Cases That Test Your Skills

CASE: New-onset seizures

Ms. R, age 33, is referred by her neurologist for treatment of depressive symptoms that have intensified after she was diagnosed with epilepsy 1 year ago. She has a history of bulimia and ongoing anxiety and depression. She also has long-standing neuropathic pain in her left lateral shin and ankle that started after her foot was amputated in a lawn mower accident at age 5. Ms. R says she didn’t take pain medication until age 24, when her pain specialist prescribed tramadol, 300 to 400 mg/d, which she continues to take.

Ms. R’s first seizure occurred 1 year ago. Despite trials of several antiepileptics, her seizures persist; she is taking lamotrigine, 200 mg/d, when she presents for treatment. She has no history of brain injuries or strokes to explain her epilepsy. An MRI and 3 electroencephalograms show no signs of focal, potentially epileptogenic lesions.

Ms. R reports worsening depressive symptoms—particularly impaired attention and concentration—over several months that interfere with her housekeeping and ability to finish simple tasks at work. She says she drinks alcohol occasionally, but denies substance abuse. We initiate venlafaxine, titrated to 300 mg/d, because Ms. R has a history of intolerable side effects with fluoxetine (gastrointestinal distress) and citalopram (weight gain).

The authors’ observations

Tramadol, a centrally acting synthetic analgesic, consists of 2 enantiomers that act as weak agonists at μ-opioid receptors while also inhibiting serotonin and norepinephrine reuptake.¹ Euphoria associated with μ receptor activation often is considered a “high.” Most abused opioids are prototypical μ agonists. When opioids are injected or inhaled, drug levels in the brain rise rapidly, causing a “rush”—a brief, intense, pleasurable sensation—followed by a longer-lasting high. Tolerance and physical dependence occur when opioids are used chronically.

Despite tramadol’s μ-opioid activity, the FDA approved it as an unscheduled analgesic in 1994 based on several human studies.² Experience with tramadol has confirmed it has low abuse potential, yet human laboratory data—and some epidemiologic data—show that repeated use can lead to physical dependence. Although tramadol is considered a relatively weak opioid, human studies suggest that it possesses μ-agonist activity. The Drug Abuse Warning Network reported >15,000 emergency department (ED) visits for nonmedical tramadol use in 2009, which was more than the number of ED visits for codeine products (7,958) or propoxyphene products (9,526), but much fewer than visits for hydrocodone (86,258) or oxycodone (148,449) products.³

The recommended tramadol dose is 50 to 100 mg every 4 to 6 hours (maximum 400 mg/d). Adverse effects range from dysphoria, constipation, and nausea to agitation, seizures, respiratory depression, and coma.⁴ Tramadol withdrawal is similar to opioid withdrawal, and is characterized by anxiety, restlessness, insomnia, yawning, rhinorrhea, lacrimation, diaphoresis, tremor, muscle spasms, vomiting, diarrhea, and tachycardia. Rarely, psychomotor agitation and confusion may occur.⁵

Tramadol and seizures

At clinically appropriate doses, tramadol slightly suppresses seizure severity,⁶ but higher doses can induce seizures.^7-12 This paradox is explained by tramadol’s effect on γ-aminobutyric acid (GABA) receptors. Although at clinical doses tramadol does not affect GABA, which could precipitate seizures, at higher doses it has been shown to have an inhibitory effect on GABA receptors.^13,14 No prospective studies have assessed how often tramadol-induced seizures occur. Case reports^12,15 suggest that seizures are more likely with acute tramadol intoxication, in patients with a history of alcohol abuse, or with pharmacologic regimens that include other medications that may cause seizures. Tramadol-induced seizures are generalized tonic-clonic in nature, and typically occur within 24 hours of the last dose.¹⁶

HISTORY: Worsening seizures

Two months after she presents for psychiatric evaluation, Ms. R experiences 6 generalized convulsions lasting from 15 minutes to 1 hour with no identifiable precipitant. Because oxcarbazepine and lamotrigine have failed to suppress her seizures, her neurologist adds phenytoin, 200 mg/d, and increases lamotrigine from 200 to 300 mg/d. Her depression continues to worsen. She reports severe insomnia, anhedonia, restlessness, and hopelessness, so we add sertraline, 50 mg/d, to venlafaxine. Ms. R says the seizures are terrifying and she cannot work. She moves in with her parents because she is unable to care for herself.

During a psychiatric appointment, Ms. R confesses that for 2 years her pain has been so unbearable that she has been buying extra tramadol from Internet retailers and taking 600 to 800 mg/d in addition to the prescribed 400 mg/d.

The authors’ observations

Ms. R had a history of chronic pain Table 1¹⁷ and developed seizures after escalating her tramadol use. After her first epilepsy attack, she did not tell her physicians she was taking additional tramadol nor did she stop taking it. Treatment with several antiepileptics was unsuccessful. Her seizures persisted as long as her tramadol addiction continued.

Table 1

DSM-IV-TR criteria for pain disorder

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

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

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufactur-ers of competing products.

CASE: New-onset seizures

Ms. R, age 33, is referred by her neurologist for treatment of depressive symptoms that have intensified after she was diagnosed with epilepsy 1 year ago. She has a history of bulimia and ongoing anxiety and depression. She also has long-standing neuropathic pain in her left lateral shin and ankle that started after her foot was amputated in a lawn mower accident at age 5. Ms. R says she didn’t take pain medication until age 24, when her pain specialist prescribed tramadol, 300 to 400 mg/d, which she continues to take.

Ms. R’s first seizure occurred 1 year ago. Despite trials of several antiepileptics, her seizures persist; she is taking lamotrigine, 200 mg/d, when she presents for treatment. She has no history of brain injuries or strokes to explain her epilepsy. An MRI and 3 electroencephalograms show no signs of focal, potentially epileptogenic lesions.

Ms. R reports worsening depressive symptoms—particularly impaired attention and concentration—over several months that interfere with her housekeeping and ability to finish simple tasks at work. She says she drinks alcohol occasionally, but denies substance abuse. We initiate venlafaxine, titrated to 300 mg/d, because Ms. R has a history of intolerable side effects with fluoxetine (gastrointestinal distress) and citalopram (weight gain).

The authors’ observations

Tramadol, a centrally acting synthetic analgesic, consists of 2 enantiomers that act as weak agonists at μ-opioid receptors while also inhibiting serotonin and norepinephrine reuptake.¹ Euphoria associated with μ receptor activation often is considered a “high.” Most abused opioids are prototypical μ agonists. When opioids are injected or inhaled, drug levels in the brain rise rapidly, causing a “rush”—a brief, intense, pleasurable sensation—followed by a longer-lasting high. Tolerance and physical dependence occur when opioids are used chronically.

Despite tramadol’s μ-opioid activity, the FDA approved it as an unscheduled analgesic in 1994 based on several human studies.² Experience with tramadol has confirmed it has low abuse potential, yet human laboratory data—and some epidemiologic data—show that repeated use can lead to physical dependence. Although tramadol is considered a relatively weak opioid, human studies suggest that it possesses μ-agonist activity. The Drug Abuse Warning Network reported >15,000 emergency department (ED) visits for nonmedical tramadol use in 2009, which was more than the number of ED visits for codeine products (7,958) or propoxyphene products (9,526), but much fewer than visits for hydrocodone (86,258) or oxycodone (148,449) products.³

The recommended tramadol dose is 50 to 100 mg every 4 to 6 hours (maximum 400 mg/d). Adverse effects range from dysphoria, constipation, and nausea to agitation, seizures, respiratory depression, and coma.⁴ Tramadol withdrawal is similar to opioid withdrawal, and is characterized by anxiety, restlessness, insomnia, yawning, rhinorrhea, lacrimation, diaphoresis, tremor, muscle spasms, vomiting, diarrhea, and tachycardia. Rarely, psychomotor agitation and confusion may occur.⁵

Tramadol and seizures

At clinically appropriate doses, tramadol slightly suppresses seizure severity,⁶ but higher doses can induce seizures.^7-12 This paradox is explained by tramadol’s effect on γ-aminobutyric acid (GABA) receptors. Although at clinical doses tramadol does not affect GABA, which could precipitate seizures, at higher doses it has been shown to have an inhibitory effect on GABA receptors.^13,14 No prospective studies have assessed how often tramadol-induced seizures occur. Case reports^12,15 suggest that seizures are more likely with acute tramadol intoxication, in patients with a history of alcohol abuse, or with pharmacologic regimens that include other medications that may cause seizures. Tramadol-induced seizures are generalized tonic-clonic in nature, and typically occur within 24 hours of the last dose.¹⁶

HISTORY: Worsening seizures

Two months after she presents for psychiatric evaluation, Ms. R experiences 6 generalized convulsions lasting from 15 minutes to 1 hour with no identifiable precipitant. Because oxcarbazepine and lamotrigine have failed to suppress her seizures, her neurologist adds phenytoin, 200 mg/d, and increases lamotrigine from 200 to 300 mg/d. Her depression continues to worsen. She reports severe insomnia, anhedonia, restlessness, and hopelessness, so we add sertraline, 50 mg/d, to venlafaxine. Ms. R says the seizures are terrifying and she cannot work. She moves in with her parents because she is unable to care for herself.

During a psychiatric appointment, Ms. R confesses that for 2 years her pain has been so unbearable that she has been buying extra tramadol from Internet retailers and taking 600 to 800 mg/d in addition to the prescribed 400 mg/d.

The authors’ observations

Ms. R had a history of chronic pain Table 1¹⁷ and developed seizures after escalating her tramadol use. After her first epilepsy attack, she did not tell her physicians she was taking additional tramadol nor did she stop taking it. Treatment with several antiepileptics was unsuccessful. Her seizures persisted as long as her tramadol addiction continued.

Table 1

DSM-IV-TR criteria for pain disorder

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

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

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufactur-ers of competing products.

CASE: New-onset seizures

Ms. R, age 33, is referred by her neurologist for treatment of depressive symptoms that have intensified after she was diagnosed with epilepsy 1 year ago. She has a history of bulimia and ongoing anxiety and depression. She also has long-standing neuropathic pain in her left lateral shin and ankle that started after her foot was amputated in a lawn mower accident at age 5. Ms. R says she didn’t take pain medication until age 24, when her pain specialist prescribed tramadol, 300 to 400 mg/d, which she continues to take.

Ms. R’s first seizure occurred 1 year ago. Despite trials of several antiepileptics, her seizures persist; she is taking lamotrigine, 200 mg/d, when she presents for treatment. She has no history of brain injuries or strokes to explain her epilepsy. An MRI and 3 electroencephalograms show no signs of focal, potentially epileptogenic lesions.

Ms. R reports worsening depressive symptoms—particularly impaired attention and concentration—over several months that interfere with her housekeeping and ability to finish simple tasks at work. She says she drinks alcohol occasionally, but denies substance abuse. We initiate venlafaxine, titrated to 300 mg/d, because Ms. R has a history of intolerable side effects with fluoxetine (gastrointestinal distress) and citalopram (weight gain).

The authors’ observations

Tramadol, a centrally acting synthetic analgesic, consists of 2 enantiomers that act as weak agonists at μ-opioid receptors while also inhibiting serotonin and norepinephrine reuptake.¹ Euphoria associated with μ receptor activation often is considered a “high.” Most abused opioids are prototypical μ agonists. When opioids are injected or inhaled, drug levels in the brain rise rapidly, causing a “rush”—a brief, intense, pleasurable sensation—followed by a longer-lasting high. Tolerance and physical dependence occur when opioids are used chronically.

Despite tramadol’s μ-opioid activity, the FDA approved it as an unscheduled analgesic in 1994 based on several human studies.² Experience with tramadol has confirmed it has low abuse potential, yet human laboratory data—and some epidemiologic data—show that repeated use can lead to physical dependence. Although tramadol is considered a relatively weak opioid, human studies suggest that it possesses μ-agonist activity. The Drug Abuse Warning Network reported >15,000 emergency department (ED) visits for nonmedical tramadol use in 2009, which was more than the number of ED visits for codeine products (7,958) or propoxyphene products (9,526), but much fewer than visits for hydrocodone (86,258) or oxycodone (148,449) products.³

The recommended tramadol dose is 50 to 100 mg every 4 to 6 hours (maximum 400 mg/d). Adverse effects range from dysphoria, constipation, and nausea to agitation, seizures, respiratory depression, and coma.⁴ Tramadol withdrawal is similar to opioid withdrawal, and is characterized by anxiety, restlessness, insomnia, yawning, rhinorrhea, lacrimation, diaphoresis, tremor, muscle spasms, vomiting, diarrhea, and tachycardia. Rarely, psychomotor agitation and confusion may occur.⁵

Tramadol and seizures

At clinically appropriate doses, tramadol slightly suppresses seizure severity,⁶ but higher doses can induce seizures.^7-12 This paradox is explained by tramadol’s effect on γ-aminobutyric acid (GABA) receptors. Although at clinical doses tramadol does not affect GABA, which could precipitate seizures, at higher doses it has been shown to have an inhibitory effect on GABA receptors.^13,14 No prospective studies have assessed how often tramadol-induced seizures occur. Case reports^12,15 suggest that seizures are more likely with acute tramadol intoxication, in patients with a history of alcohol abuse, or with pharmacologic regimens that include other medications that may cause seizures. Tramadol-induced seizures are generalized tonic-clonic in nature, and typically occur within 24 hours of the last dose.¹⁶

HISTORY: Worsening seizures

Two months after she presents for psychiatric evaluation, Ms. R experiences 6 generalized convulsions lasting from 15 minutes to 1 hour with no identifiable precipitant. Because oxcarbazepine and lamotrigine have failed to suppress her seizures, her neurologist adds phenytoin, 200 mg/d, and increases lamotrigine from 200 to 300 mg/d. Her depression continues to worsen. She reports severe insomnia, anhedonia, restlessness, and hopelessness, so we add sertraline, 50 mg/d, to venlafaxine. Ms. R says the seizures are terrifying and she cannot work. She moves in with her parents because she is unable to care for herself.

During a psychiatric appointment, Ms. R confesses that for 2 years her pain has been so unbearable that she has been buying extra tramadol from Internet retailers and taking 600 to 800 mg/d in addition to the prescribed 400 mg/d.

The authors’ observations

Ms. R had a history of chronic pain Table 1¹⁷ and developed seizures after escalating her tramadol use. After her first epilepsy attack, she did not tell her physicians she was taking additional tramadol nor did she stop taking it. Treatment with several antiepileptics was unsuccessful. Her seizures persisted as long as her tramadol addiction continued.

Table 1

DSM-IV-TR criteria for pain disorder

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

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

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufactur-ers of competing products.

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CASE: Depressed and delusional

Mrs. P, age 58, is a retired art teacher who presents for inpatient psychiatric admission after an 8-month depressive and psychotic illness. She reports profound feelings of worthlessness, anhedonia, psychomotor retardation, daily spontaneous crying spells, and worsening suicidal ideation. She is unkempt, disheveled, and makes limited eye contact. She is floridly psychotic, exhibits hebephrenia at times, and appears to be having conversations with people who are not there. Mrs. P reports derogatory intracranial auditory hallucinations of her brother’s and father’s voices. She also describes a complex delusional system relating to sexual trauma she experienced as a child perpetrated by her brother. Her family corroborates some details of the trauma; however, she says her father, neighbors, pastor, and outpatient psychiatrist are involved. Mrs. P believes these individuals are members of a cult, she has been the victim of a satanic sexual rite, and a television news personality knows about this conspiracy and has been attempting to contact her.

Mrs. P suffers from severe, debilitating chronic pain experienced as shock-like pain lasting for several minutes that starts in her throat and radiates to her left ear. Her pain began several years ago and prompted a neurologic workup, including MRI of the head and somatosensory evoked potentials of the glossopharyngeal nerve. She was diagnosed with “probable” glossopharyngeal neuralgia and failed multiple medication trials, including carbamazepine, phenytoin, gabapentin, and amitriptyline. She underwent microvascular decompression surgery 3 years ago. The operation, which has an 80% to 90% success rate for neuralgias,^1,2 offered only brief symptomatic relief. She was maintained on immediate-release opiates until the pain became “unbearable” 8 months ago. This prompted a second neurologic workup, which was unremarkable. Mrs. P was diagnosed with pain disorder associated with psychological factors and a general medical condition.

Ten years ago she had 2 major depressive episodes with inpatient hospitalization and 2 suicide attempts within 1 year, but no history of psychosis before 8 months ago. Mrs. P’s husband says his wife has no history of manic or hypomanic episodes. Her medications are ziprasidone, 20 mg/d, thiothixene, 10 mg/d, benztropine, 3 mg/d, and escitalopram, 30 mg/d. She also receives oxycodone/acetaminophen, 5 mg/325 mg as needed for facial pain and headaches, and clonazepam, 1 mg as needed for panic attacks.

The authors’ observations

Psychosis can be a feature of any of the disorders listed in Table 1³; however, several features of Mrs. P’s illness led us to diagnose MDD, recurrent, severe with psychotic features.⁴ Mrs. P and her husband described several discreet episodes of major debilitating depression without alternating periods of hypomanic or manic symptoms (Table 2).⁴ Comorbid depressive symptoms and a timeline indicating persistence of psychotic symptoms make a brief psychotic episode less likely. Although uncommon, patients can develop psychotic or mood disorders as a result of opiate abuse or dependence. However, Mrs. P was taking opiates as prescribed and not asking for early refills, which makes substance abuse an unlikely cause of her psychosis. In addition, because Mrs. P had 2 major depressive episodes in the absence of opiate use, a primary mood disorder seemed the more appropriate diagnosis. Schizophrenia is ruled out based on history. Although Mrs. P was suffering from complex delusional constructs, auditory hallucinations, and grossly disorganized behavior, these symptoms occurred only within the context of her depressive episode. New-onset delusional guilt relating to her childhood sexual trauma and hypochondriacal preoccupations within the context of pain complaints make psychotic depression more likely.⁵

Table 1

Psychiatric diseases in which patients may present with psychotic symptoms

Table 2

DSM-IV-TR criteria for major depressive episode

Depression, psychosis, and pain

From the beginning of Mrs. P’s treatment, we considered psychotic depression worsened—if not completely explained—her pain. Her somatic complaints appeared to be subtly woven into her delusional constructs. For instance, she complained that a device had been implanted in her head and she had the scar to prove it, pointing to the scar from her microvascular decompression surgery. Research indicates that depressive illness and chronic pain syndromes are highly comorbid and depressive illness can worsen pain syndromes.^6,7 In addition, Mrs. P failed several medical and 1 surgical interventions for her pain condition that had high success rates. Her husband notes that when her outpatient psychiatrist started olanzapine 3 months ago for emerging psychotic symptoms, her pain complaints initially decreased with her psychotic symptoms, and she used less opiate medication during that time. Several months later Mrs. P’s pain complaints increased as her psychotic symptoms worsened. Second-generation antipsychotics have been evaluated as treatment for chronic pain syndromes, and may exert a primary analgesic effect.^8,9 However, because of the correlation between her fluctuating psychotic symptoms and pain complaints, the more plausible explanation for olanzapine’s initial efficacy in treating Mrs. P’s pain is a secondary analgesic effect from decreased psychotic somatic preoccupation.

TREATMENT: ECT

Mrs. P is admitted to the inpatient psychiatric unit and placed on suicide precautions. Oxycodone/acetaminophen and clonazepam are tapered and limited to twice daily as needed. Escitalopram is tapered and discontinued. Thiothixene is tapered and replaced by olanzapine, 5 mg/d. Mrs. P receives 3 bifrontal, brief pulse-width ECT treatments. These result in marked improvement in her depressive and psychotic symptoms. In addition, her pain complaints become minimal. She becomes less preoccupied with her sexual trauma and grows to trust many staff members whom she previously believed were part of her traumatic childhood events. Mrs. P is no longer suicidal and asks to continue ECT treatments as an outpatient. She is discharged on olanzapine, 5 mg/d, trazodone, 100 mg/d for insomnia, benztropine, 2 mg/d, clonazepam 0.5 mg twice daily as needed for panic attacks, and oxycodone/acetaminophen, 5 mg/325 mg twice daily as needed for pain.

The authors’ observations

According to the Harvard South Shore Algorithm, treatment strategies for psychotic depression include antidepressant and antipsychotic combinations, lithium augmentation, clozapine, and ECT.¹⁰ Several factors made ECT the best option for Mrs. P. She had failed multiple treatment strategies and was suicidal. ECT is an effective treatment for MDD with psychotic features, single or recurrent episode.¹¹ ECT can be used as a primary treatment before psychotropic medications or secondarily when there has been lack of clinical response to medications, intolerable side effects, deterioration in psychiatric condition, or suicidality.^11,12 In addition, when treated with ECT, psychotic depression has a significantly higher remission rate than major depression without psychosis.¹² Delusional guilt, psychomotor retardation, hypochondriacal preoccupations, loss of insight, paranoia, and obsessive-compulsive symptoms predict a favorable response.¹² ECT also has demonstrated efficacy for treating pain secondary to psychotic depression or melancholic depression.¹³ In addition, ECT has been shown to have analgesic properties beyond treating underlying depression.¹⁴ Our primary focus was not to treat Mrs. P’s pain syndrome with ECT; however, in treating her psychotic depression we had hoped that her pain tolerance would improve and she would rely less on opiates.

OUTCOME: Pain relief

As an outpatient, Mrs. P receives 11 bifrontal ECT treatments in her initial series, followed by 7 bifrontal maintenance treatments. Her speech is more spontaneous, her grooming and hygiene improve, and she exhibits a brighter and more reactive affect. Suicidal ideation has resolved. Pain improves from a “10 out of 10” to a “2 out of 10.” Mrs. P consistently requires less oxycodone/acetaminophen. She relates better to her family and begins exploring new hobbies such as pottery. In addition to monthly maintenance bifrontal ECT treatments, she is stable on citalopram, 60 mg/d, and trazodone, 50 mg/d as needed for insomnia.

The authors’ observations

The relationship between depressive illness and chronic pain is complex. Treating a primary depressive illness can lead to improved functional outcomes and decreased disability from chronic pain complaints.¹⁵ Patients with comorbid chronic pain and depressive illness are more likely to suffer from unremitting pain despite compliance with evidence-based treatment strategies.¹⁶ Mrs. P had 2 co-occurring disorders: psychotic depression and chronic pain disorder secondary to glossopharyngeal neuralgia. Our opinion is that Mrs. P’s psychotic depression worsened her experience of pain.

Treatment strategies that address both depressive symptoms and chronic pain are ideal.¹⁷ These treatment modalities include psychotherapeutic techniques such as cognitive-behavioral therapy, medications, and somatic treatments such as ECT.¹⁸ In Mrs. P’s case, ECT was an effective treatment that caused remission of psychotic depressive symptoms, which lead to improved pain control and restored social and occupational functioning.

Related Resources

• Schreiber S, Shmueli D, Grunhaus L, et al. The influence of electroconvulsive therapy on pain threshold and pain tolerance in major depression patients before, during and after treatment. Eur J Pain. 2003;7(5):419-424.
• Suzuki K, Ebina Y, Shindo T, et al. Repeated electroconvulsive therapy courses improved chronic regional pain with depression caused by failed back syndrome. Med Sci Monit. 2009;15(4):CS77-CS79.
• Giesecke T, Gracely RH, Williams DA, et al. The relationship between depression, clinical pain, and experimental pain in a chronic pain cohort. Arthritis Rheum. 2005;52(5):1577-1584.

Drug Brand Names

• Amitriptyline • Elavil
• Benztropine • Cogentin
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Escitalopram • Lexapro
• Gabapentin • Neurontin
• Lithium • Eskalith, Lithobid
• Olanzapine • Zyprexa
• Oxycodone/ acetaminophen • Vicodin
• Phenytoin • Dilantin
• Thiothixene • Navane
• Trazodone • Desyrel, Oleptro
• Ziprasidone • Geodon

Disclosures

Dr. Kugler reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Magid receives NARSAD grant support.

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Depressed and delusional

Mrs. P, age 58, is a retired art teacher who presents for inpatient psychiatric admission after an 8-month depressive and psychotic illness. She reports profound feelings of worthlessness, anhedonia, psychomotor retardation, daily spontaneous crying spells, and worsening suicidal ideation. She is unkempt, disheveled, and makes limited eye contact. She is floridly psychotic, exhibits hebephrenia at times, and appears to be having conversations with people who are not there. Mrs. P reports derogatory intracranial auditory hallucinations of her brother’s and father’s voices. She also describes a complex delusional system relating to sexual trauma she experienced as a child perpetrated by her brother. Her family corroborates some details of the trauma; however, she says her father, neighbors, pastor, and outpatient psychiatrist are involved. Mrs. P believes these individuals are members of a cult, she has been the victim of a satanic sexual rite, and a television news personality knows about this conspiracy and has been attempting to contact her.

Mrs. P suffers from severe, debilitating chronic pain experienced as shock-like pain lasting for several minutes that starts in her throat and radiates to her left ear. Her pain began several years ago and prompted a neurologic workup, including MRI of the head and somatosensory evoked potentials of the glossopharyngeal nerve. She was diagnosed with “probable” glossopharyngeal neuralgia and failed multiple medication trials, including carbamazepine, phenytoin, gabapentin, and amitriptyline. She underwent microvascular decompression surgery 3 years ago. The operation, which has an 80% to 90% success rate for neuralgias,^1,2 offered only brief symptomatic relief. She was maintained on immediate-release opiates until the pain became “unbearable” 8 months ago. This prompted a second neurologic workup, which was unremarkable. Mrs. P was diagnosed with pain disorder associated with psychological factors and a general medical condition.

Ten years ago she had 2 major depressive episodes with inpatient hospitalization and 2 suicide attempts within 1 year, but no history of psychosis before 8 months ago. Mrs. P’s husband says his wife has no history of manic or hypomanic episodes. Her medications are ziprasidone, 20 mg/d, thiothixene, 10 mg/d, benztropine, 3 mg/d, and escitalopram, 30 mg/d. She also receives oxycodone/acetaminophen, 5 mg/325 mg as needed for facial pain and headaches, and clonazepam, 1 mg as needed for panic attacks.

The authors’ observations

Psychosis can be a feature of any of the disorders listed in Table 1³; however, several features of Mrs. P’s illness led us to diagnose MDD, recurrent, severe with psychotic features.⁴ Mrs. P and her husband described several discreet episodes of major debilitating depression without alternating periods of hypomanic or manic symptoms (Table 2).⁴ Comorbid depressive symptoms and a timeline indicating persistence of psychotic symptoms make a brief psychotic episode less likely. Although uncommon, patients can develop psychotic or mood disorders as a result of opiate abuse or dependence. However, Mrs. P was taking opiates as prescribed and not asking for early refills, which makes substance abuse an unlikely cause of her psychosis. In addition, because Mrs. P had 2 major depressive episodes in the absence of opiate use, a primary mood disorder seemed the more appropriate diagnosis. Schizophrenia is ruled out based on history. Although Mrs. P was suffering from complex delusional constructs, auditory hallucinations, and grossly disorganized behavior, these symptoms occurred only within the context of her depressive episode. New-onset delusional guilt relating to her childhood sexual trauma and hypochondriacal preoccupations within the context of pain complaints make psychotic depression more likely.⁵

Table 1

Psychiatric diseases in which patients may present with psychotic symptoms

Table 2

DSM-IV-TR criteria for major depressive episode

Depression, psychosis, and pain

From the beginning of Mrs. P’s treatment, we considered psychotic depression worsened—if not completely explained—her pain. Her somatic complaints appeared to be subtly woven into her delusional constructs. For instance, she complained that a device had been implanted in her head and she had the scar to prove it, pointing to the scar from her microvascular decompression surgery. Research indicates that depressive illness and chronic pain syndromes are highly comorbid and depressive illness can worsen pain syndromes.^6,7 In addition, Mrs. P failed several medical and 1 surgical interventions for her pain condition that had high success rates. Her husband notes that when her outpatient psychiatrist started olanzapine 3 months ago for emerging psychotic symptoms, her pain complaints initially decreased with her psychotic symptoms, and she used less opiate medication during that time. Several months later Mrs. P’s pain complaints increased as her psychotic symptoms worsened. Second-generation antipsychotics have been evaluated as treatment for chronic pain syndromes, and may exert a primary analgesic effect.^8,9 However, because of the correlation between her fluctuating psychotic symptoms and pain complaints, the more plausible explanation for olanzapine’s initial efficacy in treating Mrs. P’s pain is a secondary analgesic effect from decreased psychotic somatic preoccupation.

TREATMENT: ECT

Mrs. P is admitted to the inpatient psychiatric unit and placed on suicide precautions. Oxycodone/acetaminophen and clonazepam are tapered and limited to twice daily as needed. Escitalopram is tapered and discontinued. Thiothixene is tapered and replaced by olanzapine, 5 mg/d. Mrs. P receives 3 bifrontal, brief pulse-width ECT treatments. These result in marked improvement in her depressive and psychotic symptoms. In addition, her pain complaints become minimal. She becomes less preoccupied with her sexual trauma and grows to trust many staff members whom she previously believed were part of her traumatic childhood events. Mrs. P is no longer suicidal and asks to continue ECT treatments as an outpatient. She is discharged on olanzapine, 5 mg/d, trazodone, 100 mg/d for insomnia, benztropine, 2 mg/d, clonazepam 0.5 mg twice daily as needed for panic attacks, and oxycodone/acetaminophen, 5 mg/325 mg twice daily as needed for pain.

The authors’ observations

According to the Harvard South Shore Algorithm, treatment strategies for psychotic depression include antidepressant and antipsychotic combinations, lithium augmentation, clozapine, and ECT.¹⁰ Several factors made ECT the best option for Mrs. P. She had failed multiple treatment strategies and was suicidal. ECT is an effective treatment for MDD with psychotic features, single or recurrent episode.¹¹ ECT can be used as a primary treatment before psychotropic medications or secondarily when there has been lack of clinical response to medications, intolerable side effects, deterioration in psychiatric condition, or suicidality.^11,12 In addition, when treated with ECT, psychotic depression has a significantly higher remission rate than major depression without psychosis.¹² Delusional guilt, psychomotor retardation, hypochondriacal preoccupations, loss of insight, paranoia, and obsessive-compulsive symptoms predict a favorable response.¹² ECT also has demonstrated efficacy for treating pain secondary to psychotic depression or melancholic depression.¹³ In addition, ECT has been shown to have analgesic properties beyond treating underlying depression.¹⁴ Our primary focus was not to treat Mrs. P’s pain syndrome with ECT; however, in treating her psychotic depression we had hoped that her pain tolerance would improve and she would rely less on opiates.

OUTCOME: Pain relief

As an outpatient, Mrs. P receives 11 bifrontal ECT treatments in her initial series, followed by 7 bifrontal maintenance treatments. Her speech is more spontaneous, her grooming and hygiene improve, and she exhibits a brighter and more reactive affect. Suicidal ideation has resolved. Pain improves from a “10 out of 10” to a “2 out of 10.” Mrs. P consistently requires less oxycodone/acetaminophen. She relates better to her family and begins exploring new hobbies such as pottery. In addition to monthly maintenance bifrontal ECT treatments, she is stable on citalopram, 60 mg/d, and trazodone, 50 mg/d as needed for insomnia.

The authors’ observations

The relationship between depressive illness and chronic pain is complex. Treating a primary depressive illness can lead to improved functional outcomes and decreased disability from chronic pain complaints.¹⁵ Patients with comorbid chronic pain and depressive illness are more likely to suffer from unremitting pain despite compliance with evidence-based treatment strategies.¹⁶ Mrs. P had 2 co-occurring disorders: psychotic depression and chronic pain disorder secondary to glossopharyngeal neuralgia. Our opinion is that Mrs. P’s psychotic depression worsened her experience of pain.

Treatment strategies that address both depressive symptoms and chronic pain are ideal.¹⁷ These treatment modalities include psychotherapeutic techniques such as cognitive-behavioral therapy, medications, and somatic treatments such as ECT.¹⁸ In Mrs. P’s case, ECT was an effective treatment that caused remission of psychotic depressive symptoms, which lead to improved pain control and restored social and occupational functioning.

Related Resources

• Schreiber S, Shmueli D, Grunhaus L, et al. The influence of electroconvulsive therapy on pain threshold and pain tolerance in major depression patients before, during and after treatment. Eur J Pain. 2003;7(5):419-424.
• Suzuki K, Ebina Y, Shindo T, et al. Repeated electroconvulsive therapy courses improved chronic regional pain with depression caused by failed back syndrome. Med Sci Monit. 2009;15(4):CS77-CS79.
• Giesecke T, Gracely RH, Williams DA, et al. The relationship between depression, clinical pain, and experimental pain in a chronic pain cohort. Arthritis Rheum. 2005;52(5):1577-1584.

Drug Brand Names

• Amitriptyline • Elavil
• Benztropine • Cogentin
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Escitalopram • Lexapro
• Gabapentin • Neurontin
• Lithium • Eskalith, Lithobid
• Olanzapine • Zyprexa
• Oxycodone/ acetaminophen • Vicodin
• Phenytoin • Dilantin
• Thiothixene • Navane
• Trazodone • Desyrel, Oleptro
• Ziprasidone • Geodon

Disclosures

Dr. Kugler reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Magid receives NARSAD grant support.

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Depressed and delusional

Mrs. P, age 58, is a retired art teacher who presents for inpatient psychiatric admission after an 8-month depressive and psychotic illness. She reports profound feelings of worthlessness, anhedonia, psychomotor retardation, daily spontaneous crying spells, and worsening suicidal ideation. She is unkempt, disheveled, and makes limited eye contact. She is floridly psychotic, exhibits hebephrenia at times, and appears to be having conversations with people who are not there. Mrs. P reports derogatory intracranial auditory hallucinations of her brother’s and father’s voices. She also describes a complex delusional system relating to sexual trauma she experienced as a child perpetrated by her brother. Her family corroborates some details of the trauma; however, she says her father, neighbors, pastor, and outpatient psychiatrist are involved. Mrs. P believes these individuals are members of a cult, she has been the victim of a satanic sexual rite, and a television news personality knows about this conspiracy and has been attempting to contact her.

Mrs. P suffers from severe, debilitating chronic pain experienced as shock-like pain lasting for several minutes that starts in her throat and radiates to her left ear. Her pain began several years ago and prompted a neurologic workup, including MRI of the head and somatosensory evoked potentials of the glossopharyngeal nerve. She was diagnosed with “probable” glossopharyngeal neuralgia and failed multiple medication trials, including carbamazepine, phenytoin, gabapentin, and amitriptyline. She underwent microvascular decompression surgery 3 years ago. The operation, which has an 80% to 90% success rate for neuralgias,^1,2 offered only brief symptomatic relief. She was maintained on immediate-release opiates until the pain became “unbearable” 8 months ago. This prompted a second neurologic workup, which was unremarkable. Mrs. P was diagnosed with pain disorder associated with psychological factors and a general medical condition.

Ten years ago she had 2 major depressive episodes with inpatient hospitalization and 2 suicide attempts within 1 year, but no history of psychosis before 8 months ago. Mrs. P’s husband says his wife has no history of manic or hypomanic episodes. Her medications are ziprasidone, 20 mg/d, thiothixene, 10 mg/d, benztropine, 3 mg/d, and escitalopram, 30 mg/d. She also receives oxycodone/acetaminophen, 5 mg/325 mg as needed for facial pain and headaches, and clonazepam, 1 mg as needed for panic attacks.

The authors’ observations

Psychosis can be a feature of any of the disorders listed in Table 1³; however, several features of Mrs. P’s illness led us to diagnose MDD, recurrent, severe with psychotic features.⁴ Mrs. P and her husband described several discreet episodes of major debilitating depression without alternating periods of hypomanic or manic symptoms (Table 2).⁴ Comorbid depressive symptoms and a timeline indicating persistence of psychotic symptoms make a brief psychotic episode less likely. Although uncommon, patients can develop psychotic or mood disorders as a result of opiate abuse or dependence. However, Mrs. P was taking opiates as prescribed and not asking for early refills, which makes substance abuse an unlikely cause of her psychosis. In addition, because Mrs. P had 2 major depressive episodes in the absence of opiate use, a primary mood disorder seemed the more appropriate diagnosis. Schizophrenia is ruled out based on history. Although Mrs. P was suffering from complex delusional constructs, auditory hallucinations, and grossly disorganized behavior, these symptoms occurred only within the context of her depressive episode. New-onset delusional guilt relating to her childhood sexual trauma and hypochondriacal preoccupations within the context of pain complaints make psychotic depression more likely.⁵

Table 1

Psychiatric diseases in which patients may present with psychotic symptoms

Table 2

DSM-IV-TR criteria for major depressive episode

Depression, psychosis, and pain

From the beginning of Mrs. P’s treatment, we considered psychotic depression worsened—if not completely explained—her pain. Her somatic complaints appeared to be subtly woven into her delusional constructs. For instance, she complained that a device had been implanted in her head and she had the scar to prove it, pointing to the scar from her microvascular decompression surgery. Research indicates that depressive illness and chronic pain syndromes are highly comorbid and depressive illness can worsen pain syndromes.^6,7 In addition, Mrs. P failed several medical and 1 surgical interventions for her pain condition that had high success rates. Her husband notes that when her outpatient psychiatrist started olanzapine 3 months ago for emerging psychotic symptoms, her pain complaints initially decreased with her psychotic symptoms, and she used less opiate medication during that time. Several months later Mrs. P’s pain complaints increased as her psychotic symptoms worsened. Second-generation antipsychotics have been evaluated as treatment for chronic pain syndromes, and may exert a primary analgesic effect.^8,9 However, because of the correlation between her fluctuating psychotic symptoms and pain complaints, the more plausible explanation for olanzapine’s initial efficacy in treating Mrs. P’s pain is a secondary analgesic effect from decreased psychotic somatic preoccupation.

TREATMENT: ECT

Mrs. P is admitted to the inpatient psychiatric unit and placed on suicide precautions. Oxycodone/acetaminophen and clonazepam are tapered and limited to twice daily as needed. Escitalopram is tapered and discontinued. Thiothixene is tapered and replaced by olanzapine, 5 mg/d. Mrs. P receives 3 bifrontal, brief pulse-width ECT treatments. These result in marked improvement in her depressive and psychotic symptoms. In addition, her pain complaints become minimal. She becomes less preoccupied with her sexual trauma and grows to trust many staff members whom she previously believed were part of her traumatic childhood events. Mrs. P is no longer suicidal and asks to continue ECT treatments as an outpatient. She is discharged on olanzapine, 5 mg/d, trazodone, 100 mg/d for insomnia, benztropine, 2 mg/d, clonazepam 0.5 mg twice daily as needed for panic attacks, and oxycodone/acetaminophen, 5 mg/325 mg twice daily as needed for pain.

The authors’ observations

According to the Harvard South Shore Algorithm, treatment strategies for psychotic depression include antidepressant and antipsychotic combinations, lithium augmentation, clozapine, and ECT.¹⁰ Several factors made ECT the best option for Mrs. P. She had failed multiple treatment strategies and was suicidal. ECT is an effective treatment for MDD with psychotic features, single or recurrent episode.¹¹ ECT can be used as a primary treatment before psychotropic medications or secondarily when there has been lack of clinical response to medications, intolerable side effects, deterioration in psychiatric condition, or suicidality.^11,12 In addition, when treated with ECT, psychotic depression has a significantly higher remission rate than major depression without psychosis.¹² Delusional guilt, psychomotor retardation, hypochondriacal preoccupations, loss of insight, paranoia, and obsessive-compulsive symptoms predict a favorable response.¹² ECT also has demonstrated efficacy for treating pain secondary to psychotic depression or melancholic depression.¹³ In addition, ECT has been shown to have analgesic properties beyond treating underlying depression.¹⁴ Our primary focus was not to treat Mrs. P’s pain syndrome with ECT; however, in treating her psychotic depression we had hoped that her pain tolerance would improve and she would rely less on opiates.

OUTCOME: Pain relief

As an outpatient, Mrs. P receives 11 bifrontal ECT treatments in her initial series, followed by 7 bifrontal maintenance treatments. Her speech is more spontaneous, her grooming and hygiene improve, and she exhibits a brighter and more reactive affect. Suicidal ideation has resolved. Pain improves from a “10 out of 10” to a “2 out of 10.” Mrs. P consistently requires less oxycodone/acetaminophen. She relates better to her family and begins exploring new hobbies such as pottery. In addition to monthly maintenance bifrontal ECT treatments, she is stable on citalopram, 60 mg/d, and trazodone, 50 mg/d as needed for insomnia.

The authors’ observations

The relationship between depressive illness and chronic pain is complex. Treating a primary depressive illness can lead to improved functional outcomes and decreased disability from chronic pain complaints.¹⁵ Patients with comorbid chronic pain and depressive illness are more likely to suffer from unremitting pain despite compliance with evidence-based treatment strategies.¹⁶ Mrs. P had 2 co-occurring disorders: psychotic depression and chronic pain disorder secondary to glossopharyngeal neuralgia. Our opinion is that Mrs. P’s psychotic depression worsened her experience of pain.

Treatment strategies that address both depressive symptoms and chronic pain are ideal.¹⁷ These treatment modalities include psychotherapeutic techniques such as cognitive-behavioral therapy, medications, and somatic treatments such as ECT.¹⁸ In Mrs. P’s case, ECT was an effective treatment that caused remission of psychotic depressive symptoms, which lead to improved pain control and restored social and occupational functioning.

Related Resources

• Schreiber S, Shmueli D, Grunhaus L, et al. The influence of electroconvulsive therapy on pain threshold and pain tolerance in major depression patients before, during and after treatment. Eur J Pain. 2003;7(5):419-424.
• Suzuki K, Ebina Y, Shindo T, et al. Repeated electroconvulsive therapy courses improved chronic regional pain with depression caused by failed back syndrome. Med Sci Monit. 2009;15(4):CS77-CS79.
• Giesecke T, Gracely RH, Williams DA, et al. The relationship between depression, clinical pain, and experimental pain in a chronic pain cohort. Arthritis Rheum. 2005;52(5):1577-1584.

Drug Brand Names

• Amitriptyline • Elavil
• Benztropine • Cogentin
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Escitalopram • Lexapro
• Gabapentin • Neurontin
• Lithium • Eskalith, Lithobid
• Olanzapine • Zyprexa
• Oxycodone/ acetaminophen • Vicodin
• Phenytoin • Dilantin
• Thiothixene • Navane
• Trazodone • Desyrel, Oleptro
• Ziprasidone • Geodon

Disclosures

Dr. Kugler reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Magid receives NARSAD grant support.

CASE: Hurt and confused

Emergency medical services (EMS) are called to Ms. K’s apartment after her roommate found her lying on the floor moaning. The roommate tells EMS that Ms. K, age 29, appeared confused and was slurring her words, and reports that this change in her awareness progressed rapidly over a few hours. EMS personnel find that Ms. K has multiple contusions on her arms and face, which they presume to be self-inflicted. A marijuana pipe is discovered at Ms. K’s apartment.

In the emergency room (ER), Ms. K is inattentive and has difficulty following simple commands. Her speech is mumbled and her thoughts are disorganized. She displays psychomotor restlessness in the form of combativeness. Ms. K cannot provide meaningful historical data and is disoriented to place and time. The ER staff requests a psychiatric consultation.

Family members reveal that Ms. K has no preexisting medical conditions, is not taking prescription medications, but has a history of substance abuse (sporadic cocaine and cannabis use). Her family is unaware of recent substance use.

Physical examination reveals tachycardia (heart rate 110 to 120 beats per minute), hypotension (blood pressure 78/49 mm Hg), hypothermia (temperature 88ºF), and peripheral pulse oximetry of 84%. Her pupils are dilated and reactive to light; no conjunctival injection is noted. Her lung fields are clear on auscultation, but she is noted to have a rapid, irregular heartbeat. The abdomen is positive for bowel sounds, soft on palpation, and without any repositioning or notable overt signs of tenderness. Ms. K’s toes show purple discoloration with poor capillary refill. The dorsalis pedis pulses are reported to be 1+ bilaterally; however, the remainder of the arterial pulse examination is normal.

Her sodium, potassium, and chloride values are normal, but she has an abnormal anion gap (28.1 mEq/L), blood urea nitrogen (53 mg/dL), creatinine (2.9 mg/dL), creatine kinase (10,857 U/L), creatine kinase MB (432.6 ng/mL), and hyperglycemia (glucose 425 mg/dL). Arterial blood gas reveals hypoxia (Po₂ of 55 mm Hg), with metabolic acidosis (sodium bicarbonate 10 with compensatory Pco₂ of 33 mm Hg). Her urine is cloudy, positive for protein, ketones, hemoglobin, and glucose. She is thought to have a high anion gap acidosis related to dehydration, lactic acidosis (lactic acid 20 mEq/L), and hyperglycemia. Urine toxicology is positive for cannabinoids; ethylene glycol and methanol screen negatively, which rules these out as potential contributors to her high anion gap acidosis.

Ms. K is intubated and IV fluids are initiated for rhabdomyolysis and acute renal failure. Dialysis is implemented on a short-term basis. Her mental state improves gradually over 3 days.

The authors’ observations

Based on the abrupt onset of inattention and confusion, disorganized speech, memory impairments, and psychomotor agitation, we made an initial diagnosis of delirium; however, the precise etiology remained unclear. DSM-IV-TR diagnostic criteria for delirium are described in Table 1. Although delirium due to multiple etiologies does not have a DSM-IV-TR coding designation, we speculated that multiple causes contributed to Ms. K’s presentation. Acute renal failure secondary to dehydration as well as rhabdomyolysis, hypoxia, and hyperglycemia were implicated as general medical conditions etiologically linked to delirium. Because Ms. K has no preexisting medical conditions and her roommate and family stated she had a history of substance abuse, we also considered a presumptive diagnosis of substance-induced delirium. The medical team speculated that, based on information provided by her family, Ms. K may have had a seizure or may have fallen, which would account for her multiple contusions, and could have led to muscle injury and breakdown and the resultant rhabdomyolysis.

The possibility of cannabinoid-induced delirium has been reported, albeit rarely.^1-3 However, Ms. K’s presentation—hypothermia, variable heart rate, lack of dry mucous membranes—was not consistent with significant anticholinergic toxicity or cannabinoid intoxication (Table 2).

By contrast, cocaine-induced delirium has been reported and initially appeared to be a plausible cause of Ms. K’s symptoms (Table 2). Delirium related to excess ingestion of cocaine may be related to the drug’s secondary effects resulting in rhabdomyolysis and renal dysfunction.^4-6 Although several mechanisms underlying this relationship have been proposed, no single specific mechanism has been identified. The basis for cocaine ingestion and the resultant metabolic and renal effects, as observed in Ms. K’s case, likely are multifactorial. Mechanisms of the rhabdomyolysis might include:

• blockade of synaptic catecholamine reuptake and induction of adrenergic agonism, resulting in vasoconstriction and ischemia and leading to muscle damage
• cocaine-induced seizures and/or prolonged unconsciousness, leading to muscle compression and breakdown of muscle tissue
• a period of exertion induced by cocaine, precipitating an excited delirium and associated rhabdomyolysis
• a surge in dopamine concentrations, similar to neuroleptic malignant syndrome, precipitates hyperthermia, muscle rigidity, and psychomotor agitation, disrupting neuromuscular homeostasis and leading to rhabdomyolysis.

We were uncertain about the plausibility that acute cocaine intoxication caused Ms. K’s medical sequelae, in light of her toxicology findings. If cocaine use was the inciting event, and because the delirium reportedly had developed over several hours, we would expect cocaine to be detected in the toxicology screen. However, it was not detected. Cocaine can remain detectable in urine for 2 to 4 days,⁷ which raised our speculation that remote cocaine abuse could account for Ms. K’s current presentation and the timeline the roommate initially relayed to EMS personnel was inaccurate. We needed to clarify the timeline and progression of Ms. K’s symptoms with the roommate. In addition, we suggested to the medical team that alternative substances of abuse could be causing Ms. K’s symptoms and the roommate might be the only person who could unveil this possibility.

Table 1

DSM-IV-TR criteria for delirium due to multiple etiologies

Table 2

Diagnostic criteria for cannabis and cocaine intoxication

HISTORY: Unknown substance

Ms. K’s roommate is contacted for supplemental history. The roommate reports that recently he observed Ms. K “snorting” a brown/tan-colored substance. He had not seen her use this substance previously, and when he asked her what it was, she reportedly said that it was “PeeVee” (also called “bath salts”) purchased over the Internet.

The authors’ observations

MDPV is a novel chemical compound that is used as a recreational drug (Table 3).⁸ It commonly is acquired from Internet sources and sold as “bath salts.” Its use first emerged in approximately 2004, and its popularity has been increasing because of its easy availability and relatively low cost.⁹ The American Association of Poison Control Centers received 302 calls related to MDPV toxicity in 2010 and 5,625 calls related to MDPV use between January 1 and October 31, 2011.^10,11

MDPV has psychoactive properties, with stimulant effects acting as a norepinephrine-dopamine reuptake inhibitor.^8,9,12 When snorted, ingested orally, or inserted rectally, the agent produces effects comparable to cocaine or psychostimulants such as methylphenidate or dextroamphetamine.

Acute effects of MDPV include heightened alertness, diminished need for sleep, hyperarousal, and euphoria.^8,9 These symptoms often are accompanied by increases in heart rate and blood pressure, sweating, and peripheral vasoconstriction. Individuals may abuse MDPV to acquire sustained attention, reduce their need for sleep, or for aphrodisiac effects. In many cases, anxiety and irritability can accompany the desired euphoric effects. For some, the euphoric effects can be superseded by anxiety or agitation. Mood and attention effects are estimated to last 3 to 4 hours; however, tachycardia and hypertension can persist for 6 to 8 hours.

MDPV use can trigger cravings and lead to binging. Euphoric stimulation with MDPV can become dysphoric as the dose and duration of use increase. Extended use has been associated with agitation, irritability, aggression, panic and marked anxiety, psychosis, and delirium.^8,9 Anxiety can range from mild dysphoric stimulation to extreme panic-like states. In moderate forms, a state of sympathetic discharge can occur, producing physiologic effects resembling panic attacks, including hypertension, tachycardia, sweating, and peripheral vasoconstriction. In more severe cases, users may experience a feeling of impending doom, marked distress, and frank psychosis. Patients may experience disorientation and unsystematized paranoid delusions. Case reports of intoxication have described self-injurious behaviors, such as cutting, which may account for the contusions observed on Ms. K’s face and arms. Increasingly, MDPV use has resulted in ER presentations with patients manifesting abrupt onset confusion, anxiety, and self-injurious behaviors.

The mechanisms underlying MDPV-induced delirium have not been definitively identified. Given the similarities in mechanism of action between MDPV and cocaine, causes for delirium related to MDPV are similarly presumed to be multifactorial. The course of delirium associated with MDPV intoxication is self-limited and requires supportive measures.^8,9

Suspect MDPV abuse in patients who present with signs or symptoms of stimulant intoxication but have a negative toxicology screen for cocaine and other psychostimulants. MDPV is not detected on routine toxicology assessments; however, it can be identified through laboratories with gas chromatography/mass spectroscopy capabilities. However, the time needed to obtain the results may exceed the clinical course of the patient’s delirium. One of the limitations in Ms. K’s case was the lack of gas chromatography/mass spectroscopy to confirm MDPV ingestion. Ms. K’s roommate could not locate any unused brown powder within their apartment to bring in for laboratory investigations. Recently, screening assessments for MDPV have become commercially available (see Related Resources).

Table 3

Overview of MDPV features

OUTCOME: Referral to treatment

Dialysis is discontinued within 1 day of hospitalization. Ms. K’s peripheral arterial perfusion improves, as does her thermoregulatory status. Her mental status improvements coincide with improvements in her physical and metabolic status.

Ms. K is able to sustain attention when speaking with interviewers. She is aware of her surroundings and is no longer distracted by extraneous stimuli. Her speech is articulate and her thoughts are linear. There is no evidence of any residual thought disorganization, delusions, or hallucinations.

Initially, Ms. K is reluctant to acknowledge her substance use, but eventually, she concedes to acquiring a stimulant from an Internet source and abusing it in undetermined amounts. She had no experience with using MDPV and did not know how to avoid ingesting dangerous amounts. We educate Ms. K about the dangers she faced during this hospitalization and the potential life-threatening outcomes. She is amenable to pursuing outpatient substance abuse treatment. Her roommate is enlisted to facilitate her follow-up with this treatment.

The authors’ observations

Managing MDPV toxicity presents a diagnostic dilemma for medical personnel and psychiatrists when evaluating and managing acute delirium. MDPV ingestion may go unrecognized in clinical settings because toxicology assessments for it are not readily available and patients’ historical information may be unreliable.

Because of the seriousness of sequelae associated with MDPV use, state and federal agencies have intervened. Until recently, bath salts did not have a controlled substance designation. In October 2011, the US Drug Enforcement Administration (DEA) ruled to make MDPV a controlled substance for 1 year, with the possibility of a 6-month extension.¹³ Although this ruling is temporary, it makes possession, sale, or distribution of these chemicals, or the products that contain them, illegal in the United States. In the interim, the DEA and the US Department of Health and Human Services will determine whether MDPV should remain a controlled substance.

Related Resources

• American Screening Corp. (MDPV screening). www.americanscreeningcorp.com.
• U.S. Drug Enforcement Administration. 3, 4-Methylenedioxypyrovalerone (MDPV). www.deadiversion.usdoj.gov/drugs_concern/mdpv.pdf.
• Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones [published online ahead of print November 23, 2011]. J Med Toxicol. doi: 10.1007/s13181-011-0193-z.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Hurt and confused

Emergency medical services (EMS) are called to Ms. K’s apartment after her roommate found her lying on the floor moaning. The roommate tells EMS that Ms. K, age 29, appeared confused and was slurring her words, and reports that this change in her awareness progressed rapidly over a few hours. EMS personnel find that Ms. K has multiple contusions on her arms and face, which they presume to be self-inflicted. A marijuana pipe is discovered at Ms. K’s apartment.

In the emergency room (ER), Ms. K is inattentive and has difficulty following simple commands. Her speech is mumbled and her thoughts are disorganized. She displays psychomotor restlessness in the form of combativeness. Ms. K cannot provide meaningful historical data and is disoriented to place and time. The ER staff requests a psychiatric consultation.

Family members reveal that Ms. K has no preexisting medical conditions, is not taking prescription medications, but has a history of substance abuse (sporadic cocaine and cannabis use). Her family is unaware of recent substance use.

Physical examination reveals tachycardia (heart rate 110 to 120 beats per minute), hypotension (blood pressure 78/49 mm Hg), hypothermia (temperature 88ºF), and peripheral pulse oximetry of 84%. Her pupils are dilated and reactive to light; no conjunctival injection is noted. Her lung fields are clear on auscultation, but she is noted to have a rapid, irregular heartbeat. The abdomen is positive for bowel sounds, soft on palpation, and without any repositioning or notable overt signs of tenderness. Ms. K’s toes show purple discoloration with poor capillary refill. The dorsalis pedis pulses are reported to be 1+ bilaterally; however, the remainder of the arterial pulse examination is normal.

Her sodium, potassium, and chloride values are normal, but she has an abnormal anion gap (28.1 mEq/L), blood urea nitrogen (53 mg/dL), creatinine (2.9 mg/dL), creatine kinase (10,857 U/L), creatine kinase MB (432.6 ng/mL), and hyperglycemia (glucose 425 mg/dL). Arterial blood gas reveals hypoxia (Po₂ of 55 mm Hg), with metabolic acidosis (sodium bicarbonate 10 with compensatory Pco₂ of 33 mm Hg). Her urine is cloudy, positive for protein, ketones, hemoglobin, and glucose. She is thought to have a high anion gap acidosis related to dehydration, lactic acidosis (lactic acid 20 mEq/L), and hyperglycemia. Urine toxicology is positive for cannabinoids; ethylene glycol and methanol screen negatively, which rules these out as potential contributors to her high anion gap acidosis.

Ms. K is intubated and IV fluids are initiated for rhabdomyolysis and acute renal failure. Dialysis is implemented on a short-term basis. Her mental state improves gradually over 3 days.

The authors’ observations

Based on the abrupt onset of inattention and confusion, disorganized speech, memory impairments, and psychomotor agitation, we made an initial diagnosis of delirium; however, the precise etiology remained unclear. DSM-IV-TR diagnostic criteria for delirium are described in Table 1. Although delirium due to multiple etiologies does not have a DSM-IV-TR coding designation, we speculated that multiple causes contributed to Ms. K’s presentation. Acute renal failure secondary to dehydration as well as rhabdomyolysis, hypoxia, and hyperglycemia were implicated as general medical conditions etiologically linked to delirium. Because Ms. K has no preexisting medical conditions and her roommate and family stated she had a history of substance abuse, we also considered a presumptive diagnosis of substance-induced delirium. The medical team speculated that, based on information provided by her family, Ms. K may have had a seizure or may have fallen, which would account for her multiple contusions, and could have led to muscle injury and breakdown and the resultant rhabdomyolysis.

The possibility of cannabinoid-induced delirium has been reported, albeit rarely.^1-3 However, Ms. K’s presentation—hypothermia, variable heart rate, lack of dry mucous membranes—was not consistent with significant anticholinergic toxicity or cannabinoid intoxication (Table 2).

By contrast, cocaine-induced delirium has been reported and initially appeared to be a plausible cause of Ms. K’s symptoms (Table 2). Delirium related to excess ingestion of cocaine may be related to the drug’s secondary effects resulting in rhabdomyolysis and renal dysfunction.^4-6 Although several mechanisms underlying this relationship have been proposed, no single specific mechanism has been identified. The basis for cocaine ingestion and the resultant metabolic and renal effects, as observed in Ms. K’s case, likely are multifactorial. Mechanisms of the rhabdomyolysis might include:

• blockade of synaptic catecholamine reuptake and induction of adrenergic agonism, resulting in vasoconstriction and ischemia and leading to muscle damage
• cocaine-induced seizures and/or prolonged unconsciousness, leading to muscle compression and breakdown of muscle tissue
• a period of exertion induced by cocaine, precipitating an excited delirium and associated rhabdomyolysis
• a surge in dopamine concentrations, similar to neuroleptic malignant syndrome, precipitates hyperthermia, muscle rigidity, and psychomotor agitation, disrupting neuromuscular homeostasis and leading to rhabdomyolysis.

We were uncertain about the plausibility that acute cocaine intoxication caused Ms. K’s medical sequelae, in light of her toxicology findings. If cocaine use was the inciting event, and because the delirium reportedly had developed over several hours, we would expect cocaine to be detected in the toxicology screen. However, it was not detected. Cocaine can remain detectable in urine for 2 to 4 days,⁷ which raised our speculation that remote cocaine abuse could account for Ms. K’s current presentation and the timeline the roommate initially relayed to EMS personnel was inaccurate. We needed to clarify the timeline and progression of Ms. K’s symptoms with the roommate. In addition, we suggested to the medical team that alternative substances of abuse could be causing Ms. K’s symptoms and the roommate might be the only person who could unveil this possibility.

Table 1

DSM-IV-TR criteria for delirium due to multiple etiologies

Table 2

Diagnostic criteria for cannabis and cocaine intoxication

HISTORY: Unknown substance

Ms. K’s roommate is contacted for supplemental history. The roommate reports that recently he observed Ms. K “snorting” a brown/tan-colored substance. He had not seen her use this substance previously, and when he asked her what it was, she reportedly said that it was “PeeVee” (also called “bath salts”) purchased over the Internet.

The authors’ observations

MDPV is a novel chemical compound that is used as a recreational drug (Table 3).⁸ It commonly is acquired from Internet sources and sold as “bath salts.” Its use first emerged in approximately 2004, and its popularity has been increasing because of its easy availability and relatively low cost.⁹ The American Association of Poison Control Centers received 302 calls related to MDPV toxicity in 2010 and 5,625 calls related to MDPV use between January 1 and October 31, 2011.^10,11

MDPV has psychoactive properties, with stimulant effects acting as a norepinephrine-dopamine reuptake inhibitor.^8,9,12 When snorted, ingested orally, or inserted rectally, the agent produces effects comparable to cocaine or psychostimulants such as methylphenidate or dextroamphetamine.

Acute effects of MDPV include heightened alertness, diminished need for sleep, hyperarousal, and euphoria.^8,9 These symptoms often are accompanied by increases in heart rate and blood pressure, sweating, and peripheral vasoconstriction. Individuals may abuse MDPV to acquire sustained attention, reduce their need for sleep, or for aphrodisiac effects. In many cases, anxiety and irritability can accompany the desired euphoric effects. For some, the euphoric effects can be superseded by anxiety or agitation. Mood and attention effects are estimated to last 3 to 4 hours; however, tachycardia and hypertension can persist for 6 to 8 hours.

MDPV use can trigger cravings and lead to binging. Euphoric stimulation with MDPV can become dysphoric as the dose and duration of use increase. Extended use has been associated with agitation, irritability, aggression, panic and marked anxiety, psychosis, and delirium.^8,9 Anxiety can range from mild dysphoric stimulation to extreme panic-like states. In moderate forms, a state of sympathetic discharge can occur, producing physiologic effects resembling panic attacks, including hypertension, tachycardia, sweating, and peripheral vasoconstriction. In more severe cases, users may experience a feeling of impending doom, marked distress, and frank psychosis. Patients may experience disorientation and unsystematized paranoid delusions. Case reports of intoxication have described self-injurious behaviors, such as cutting, which may account for the contusions observed on Ms. K’s face and arms. Increasingly, MDPV use has resulted in ER presentations with patients manifesting abrupt onset confusion, anxiety, and self-injurious behaviors.

The mechanisms underlying MDPV-induced delirium have not been definitively identified. Given the similarities in mechanism of action between MDPV and cocaine, causes for delirium related to MDPV are similarly presumed to be multifactorial. The course of delirium associated with MDPV intoxication is self-limited and requires supportive measures.^8,9

Suspect MDPV abuse in patients who present with signs or symptoms of stimulant intoxication but have a negative toxicology screen for cocaine and other psychostimulants. MDPV is not detected on routine toxicology assessments; however, it can be identified through laboratories with gas chromatography/mass spectroscopy capabilities. However, the time needed to obtain the results may exceed the clinical course of the patient’s delirium. One of the limitations in Ms. K’s case was the lack of gas chromatography/mass spectroscopy to confirm MDPV ingestion. Ms. K’s roommate could not locate any unused brown powder within their apartment to bring in for laboratory investigations. Recently, screening assessments for MDPV have become commercially available (see Related Resources).

Table 3

Overview of MDPV features

OUTCOME: Referral to treatment

Dialysis is discontinued within 1 day of hospitalization. Ms. K’s peripheral arterial perfusion improves, as does her thermoregulatory status. Her mental status improvements coincide with improvements in her physical and metabolic status.

Ms. K is able to sustain attention when speaking with interviewers. She is aware of her surroundings and is no longer distracted by extraneous stimuli. Her speech is articulate and her thoughts are linear. There is no evidence of any residual thought disorganization, delusions, or hallucinations.

Initially, Ms. K is reluctant to acknowledge her substance use, but eventually, she concedes to acquiring a stimulant from an Internet source and abusing it in undetermined amounts. She had no experience with using MDPV and did not know how to avoid ingesting dangerous amounts. We educate Ms. K about the dangers she faced during this hospitalization and the potential life-threatening outcomes. She is amenable to pursuing outpatient substance abuse treatment. Her roommate is enlisted to facilitate her follow-up with this treatment.

The authors’ observations

Managing MDPV toxicity presents a diagnostic dilemma for medical personnel and psychiatrists when evaluating and managing acute delirium. MDPV ingestion may go unrecognized in clinical settings because toxicology assessments for it are not readily available and patients’ historical information may be unreliable.

Because of the seriousness of sequelae associated with MDPV use, state and federal agencies have intervened. Until recently, bath salts did not have a controlled substance designation. In October 2011, the US Drug Enforcement Administration (DEA) ruled to make MDPV a controlled substance for 1 year, with the possibility of a 6-month extension.¹³ Although this ruling is temporary, it makes possession, sale, or distribution of these chemicals, or the products that contain them, illegal in the United States. In the interim, the DEA and the US Department of Health and Human Services will determine whether MDPV should remain a controlled substance.

Related Resources

• American Screening Corp. (MDPV screening). www.americanscreeningcorp.com.
• U.S. Drug Enforcement Administration. 3, 4-Methylenedioxypyrovalerone (MDPV). www.deadiversion.usdoj.gov/drugs_concern/mdpv.pdf.
• Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones [published online ahead of print November 23, 2011]. J Med Toxicol. doi: 10.1007/s13181-011-0193-z.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Hurt and confused

Emergency medical services (EMS) are called to Ms. K’s apartment after her roommate found her lying on the floor moaning. The roommate tells EMS that Ms. K, age 29, appeared confused and was slurring her words, and reports that this change in her awareness progressed rapidly over a few hours. EMS personnel find that Ms. K has multiple contusions on her arms and face, which they presume to be self-inflicted. A marijuana pipe is discovered at Ms. K’s apartment.

In the emergency room (ER), Ms. K is inattentive and has difficulty following simple commands. Her speech is mumbled and her thoughts are disorganized. She displays psychomotor restlessness in the form of combativeness. Ms. K cannot provide meaningful historical data and is disoriented to place and time. The ER staff requests a psychiatric consultation.

Family members reveal that Ms. K has no preexisting medical conditions, is not taking prescription medications, but has a history of substance abuse (sporadic cocaine and cannabis use). Her family is unaware of recent substance use.

Physical examination reveals tachycardia (heart rate 110 to 120 beats per minute), hypotension (blood pressure 78/49 mm Hg), hypothermia (temperature 88ºF), and peripheral pulse oximetry of 84%. Her pupils are dilated and reactive to light; no conjunctival injection is noted. Her lung fields are clear on auscultation, but she is noted to have a rapid, irregular heartbeat. The abdomen is positive for bowel sounds, soft on palpation, and without any repositioning or notable overt signs of tenderness. Ms. K’s toes show purple discoloration with poor capillary refill. The dorsalis pedis pulses are reported to be 1+ bilaterally; however, the remainder of the arterial pulse examination is normal.

Her sodium, potassium, and chloride values are normal, but she has an abnormal anion gap (28.1 mEq/L), blood urea nitrogen (53 mg/dL), creatinine (2.9 mg/dL), creatine kinase (10,857 U/L), creatine kinase MB (432.6 ng/mL), and hyperglycemia (glucose 425 mg/dL). Arterial blood gas reveals hypoxia (Po₂ of 55 mm Hg), with metabolic acidosis (sodium bicarbonate 10 with compensatory Pco₂ of 33 mm Hg). Her urine is cloudy, positive for protein, ketones, hemoglobin, and glucose. She is thought to have a high anion gap acidosis related to dehydration, lactic acidosis (lactic acid 20 mEq/L), and hyperglycemia. Urine toxicology is positive for cannabinoids; ethylene glycol and methanol screen negatively, which rules these out as potential contributors to her high anion gap acidosis.

Ms. K is intubated and IV fluids are initiated for rhabdomyolysis and acute renal failure. Dialysis is implemented on a short-term basis. Her mental state improves gradually over 3 days.

The authors’ observations

Based on the abrupt onset of inattention and confusion, disorganized speech, memory impairments, and psychomotor agitation, we made an initial diagnosis of delirium; however, the precise etiology remained unclear. DSM-IV-TR diagnostic criteria for delirium are described in Table 1. Although delirium due to multiple etiologies does not have a DSM-IV-TR coding designation, we speculated that multiple causes contributed to Ms. K’s presentation. Acute renal failure secondary to dehydration as well as rhabdomyolysis, hypoxia, and hyperglycemia were implicated as general medical conditions etiologically linked to delirium. Because Ms. K has no preexisting medical conditions and her roommate and family stated she had a history of substance abuse, we also considered a presumptive diagnosis of substance-induced delirium. The medical team speculated that, based on information provided by her family, Ms. K may have had a seizure or may have fallen, which would account for her multiple contusions, and could have led to muscle injury and breakdown and the resultant rhabdomyolysis.

The possibility of cannabinoid-induced delirium has been reported, albeit rarely.^1-3 However, Ms. K’s presentation—hypothermia, variable heart rate, lack of dry mucous membranes—was not consistent with significant anticholinergic toxicity or cannabinoid intoxication (Table 2).

By contrast, cocaine-induced delirium has been reported and initially appeared to be a plausible cause of Ms. K’s symptoms (Table 2). Delirium related to excess ingestion of cocaine may be related to the drug’s secondary effects resulting in rhabdomyolysis and renal dysfunction.^4-6 Although several mechanisms underlying this relationship have been proposed, no single specific mechanism has been identified. The basis for cocaine ingestion and the resultant metabolic and renal effects, as observed in Ms. K’s case, likely are multifactorial. Mechanisms of the rhabdomyolysis might include:

• blockade of synaptic catecholamine reuptake and induction of adrenergic agonism, resulting in vasoconstriction and ischemia and leading to muscle damage
• cocaine-induced seizures and/or prolonged unconsciousness, leading to muscle compression and breakdown of muscle tissue
• a period of exertion induced by cocaine, precipitating an excited delirium and associated rhabdomyolysis
• a surge in dopamine concentrations, similar to neuroleptic malignant syndrome, precipitates hyperthermia, muscle rigidity, and psychomotor agitation, disrupting neuromuscular homeostasis and leading to rhabdomyolysis.

We were uncertain about the plausibility that acute cocaine intoxication caused Ms. K’s medical sequelae, in light of her toxicology findings. If cocaine use was the inciting event, and because the delirium reportedly had developed over several hours, we would expect cocaine to be detected in the toxicology screen. However, it was not detected. Cocaine can remain detectable in urine for 2 to 4 days,⁷ which raised our speculation that remote cocaine abuse could account for Ms. K’s current presentation and the timeline the roommate initially relayed to EMS personnel was inaccurate. We needed to clarify the timeline and progression of Ms. K’s symptoms with the roommate. In addition, we suggested to the medical team that alternative substances of abuse could be causing Ms. K’s symptoms and the roommate might be the only person who could unveil this possibility.

Table 1

DSM-IV-TR criteria for delirium due to multiple etiologies

Table 2

Diagnostic criteria for cannabis and cocaine intoxication

HISTORY: Unknown substance

Ms. K’s roommate is contacted for supplemental history. The roommate reports that recently he observed Ms. K “snorting” a brown/tan-colored substance. He had not seen her use this substance previously, and when he asked her what it was, she reportedly said that it was “PeeVee” (also called “bath salts”) purchased over the Internet.

The authors’ observations

MDPV is a novel chemical compound that is used as a recreational drug (Table 3).⁸ It commonly is acquired from Internet sources and sold as “bath salts.” Its use first emerged in approximately 2004, and its popularity has been increasing because of its easy availability and relatively low cost.⁹ The American Association of Poison Control Centers received 302 calls related to MDPV toxicity in 2010 and 5,625 calls related to MDPV use between January 1 and October 31, 2011.^10,11

MDPV has psychoactive properties, with stimulant effects acting as a norepinephrine-dopamine reuptake inhibitor.^8,9,12 When snorted, ingested orally, or inserted rectally, the agent produces effects comparable to cocaine or psychostimulants such as methylphenidate or dextroamphetamine.

Acute effects of MDPV include heightened alertness, diminished need for sleep, hyperarousal, and euphoria.^8,9 These symptoms often are accompanied by increases in heart rate and blood pressure, sweating, and peripheral vasoconstriction. Individuals may abuse MDPV to acquire sustained attention, reduce their need for sleep, or for aphrodisiac effects. In many cases, anxiety and irritability can accompany the desired euphoric effects. For some, the euphoric effects can be superseded by anxiety or agitation. Mood and attention effects are estimated to last 3 to 4 hours; however, tachycardia and hypertension can persist for 6 to 8 hours.

MDPV use can trigger cravings and lead to binging. Euphoric stimulation with MDPV can become dysphoric as the dose and duration of use increase. Extended use has been associated with agitation, irritability, aggression, panic and marked anxiety, psychosis, and delirium.^8,9 Anxiety can range from mild dysphoric stimulation to extreme panic-like states. In moderate forms, a state of sympathetic discharge can occur, producing physiologic effects resembling panic attacks, including hypertension, tachycardia, sweating, and peripheral vasoconstriction. In more severe cases, users may experience a feeling of impending doom, marked distress, and frank psychosis. Patients may experience disorientation and unsystematized paranoid delusions. Case reports of intoxication have described self-injurious behaviors, such as cutting, which may account for the contusions observed on Ms. K’s face and arms. Increasingly, MDPV use has resulted in ER presentations with patients manifesting abrupt onset confusion, anxiety, and self-injurious behaviors.

The mechanisms underlying MDPV-induced delirium have not been definitively identified. Given the similarities in mechanism of action between MDPV and cocaine, causes for delirium related to MDPV are similarly presumed to be multifactorial. The course of delirium associated with MDPV intoxication is self-limited and requires supportive measures.^8,9

Suspect MDPV abuse in patients who present with signs or symptoms of stimulant intoxication but have a negative toxicology screen for cocaine and other psychostimulants. MDPV is not detected on routine toxicology assessments; however, it can be identified through laboratories with gas chromatography/mass spectroscopy capabilities. However, the time needed to obtain the results may exceed the clinical course of the patient’s delirium. One of the limitations in Ms. K’s case was the lack of gas chromatography/mass spectroscopy to confirm MDPV ingestion. Ms. K’s roommate could not locate any unused brown powder within their apartment to bring in for laboratory investigations. Recently, screening assessments for MDPV have become commercially available (see Related Resources).

Table 3

Overview of MDPV features

OUTCOME: Referral to treatment

Dialysis is discontinued within 1 day of hospitalization. Ms. K’s peripheral arterial perfusion improves, as does her thermoregulatory status. Her mental status improvements coincide with improvements in her physical and metabolic status.

Ms. K is able to sustain attention when speaking with interviewers. She is aware of her surroundings and is no longer distracted by extraneous stimuli. Her speech is articulate and her thoughts are linear. There is no evidence of any residual thought disorganization, delusions, or hallucinations.

Initially, Ms. K is reluctant to acknowledge her substance use, but eventually, she concedes to acquiring a stimulant from an Internet source and abusing it in undetermined amounts. She had no experience with using MDPV and did not know how to avoid ingesting dangerous amounts. We educate Ms. K about the dangers she faced during this hospitalization and the potential life-threatening outcomes. She is amenable to pursuing outpatient substance abuse treatment. Her roommate is enlisted to facilitate her follow-up with this treatment.

The authors’ observations

Managing MDPV toxicity presents a diagnostic dilemma for medical personnel and psychiatrists when evaluating and managing acute delirium. MDPV ingestion may go unrecognized in clinical settings because toxicology assessments for it are not readily available and patients’ historical information may be unreliable.

Because of the seriousness of sequelae associated with MDPV use, state and federal agencies have intervened. Until recently, bath salts did not have a controlled substance designation. In October 2011, the US Drug Enforcement Administration (DEA) ruled to make MDPV a controlled substance for 1 year, with the possibility of a 6-month extension.¹³ Although this ruling is temporary, it makes possession, sale, or distribution of these chemicals, or the products that contain them, illegal in the United States. In the interim, the DEA and the US Department of Health and Human Services will determine whether MDPV should remain a controlled substance.

Related Resources

• American Screening Corp. (MDPV screening). www.americanscreeningcorp.com.
• U.S. Drug Enforcement Administration. 3, 4-Methylenedioxypyrovalerone (MDPV). www.deadiversion.usdoj.gov/drugs_concern/mdpv.pdf.
• Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones [published online ahead of print November 23, 2011]. J Med Toxicol. doi: 10.1007/s13181-011-0193-z.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Space traveler

Mr. O, age 69, is a patient at a long-term psychiatric hospital. He has a 56-year psychiatric history, a current diagnosis of schizoaffective disorder, and suffered a torn rotator cuff approximately 5 years ago. His medication regimen is haloperidol decanoate, 100 mg IM every month, duloxetine, 60 mg/d, and naproxen, as needed for chronic pain.

He frequently lies on the floor. Attendants urge him to get up and join groups or sit with other patients but he complains of pain and soon finds another spot on the floor to use as a bed.

Eight months earlier, a homeless shelter sent Mr. O to the emergency room (ER) because he tried to eat a dollar bill and a sock. In the ER he was inattentive, with loose associations and bizarre delusions; he believed he was on a spaceship. Mr. O was admitted to the hospital, where clinicians noted that his behavior remained bizarre and he complained of insomnia. They also noted a history of setting fires, which complicated discharge planning and contributed to their decision to transfer him to our psychiatric facility for longer-term care.

During our initial interview, Mr. O readily picks himself off the floor. His responses are logical and direct but abrupt and unelaborated. His first and most vehement complaint is pain. Zolpidem, he says, is the only treatment that helps.

He says he began using zolpidem approximately 5 years ago because pain from a shoulder injury kept him awake at night. When he could not obtain the drug by prescription, he bought it on the street. One day when living in the homeless shelter, he took 30 or 40 mg of zolpidem, then “blacked out” and awoke in the ER.

His first experience with psychiatric treatment was the result of problems getting along with his single mother because of “petty things” such as shooting off a BB gun in their apartment, he says. As a teenager he was sent to a boarding school; as a young adult, to a psychiatric hospital. After his release he returned to his mother’s apartment. He worked steadily for 20 years before he obtained Social Security benefits, and then worked intermittently “off the books” until approximately 15 years ago. Mr. O lived with his mother until her death 17 years earlier, and then in her apartment alone until a fire, which he set accidentally by smoking in bed after taking zolpidem, forced him to leave 3 years ago. He says, “My whole life was in that place.” He was admitted to a psychiatric hospital for an unknown reason, which was his first psychiatric admission in 40 years. After he was released from the hospital, Mr. O lived in various homeless shelters and adult homes until his current hospitalization.

The author’s observations

An effective and well-tolerated drug with a reputation for rarely being abused, zolpidem is widely prescribed as a hypnotic. Zolpidem and benzodiazepines have different chemical structures but both act at the GABA_A receptor and have comparable behavioral effects.¹ The reported incidence of zolpidem abuse is much lower than the reported rate of benzodiazepine abuse when used for sleep²; however, abuse, dependence, and withdrawal have been reported.^2-4 Zolpidem abuse seems to be more common among patients with a history of abusing other substances or a history of psychiatric illness.² A French study⁴ found that abusers fell into 2 groups. The younger group (median age 35) used higher doses—a median of 300 mg/d—and took zolpidem in the daytime to achieve euphoria. A second, older group (median age 42) used lower doses—a median of 200 mg/d—at nighttime to sleep.

There are few reports of delirium and symptoms such as visual hallucinations and distortions associated with zolpidem use.^5,6 These reactions have occurred in persons without a history of psychosis. They usually are associated with doses ≥10 mg.

In the ER Mr. O showed a disturbance in consciousness with inability to focus attention and a perceptual disturbance (he believed he was in a spaceship) that developed over hours to days. He met criteria for delirium, possibly caused by zolpidem, but his presentation also could have been attributable to an underlying psychiatric disorder.

ER and inpatient psychiatrists noted Mr. O was intoxicated with zolpidem when the shelter brought him to the ER, but both groups diagnosed schizoaffective disorder and treated him with antipsychotics. They saw his >50-year psychiatric history as evidence of an underlying, long-standing condition such as schizoaffective illness.

However, features of Mr. O’s illness are not typical of a chronic psychotic illness. He recalls psychiatric hospitalizations in his youth and recently, but not for the 40 years in between. Mr. O says he has never experienced auditory hallucinations. For these reasons, our treatment team obtains old medical records to investigate his early history (Table).

Table

Mr. O’s clinical course

HISTORY: Destructive and defiant

Mr. O’s mother reported that he had been a nervous, restless child who would scream and yell at the slightest provocation. At age 10 he became wantonly destructive. His mother bought him an expensive toy that he destroyed after a short time; he asked for another toy, which he also destroyed. When such behavior became more frequent, she took him to a city hospital, where he was treated for 6 weeks and released at age 13. He was sent to a boarding school but soon was expelled for drinking and selling beer.

Mr. O was admitted to long-term psychiatric facilities 6 times in the next 10 years, from the late 1950s to the late 1960s. He was first admitted at age 17 for temper tantrums during which he fired an air rifle and smashed windows in the home he shared with his mother. During examination he had no delusions or hallucinations but did have flat affect and a hostile attitude. Doctors documented that almost all his tantrums were as a result of interactions with his mother.

Records from this psychiatric admission state that Mr. O showed no unusual distractibility, “psychotic trends,” or paranoid thinking. After approximately 6 months in the hospital he was discharged home with the diagnosis of primary behavior disorder, simple adult maladjustment. Mr. O, who was age 18 at the time, and his mother were eager for him to complete high school and learn auto mechanics.

Nine months later, he returned to the psychiatric facility because of excessive drinking and inability to secure employment, according to his records. In the hospital, he was productive and reliable. When he was discharged home 3 months later, doctors wrote that his determination to stop drinking was firmly fixed. They encouraged Mr. O to complete high school as a night student and find employment during the day. His mother was delighted with his improvement.

A third admission, less than 2 months later, occurred after he broke a window during an argument with his mother. He had a job but quit. After 5 months he was discharged with the same diagnosis of primary behavior disorder, but his mother would not let him back in her home. He was referred to the social service department to be placed on welfare.

A year later, Mr. O had trouble managing his welfare allotment and moved repeatedly. He said he returned to the psychiatric hospital because his welfare payments had been discontinued. During this admission, doctors noted “psychopathic” symptoms; Mr. O was defiant and resented authority and regular work. Mr. O eloped from the hospital several times and brought beer into the building. After 18 months he was discharged with the same diagnosis, with plans to apply for welfare. He was not prescribed medication.

Mr. O’s fifth admission came nearly 2 years later after his mother complained that he stole from her home and carried a weapon. In the hospital he was described as manageable and without overt psychotic symptoms. When he was discharged a little more than a year after being admitted, doctors wrote that he was a psychopath who had a history of drinking, stealing, and delinquent tendencies as a teenager. His diagnosis remained primary behavior disorder.

A year after this discharge, Mr. O was arrested for causing serious property damage when he was intoxicated on alcohol. Subsequently he was readmitted.

After a few months in the hospital, Mr. O changed. He developed a silly laugh, loose associations, irrelevant and incoherent speech, and a belief that hospital staff were against him. Although Mr. O denied auditory hallucinations, a psychiatrist wrote that he seemed to be experiencing hallucinations and prescribed chlorpromazine. The next day Mr. O slashed his arms and legs in several places, requiring many sutures. His diagnosis was changed to psychosis with psychopathic personality. However, within a few months, psychiatrists determined that Mr. O had recovered, so they stopped chlorpromazine. Months later, clinicians wrote that Mr. O was idle most of the time, neat, clean, and not involved in arguments with other patients. He was discharged after 1 month in the hospital.

Over the years, psychiatrists had differing opinions about Mr. O’s diagnosis. One noted that his mental illness was characterized by emotional instability and poor judgment. He had impulsive reactions without regard for others, rapid mood swings, irritability, and depression with transient paranoia. Another clinician detected evidence of schizoid personality disorder because Mr. O did not experience hallucinations or a gross thought disorder, but did have rambling, circumstantial, autistic (unrealistic), and ambivalent thought content. Another psychiatrist wrote Mr. O best fit in the category of psychosis with psychopathic personality, which was his diagnosis at discharge from his sixth hospitalization.

The author’s observations

Mr. O’s old medical records revealed the diagnostic thinking and treatment practices of a past era. They did not demonstrate that Mr. O met current criteria for schizophrenia or schizoaffective disorder, although he may have had a brief psychotic episode. Because there was little support for a diagnosis of schizoaffective illness and haloperidol use, we stopped the drug but continued duloxetine for chronic pain. It was clear that he has a substance use disorder and perhaps met criteria for antisocial personality disorder.

OUTCOME: Further explanations

Approximately 2 months after stopping haloperidol, Mr. O is more spontaneous, logical, and relevant. He does not have delusions or hallucinations. Despite further attempts at pain management with physical therapy and increased doses of duloxetine, he still complains of pain. We do not prescribe zolpidem.

Mr. O is unwilling to discuss the incident more than 40 years ago when he cut his arms and legs except to say, “That’s the past. My life wasn’t so good at that time.” When we ask why he had been a client of Adult Protective Services 5 years before he was burned out of his apartment, he admitted that he was 21 months in arrears in his rent. “I used to do this thing called crack,” he explains. He was discharged to an adult home with a prescription for duloxetine after he promised to never smoke in his room again.

Related Resource

• Aggarwal A, Sharma DD. Zolpidem withdrawal delirium: a case report. J Neuropsychiatry Clin Neurosci. 2010;22(4):451.

Drug Brand Names

• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Duloxetine • Cymbalta
• Haloperidol decanoate • Haloperidol decanoate
• Haloperidol • Haldol
• Naproxen • Naproxyn, Aleve, others
• Zolpidem • Ambien

Disclosure

The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Space traveler

Mr. O, age 69, is a patient at a long-term psychiatric hospital. He has a 56-year psychiatric history, a current diagnosis of schizoaffective disorder, and suffered a torn rotator cuff approximately 5 years ago. His medication regimen is haloperidol decanoate, 100 mg IM every month, duloxetine, 60 mg/d, and naproxen, as needed for chronic pain.

He frequently lies on the floor. Attendants urge him to get up and join groups or sit with other patients but he complains of pain and soon finds another spot on the floor to use as a bed.

Eight months earlier, a homeless shelter sent Mr. O to the emergency room (ER) because he tried to eat a dollar bill and a sock. In the ER he was inattentive, with loose associations and bizarre delusions; he believed he was on a spaceship. Mr. O was admitted to the hospital, where clinicians noted that his behavior remained bizarre and he complained of insomnia. They also noted a history of setting fires, which complicated discharge planning and contributed to their decision to transfer him to our psychiatric facility for longer-term care.

During our initial interview, Mr. O readily picks himself off the floor. His responses are logical and direct but abrupt and unelaborated. His first and most vehement complaint is pain. Zolpidem, he says, is the only treatment that helps.

He says he began using zolpidem approximately 5 years ago because pain from a shoulder injury kept him awake at night. When he could not obtain the drug by prescription, he bought it on the street. One day when living in the homeless shelter, he took 30 or 40 mg of zolpidem, then “blacked out” and awoke in the ER.

His first experience with psychiatric treatment was the result of problems getting along with his single mother because of “petty things” such as shooting off a BB gun in their apartment, he says. As a teenager he was sent to a boarding school; as a young adult, to a psychiatric hospital. After his release he returned to his mother’s apartment. He worked steadily for 20 years before he obtained Social Security benefits, and then worked intermittently “off the books” until approximately 15 years ago. Mr. O lived with his mother until her death 17 years earlier, and then in her apartment alone until a fire, which he set accidentally by smoking in bed after taking zolpidem, forced him to leave 3 years ago. He says, “My whole life was in that place.” He was admitted to a psychiatric hospital for an unknown reason, which was his first psychiatric admission in 40 years. After he was released from the hospital, Mr. O lived in various homeless shelters and adult homes until his current hospitalization.

The author’s observations

An effective and well-tolerated drug with a reputation for rarely being abused, zolpidem is widely prescribed as a hypnotic. Zolpidem and benzodiazepines have different chemical structures but both act at the GABA_A receptor and have comparable behavioral effects.¹ The reported incidence of zolpidem abuse is much lower than the reported rate of benzodiazepine abuse when used for sleep²; however, abuse, dependence, and withdrawal have been reported.^2-4 Zolpidem abuse seems to be more common among patients with a history of abusing other substances or a history of psychiatric illness.² A French study⁴ found that abusers fell into 2 groups. The younger group (median age 35) used higher doses—a median of 300 mg/d—and took zolpidem in the daytime to achieve euphoria. A second, older group (median age 42) used lower doses—a median of 200 mg/d—at nighttime to sleep.

There are few reports of delirium and symptoms such as visual hallucinations and distortions associated with zolpidem use.^5,6 These reactions have occurred in persons without a history of psychosis. They usually are associated with doses ≥10 mg.

In the ER Mr. O showed a disturbance in consciousness with inability to focus attention and a perceptual disturbance (he believed he was in a spaceship) that developed over hours to days. He met criteria for delirium, possibly caused by zolpidem, but his presentation also could have been attributable to an underlying psychiatric disorder.

ER and inpatient psychiatrists noted Mr. O was intoxicated with zolpidem when the shelter brought him to the ER, but both groups diagnosed schizoaffective disorder and treated him with antipsychotics. They saw his >50-year psychiatric history as evidence of an underlying, long-standing condition such as schizoaffective illness.

However, features of Mr. O’s illness are not typical of a chronic psychotic illness. He recalls psychiatric hospitalizations in his youth and recently, but not for the 40 years in between. Mr. O says he has never experienced auditory hallucinations. For these reasons, our treatment team obtains old medical records to investigate his early history (Table).

Table

Mr. O’s clinical course

HISTORY: Destructive and defiant

Mr. O’s mother reported that he had been a nervous, restless child who would scream and yell at the slightest provocation. At age 10 he became wantonly destructive. His mother bought him an expensive toy that he destroyed after a short time; he asked for another toy, which he also destroyed. When such behavior became more frequent, she took him to a city hospital, where he was treated for 6 weeks and released at age 13. He was sent to a boarding school but soon was expelled for drinking and selling beer.

Mr. O was admitted to long-term psychiatric facilities 6 times in the next 10 years, from the late 1950s to the late 1960s. He was first admitted at age 17 for temper tantrums during which he fired an air rifle and smashed windows in the home he shared with his mother. During examination he had no delusions or hallucinations but did have flat affect and a hostile attitude. Doctors documented that almost all his tantrums were as a result of interactions with his mother.

Records from this psychiatric admission state that Mr. O showed no unusual distractibility, “psychotic trends,” or paranoid thinking. After approximately 6 months in the hospital he was discharged home with the diagnosis of primary behavior disorder, simple adult maladjustment. Mr. O, who was age 18 at the time, and his mother were eager for him to complete high school and learn auto mechanics.

Nine months later, he returned to the psychiatric facility because of excessive drinking and inability to secure employment, according to his records. In the hospital, he was productive and reliable. When he was discharged home 3 months later, doctors wrote that his determination to stop drinking was firmly fixed. They encouraged Mr. O to complete high school as a night student and find employment during the day. His mother was delighted with his improvement.

A third admission, less than 2 months later, occurred after he broke a window during an argument with his mother. He had a job but quit. After 5 months he was discharged with the same diagnosis of primary behavior disorder, but his mother would not let him back in her home. He was referred to the social service department to be placed on welfare.

A year later, Mr. O had trouble managing his welfare allotment and moved repeatedly. He said he returned to the psychiatric hospital because his welfare payments had been discontinued. During this admission, doctors noted “psychopathic” symptoms; Mr. O was defiant and resented authority and regular work. Mr. O eloped from the hospital several times and brought beer into the building. After 18 months he was discharged with the same diagnosis, with plans to apply for welfare. He was not prescribed medication.

Mr. O’s fifth admission came nearly 2 years later after his mother complained that he stole from her home and carried a weapon. In the hospital he was described as manageable and without overt psychotic symptoms. When he was discharged a little more than a year after being admitted, doctors wrote that he was a psychopath who had a history of drinking, stealing, and delinquent tendencies as a teenager. His diagnosis remained primary behavior disorder.

A year after this discharge, Mr. O was arrested for causing serious property damage when he was intoxicated on alcohol. Subsequently he was readmitted.

After a few months in the hospital, Mr. O changed. He developed a silly laugh, loose associations, irrelevant and incoherent speech, and a belief that hospital staff were against him. Although Mr. O denied auditory hallucinations, a psychiatrist wrote that he seemed to be experiencing hallucinations and prescribed chlorpromazine. The next day Mr. O slashed his arms and legs in several places, requiring many sutures. His diagnosis was changed to psychosis with psychopathic personality. However, within a few months, psychiatrists determined that Mr. O had recovered, so they stopped chlorpromazine. Months later, clinicians wrote that Mr. O was idle most of the time, neat, clean, and not involved in arguments with other patients. He was discharged after 1 month in the hospital.

Over the years, psychiatrists had differing opinions about Mr. O’s diagnosis. One noted that his mental illness was characterized by emotional instability and poor judgment. He had impulsive reactions without regard for others, rapid mood swings, irritability, and depression with transient paranoia. Another clinician detected evidence of schizoid personality disorder because Mr. O did not experience hallucinations or a gross thought disorder, but did have rambling, circumstantial, autistic (unrealistic), and ambivalent thought content. Another psychiatrist wrote Mr. O best fit in the category of psychosis with psychopathic personality, which was his diagnosis at discharge from his sixth hospitalization.

The author’s observations

Mr. O’s old medical records revealed the diagnostic thinking and treatment practices of a past era. They did not demonstrate that Mr. O met current criteria for schizophrenia or schizoaffective disorder, although he may have had a brief psychotic episode. Because there was little support for a diagnosis of schizoaffective illness and haloperidol use, we stopped the drug but continued duloxetine for chronic pain. It was clear that he has a substance use disorder and perhaps met criteria for antisocial personality disorder.

OUTCOME: Further explanations

Approximately 2 months after stopping haloperidol, Mr. O is more spontaneous, logical, and relevant. He does not have delusions or hallucinations. Despite further attempts at pain management with physical therapy and increased doses of duloxetine, he still complains of pain. We do not prescribe zolpidem.

Mr. O is unwilling to discuss the incident more than 40 years ago when he cut his arms and legs except to say, “That’s the past. My life wasn’t so good at that time.” When we ask why he had been a client of Adult Protective Services 5 years before he was burned out of his apartment, he admitted that he was 21 months in arrears in his rent. “I used to do this thing called crack,” he explains. He was discharged to an adult home with a prescription for duloxetine after he promised to never smoke in his room again.

Related Resource

• Aggarwal A, Sharma DD. Zolpidem withdrawal delirium: a case report. J Neuropsychiatry Clin Neurosci. 2010;22(4):451.

Drug Brand Names

• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Duloxetine • Cymbalta
• Haloperidol decanoate • Haloperidol decanoate
• Haloperidol • Haldol
• Naproxen • Naproxyn, Aleve, others
• Zolpidem • Ambien

Disclosure

The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Space traveler

Mr. O, age 69, is a patient at a long-term psychiatric hospital. He has a 56-year psychiatric history, a current diagnosis of schizoaffective disorder, and suffered a torn rotator cuff approximately 5 years ago. His medication regimen is haloperidol decanoate, 100 mg IM every month, duloxetine, 60 mg/d, and naproxen, as needed for chronic pain.

He frequently lies on the floor. Attendants urge him to get up and join groups or sit with other patients but he complains of pain and soon finds another spot on the floor to use as a bed.

Eight months earlier, a homeless shelter sent Mr. O to the emergency room (ER) because he tried to eat a dollar bill and a sock. In the ER he was inattentive, with loose associations and bizarre delusions; he believed he was on a spaceship. Mr. O was admitted to the hospital, where clinicians noted that his behavior remained bizarre and he complained of insomnia. They also noted a history of setting fires, which complicated discharge planning and contributed to their decision to transfer him to our psychiatric facility for longer-term care.

During our initial interview, Mr. O readily picks himself off the floor. His responses are logical and direct but abrupt and unelaborated. His first and most vehement complaint is pain. Zolpidem, he says, is the only treatment that helps.

He says he began using zolpidem approximately 5 years ago because pain from a shoulder injury kept him awake at night. When he could not obtain the drug by prescription, he bought it on the street. One day when living in the homeless shelter, he took 30 or 40 mg of zolpidem, then “blacked out” and awoke in the ER.

His first experience with psychiatric treatment was the result of problems getting along with his single mother because of “petty things” such as shooting off a BB gun in their apartment, he says. As a teenager he was sent to a boarding school; as a young adult, to a psychiatric hospital. After his release he returned to his mother’s apartment. He worked steadily for 20 years before he obtained Social Security benefits, and then worked intermittently “off the books” until approximately 15 years ago. Mr. O lived with his mother until her death 17 years earlier, and then in her apartment alone until a fire, which he set accidentally by smoking in bed after taking zolpidem, forced him to leave 3 years ago. He says, “My whole life was in that place.” He was admitted to a psychiatric hospital for an unknown reason, which was his first psychiatric admission in 40 years. After he was released from the hospital, Mr. O lived in various homeless shelters and adult homes until his current hospitalization.

The author’s observations

An effective and well-tolerated drug with a reputation for rarely being abused, zolpidem is widely prescribed as a hypnotic. Zolpidem and benzodiazepines have different chemical structures but both act at the GABA_A receptor and have comparable behavioral effects.¹ The reported incidence of zolpidem abuse is much lower than the reported rate of benzodiazepine abuse when used for sleep²; however, abuse, dependence, and withdrawal have been reported.^2-4 Zolpidem abuse seems to be more common among patients with a history of abusing other substances or a history of psychiatric illness.² A French study⁴ found that abusers fell into 2 groups. The younger group (median age 35) used higher doses—a median of 300 mg/d—and took zolpidem in the daytime to achieve euphoria. A second, older group (median age 42) used lower doses—a median of 200 mg/d—at nighttime to sleep.

There are few reports of delirium and symptoms such as visual hallucinations and distortions associated with zolpidem use.^5,6 These reactions have occurred in persons without a history of psychosis. They usually are associated with doses ≥10 mg.

In the ER Mr. O showed a disturbance in consciousness with inability to focus attention and a perceptual disturbance (he believed he was in a spaceship) that developed over hours to days. He met criteria for delirium, possibly caused by zolpidem, but his presentation also could have been attributable to an underlying psychiatric disorder.

ER and inpatient psychiatrists noted Mr. O was intoxicated with zolpidem when the shelter brought him to the ER, but both groups diagnosed schizoaffective disorder and treated him with antipsychotics. They saw his >50-year psychiatric history as evidence of an underlying, long-standing condition such as schizoaffective illness.

However, features of Mr. O’s illness are not typical of a chronic psychotic illness. He recalls psychiatric hospitalizations in his youth and recently, but not for the 40 years in between. Mr. O says he has never experienced auditory hallucinations. For these reasons, our treatment team obtains old medical records to investigate his early history (Table).

Table

Mr. O’s clinical course

HISTORY: Destructive and defiant

Mr. O’s mother reported that he had been a nervous, restless child who would scream and yell at the slightest provocation. At age 10 he became wantonly destructive. His mother bought him an expensive toy that he destroyed after a short time; he asked for another toy, which he also destroyed. When such behavior became more frequent, she took him to a city hospital, where he was treated for 6 weeks and released at age 13. He was sent to a boarding school but soon was expelled for drinking and selling beer.

Mr. O was admitted to long-term psychiatric facilities 6 times in the next 10 years, from the late 1950s to the late 1960s. He was first admitted at age 17 for temper tantrums during which he fired an air rifle and smashed windows in the home he shared with his mother. During examination he had no delusions or hallucinations but did have flat affect and a hostile attitude. Doctors documented that almost all his tantrums were as a result of interactions with his mother.

Records from this psychiatric admission state that Mr. O showed no unusual distractibility, “psychotic trends,” or paranoid thinking. After approximately 6 months in the hospital he was discharged home with the diagnosis of primary behavior disorder, simple adult maladjustment. Mr. O, who was age 18 at the time, and his mother were eager for him to complete high school and learn auto mechanics.

Nine months later, he returned to the psychiatric facility because of excessive drinking and inability to secure employment, according to his records. In the hospital, he was productive and reliable. When he was discharged home 3 months later, doctors wrote that his determination to stop drinking was firmly fixed. They encouraged Mr. O to complete high school as a night student and find employment during the day. His mother was delighted with his improvement.

A third admission, less than 2 months later, occurred after he broke a window during an argument with his mother. He had a job but quit. After 5 months he was discharged with the same diagnosis of primary behavior disorder, but his mother would not let him back in her home. He was referred to the social service department to be placed on welfare.

A year later, Mr. O had trouble managing his welfare allotment and moved repeatedly. He said he returned to the psychiatric hospital because his welfare payments had been discontinued. During this admission, doctors noted “psychopathic” symptoms; Mr. O was defiant and resented authority and regular work. Mr. O eloped from the hospital several times and brought beer into the building. After 18 months he was discharged with the same diagnosis, with plans to apply for welfare. He was not prescribed medication.

Mr. O’s fifth admission came nearly 2 years later after his mother complained that he stole from her home and carried a weapon. In the hospital he was described as manageable and without overt psychotic symptoms. When he was discharged a little more than a year after being admitted, doctors wrote that he was a psychopath who had a history of drinking, stealing, and delinquent tendencies as a teenager. His diagnosis remained primary behavior disorder.

A year after this discharge, Mr. O was arrested for causing serious property damage when he was intoxicated on alcohol. Subsequently he was readmitted.

After a few months in the hospital, Mr. O changed. He developed a silly laugh, loose associations, irrelevant and incoherent speech, and a belief that hospital staff were against him. Although Mr. O denied auditory hallucinations, a psychiatrist wrote that he seemed to be experiencing hallucinations and prescribed chlorpromazine. The next day Mr. O slashed his arms and legs in several places, requiring many sutures. His diagnosis was changed to psychosis with psychopathic personality. However, within a few months, psychiatrists determined that Mr. O had recovered, so they stopped chlorpromazine. Months later, clinicians wrote that Mr. O was idle most of the time, neat, clean, and not involved in arguments with other patients. He was discharged after 1 month in the hospital.

Over the years, psychiatrists had differing opinions about Mr. O’s diagnosis. One noted that his mental illness was characterized by emotional instability and poor judgment. He had impulsive reactions without regard for others, rapid mood swings, irritability, and depression with transient paranoia. Another clinician detected evidence of schizoid personality disorder because Mr. O did not experience hallucinations or a gross thought disorder, but did have rambling, circumstantial, autistic (unrealistic), and ambivalent thought content. Another psychiatrist wrote Mr. O best fit in the category of psychosis with psychopathic personality, which was his diagnosis at discharge from his sixth hospitalization.

The author’s observations

Mr. O’s old medical records revealed the diagnostic thinking and treatment practices of a past era. They did not demonstrate that Mr. O met current criteria for schizophrenia or schizoaffective disorder, although he may have had a brief psychotic episode. Because there was little support for a diagnosis of schizoaffective illness and haloperidol use, we stopped the drug but continued duloxetine for chronic pain. It was clear that he has a substance use disorder and perhaps met criteria for antisocial personality disorder.

OUTCOME: Further explanations

Approximately 2 months after stopping haloperidol, Mr. O is more spontaneous, logical, and relevant. He does not have delusions or hallucinations. Despite further attempts at pain management with physical therapy and increased doses of duloxetine, he still complains of pain. We do not prescribe zolpidem.

Mr. O is unwilling to discuss the incident more than 40 years ago when he cut his arms and legs except to say, “That’s the past. My life wasn’t so good at that time.” When we ask why he had been a client of Adult Protective Services 5 years before he was burned out of his apartment, he admitted that he was 21 months in arrears in his rent. “I used to do this thing called crack,” he explains. He was discharged to an adult home with a prescription for duloxetine after he promised to never smoke in his room again.

Related Resource

• Aggarwal A, Sharma DD. Zolpidem withdrawal delirium: a case report. J Neuropsychiatry Clin Neurosci. 2010;22(4):451.

Drug Brand Names

• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Duloxetine • Cymbalta
• Haloperidol decanoate • Haloperidol decanoate
• Haloperidol • Haldol
• Naproxen • Naproxyn, Aleve, others
• Zolpidem • Ambien

Disclosure

The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.