 1 Tramadol and seizures DSM-IV-TR criteria for pain At clinically appropriate doses, tramadol disorder slightly suppresses seizure severity,6 but higher doses can induce seizures.7-12 This A) Pain in ≥1 anatomical site is the predominant paradox is explained by tramadol’s effect focus of the clinical presentation and is of sufficient severity to warrant clinical attention on γ-aminobutyric acid (GABA) receptors. Although at clinical doses tramadol does B) The pain causes clinically significant distress or impairment in social, occupational, or not affect GABA, which could precipitate other important areas of functioning seizures, at higher doses it has been shown C) Psychological factors are judged to have to have an inhibitory effect on GABA re- an important role in the onset, severity, ceptors.13,14 No prospective studies have exacerbation, or maintenance of the pain assessed how often tramadol-induced sei- Clinical Point D) The symptom or deficit is not intentionally zures occur. Case reports12,15 suggest that produced or feigned (as in factitious disorder seizures are more likely with acute tramad- or malingering) At clinically ol intoxication, in patients with a history of appropriate doses, E) The pain is not better accounted for by a alcohol abuse, or with pharmacologic regi- mood, anxiety, or psychotic disorder and tramadol slightly does not meet criteria for dyspareunia mens that include other medications that may cause seizures. Tramadol-induced suppresses seizure Source: Reference 17 severity, but higher seizures are generalized tonic-clonic in na- ture, and typically occur within 24 hours of doses can induce the last dose.16 seizures human laboratory data—and some epi- demiologic data—show that repeated use can lead to physical dependence. Although HISTORY Worsening seizures tramadol is considered a relatively weak Two months after she presents for psychiat- opioid, human studies suggest that it pos- ric evaluation, Ms. R experiences 6 general- sesses µ-agonist activity. The Drug Abuse ized convulsions lasting from 15 minutes to 1 Warning Network reported >15,000 emer- hour with no identifiable precipitant. Because gency department (ED) visits for nonmedi- oxcarbazepine and lamotrigine have failed to cal tramadol use in 2009, which was more suppress her seizures, her neurologist adds than the number of ED visits for codeine phenytoin, 200 mg/d, and increases lamotri- products (7,958) or propoxyphene prod- gine from 200 to 300 mg/d. Her depression ucts (9,526), but much fewer than visits continues to worsen. She reports severe insom- for hydrocodone (86,258) or oxycodone nia, anhedonia, restlessness, and hopelessness, (148,449) products.3 so we add sertraline, 50 mg/d, to venlafaxine. The recommended tramadol dose is Ms. R says the seizures are terrifying and she 50 to 100 mg every 4 to 6 hours (maxi- cannot work. She moves in with her parents be- mum 400 mg/d). Adverse effects range cause she is unable to care for herself. from dysphoria, constipation, and nausea During a psychiatric appointment, Ms. R to agitation, seizures, respiratory depres- confesses that for 2 years her pain has been Discuss this article at sion, and coma.4 Tramadol withdrawal so unbearable that she has been buying extra www.facebook.com/ is similar to opioid withdrawal, and is tramadol from Internet retailers and taking CurrentPsychiatry characterized by anxiety, restlessness, in- 600 to 800 mg/d in addition to the prescribed somnia, yawning, rhinorrhea, lacrimation, 400 mg/d. diaphoresis, tremor, muscle spasms, vom- iting, diarrhea, and tachycardia. Rarely, How would you manage Ms. R? psychomotor agitation and confusion a) ask for her permission to discuss her Current Psychiatry 46 May 2012 may occur.5 tramadol abuse with her neurologist Cases That Test Your Skills Table 2 Tramadol: Major drug-drug interactions Drug Symptoms Selegiline Nausea, vomiting, cardiovascular collapse, respiratory depression, seizures, or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes); use of the transdermal formulation with tramadol is contraindicated Carbamazepine Decreased tramadol efficacy and increased seizure risk Venlafaxine Increased risk of serotonin syndrome Linezolid Increased risk of serotonin syndrome Fluoxetine Increased risk of seizures and serotonin syndrome; increased concentrations of tramadol and decreased concentrations of tramadol active metabolite, O-desmethyltramadol (M1) Olanzapine Increased risk of serotonin syndrome Clinical Point Mirtazapine Increased risk of serotonin syndrome Haloperidol Increased risk of seizures Seizures have been Escitalopram Increased risk of seizures and serotonin syndrome observed with Clomipramine Increased risk of seizures tramadol doses as low Risperidone Increased risk of seizures as 100 mg/d Ketamine Increased risk of respiratory depression and excessive CNS depression Imipramine Increased risk of seizures Duloxetine Increased risk of serotonin syndrome Nortriptyline Increased risk of seizures Clozapine Increased risk of seizures Sertraline Increased risk of seizures and serotonin syndrome Paroxetine Increased risk of seizures and serotonin syndrome; decrease in the analgesic effect of tramadol Amitriptyline Increased risk of seizures; increased concentrations of tramadol and decreased concentrations of tramadol active metabolite, M1 Desipramine Increased risk of seizures Doxepin Increased risk of seizures Citalopram Increased risk of seizures and serotonin syndrome Fluvoxamine Increased risk of seizures and serotonin syndrome Source: Reference 19 b) try to manage her condition on your own antiepileptics was unsuccessful. Her sei- c) report her to her employer and ask zures persisted as long as her tramadol ad- preventive health services to follow up on diction continued. her treatment Spiller et al18 reported the lowest daily d) none of the above tramadol dose associated with seizures is 500 mg/d, although Talaie et al16 observed The authors’ observations seizures at doses as low as 100 mg/d. Ms. R had a history of chronic pain (Table Additionally, seizure risk may increase 1)17 and developed seizures after escalating through tramadol’s interactions with her tramadol use. After her first epilepsy several medications, including tricyclic attack, she did not tell her physicians she antidepressants, selective serotonin reup- was taking additional tramadol nor did take inhibitors, phenothiazines, fluoroqui- Current Psychiatry she stop taking it. Treatment with several nolone antibiotics,