Cases That Test Your Skills

Epileptic and depressed

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Table 1

DSM-IV-TR criteria for pain disorder

  1. Pain in ≥1 anatomical site is the predominant focus of the clinical presentation and is of sufficient severity to warrant clinical attention
  2. The pain causes clinically significant distress or impairment in social, occupational, or other important areas of functioning
  3. Psychological factors are judged to have an important role in the onset, severity, exacerbation, or maintenance of the pain
  4. The symptom or deficit is not intentionally produced or feigned (as in factitious disorder or malingering)
  5. The pain is not better accounted for by a mood, anxiety, or psychotic disorder and does not meet criteria for dyspareunia
Source: Reference 17

Spiller et al18 reported the lowest daily tramadol dose associated with seizures is 500 mg/d, although Talaie et al16 observed seizures at doses as low as 100 mg/d. Additionally, seizure risk may increase through tramadol’s interactions with several medications, including tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazines, fluoroquinolone antibiotics, meperidine, clozapine, buspirone, bupropion, phenylephrine, guaifenesin, tripelennamine, thioridazine, theophylline, and acetaminophen, butalbital, and caffeine combination (Table 2).19 Transdermal selegiline is contraindicated with tramadol. For Ms. R, the sertraline and venlafaxine she was taking may have augmented tramadol’s seizure potential.

Table 2

Tramadol: Major drug-drug interactions

SelegilineNausea, vomiting, cardiovascular collapse, respiratory depression, seizures, or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes); use of the transdermal formulation with tramadol is contraindicated
CarbamazepineDecreased tramadol efficacy and increased seizure risk
VenlafaxineIncreased risk of serotonin syndrome
LinezolidIncreased risk of serotonin syndrome
FluoxetineIncreased risk of seizures and serotonin syndrome; increased concentrations of tramadol and decreased concentrations of tramadol active metabolite, O-desmethyltramadol (M1)
OlanzapineIncreased risk of serotonin syndrome
MirtazapineIncreased risk of serotonin syndrome
HaloperidolIncreased risk of seizures
EscitalopramIncreased risk of seizures and serotonin syndrome
ClomipramineIncreased risk of seizures
RisperidoneIncreased risk of seizures
KetamineIncreased risk of respiratory depression and excessive CNS depression
ImipramineIncreased risk of seizures
DuloxetineIncreased risk of serotonin syndrome
NortriptylineIncreased risk of seizures
ClozapineIncreased risk of seizures
SertralineIncreased risk of seizures and serotonin syndrome
ParoxetineIncreased risk of seizures and serotonin syndrome; decrease in the analgesic effect of tramadol
AmitriptylineIncreased risk of seizures; increased concentrations of tramadol and decreased concentrations of tramadol active metabolite, M1
DesipramineIncreased risk of seizures
DoxepinIncreased risk of seizures
CitalopramIncreased risk of seizures and serotonin syndrome
FluvoxamineIncreased risk of seizures and serotonin syndrome
Source: Reference 19

It is important to avoid polypharmacy in patients taking tramadol.20 Most psychiatrists are aware of the risk of serotonin syndrome with antidepressants, but may be less likely to attribute serotonergic additive effects from other medication classes such as analgesics. Recognizing tramadol’s potential to contribute to serotonin syndrome—especially in light of concomitant usage with other serotonergic medications such as antidepressants—is essential.

Tramadol toxicity appears to be caused by monoamine uptake inhibition rather than its opioid effects.21 The most frequent pharmacokinetic drug-drug interactions that lead to side effects such as serotonin syndrome or seizures involve several isoenzymes of the hepatic cytochrome P450 (CYP). The isoenzymes CYP2D6 (substrates—eg, amitriptyline, tramadol, and venlafaxine; inhibitors—eg, fluoxetine and duloxetine) and CYP3A4 (substrates—eg, carbamazepine, oxycodone, and venlafaxine; inductors—eg, carbamazepine; inhibitors, eg—grapefruit juice) are most important clinically.22

Ms. R readily obtained tramadol from Internet retailers. In a 2004 report, a Google search yielded 2,150,000 sources for acquiring tramadol, most of which did not require a prescription.23 Chronic pain patients have a higher prevalence of substance abuse than the general population.24 Because Ms. R did not have a documented substance abuse history, none of her physicians screened her for drug abuse, although toxicology screening wouldn’t have helped because the tramadol had been prescribed. We didn’t think to directly ask Ms. R about medication misuse, but if we had, she might have revealed it sooner.

OUTCOME: Seizure free

With Ms. R’s permission, we speak to her neurologist, who agrees that excess tramadol likely induced her seizures. The seizures stop after Ms. R discontinues tramadol. After 3 months without seizures, phenytoin is discontinued and lamotrigine is tapered to 200 mg/d. Ms. R participates in a pain rehabilitation program and continues to take venlafaxine, 300 mg/d, and sertraline, 50 mg/d. Her mood improves and she returns to work. Her pain is managed by non-steroidal anti-inflammatory drugs because she decides to decrease her activity level. Ms. R also is trying alternative medicine modalities such as acupuncture and acupressure.

Related Resource

  • Clark MR, Treisman GJ. Chronic pain and addiction. Basel, Switzerland: Karger; 2011.

Drug Brand Names

  • Acetaminophen, butalbital, and caffeine • Fioricet
  • Amitriptyline • Elavil
  • Bupropion • Wellbutrin
  • Buspirone • Buspar
  • Carbamazepine • Tegretol, Carbatrol
  • Citalopram • Celexa
  • Clomipramine • Anafranil
  • Clozapine • Clozaril
  • Desipramine • Norpramin
  • Doxepin • Adapin, Silenor
  • Duloxetine • Cymbalta
  • Escitalopram • Lexapro
  • Fluoxetine • Prozac
  • Fluvoxamine • Luvox
  • Guaifenesin • Tenex
  • Haloperidol • Haldol
  • Imipramine • Tofranil
  • Ketamine • Ketalar
  • Lamotrigine • Lamictal
  • Linezolid • Zyvox
  • Meperidine • Demerol
  • Mirtazapine • Remeron
  • Nortriptyline • Aventyl
  • Olanzapine • Zyprexa
  • Oxcarbazepine • Trileptal
  • Oxycodone • Percolone, OxyContin
  • Paroxetine • Paxil
  • Phenylephrine • Lusonal
  • Phenytoin • Dilantin
  • Propoxyphene • Darvon
  • Risperidone • Risperdal
  • Selegiline • Eldepryl, EMSAM
  • Sertraline • Zoloft
  • Theophylline • Aerolate
  • Thioridazine • Mellaril
  • Tramadol • Ultram
  • Tripelennamine • Pyribenzamine
  • Venlafaxine • Effexor

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