Cases That Test Your Skills

Epileptic and depressed

Current Psychiatry. 2012 May;11(5):45-49

References

1. Katz KD. Tramadol is an opioid. J Med Toxicol. 2008;4(2):145-

2. Preston KL, Jasinski DR, Testa M. Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend. 1991;27(1):7-17.

3. U.S. Department of Health and Human Services. Substance Abuse and Mental Health Services Administration. Drug abuse warning network, 2009: national estimates of drug-related emergency department visits. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2011. HHS publication (SMA) 11-4659, DAWN Series D-35.

4. Afshari R, Ghooshkhanehee H. Tramadol overdose induced seizure dramatic rise of CPK and acute renal failure. J Pak Med Assoc. 2009;59(3):178.-

5. Rodriguez Villamañan JC, Albaladejo Blanco C, Sanchez Sanchez A, et al. Withdrawal syndrome after long-term treatment with tramadol. Br J Gen Pract. 2000;50(454):406.-

6. Manocha A, Sharma KK, Mediratta PK. On the mechanism of anticonvulsant effect of tramadol in mice. Pharmacol Biochem Behav. 2005;82(1):74-81.

7. Boyd IW. Tramadol and seizures. Med J Aust. 2005;182(11):595-596.

8. Labate A, Newton MR, Vernon GM, et al. Tramadol and new-onset seizures. Med J Aust. 2005;182(1):42-43.

9. Gasse C, Derby L, Vasilakis-Scaramozza C, et al. Incidence of first-time idiopathic seizures in users of tramadol. Pharmacotherapy. 2000;20(6):629-634.

10. Kahn LH, Alderfer RJ, Graham DJ. Seizures reported with tramadol. JAMA. 1997;278(20):1661.-

11. Mazor SS, Feldman KW, Sugar NF, et al. Pediatric tramadol ingestion resulting in seizurelike activity: a case series. Pediatr Emerg Care. 2008;24(6):380-381.

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16. Talaie H, Panahandeh R, Fayaznouri M, et al. Dose-independent occurrence of seizure with tramadol. J Med Toxicol. 2009;5(2):63-67.

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Table 1

DSM-IV-TR criteria for pain disorder

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

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

Source: Reference 17

Clinical Point

Seizures have been observed with tramadol doses as low as 100 mg/d

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

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
Mirtazapine	Increased risk of serotonin syndrome
Haloperidol	Increased risk of seizures
Escitalopram	Increased risk of seizures and serotonin syndrome
Clomipramine	Increased risk of seizures
Risperidone	Increased risk of seizures
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

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.

Clinical Point

Seizure risk may increase through tramadol’s interactions with several medications, including some antidepressants

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.

Clinical Point

Chronic pain patients have a higher prevalence of substance abuse than the general population

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