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Abstract _Top

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#top)

Abstract

_Introduction

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#BDY) _CASE

REPORTS

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#SEC1)

_DISCUSSION

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#SEC2)

_REFERENCES

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#BIBL)

Serotonin syndrome is a potentially lethal adverse drug reaction that may

occur in patients taking proserotoninergic medications. Drug interactions are

often responsible for the causation of this syndrome. We report two cases of

severe serotonin syndrome induced by the administration of cyclobenzaprine in

postoperative patients already receiving another proserotoninergic drug

(phenelzine in one case and duloxetine in the other). In both cases, symptoms

of

autonomic instability and severe agitation started within hours of initiation

of cyclobenzaprine and fully resolved within 3 days after discontinuing the

proserotoninergic drugs. We conclude that cyclobenzaprine should be used

with extreme caution in patients receiving other serotonin-enhancing drugs;

these patients should be closely monitored for manifestations of serotonin

syndrome.

Introduction _Top

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#top)

_Abstract

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#ABS)

Introduction

_CASE REPORTS

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#SEC1)

_DISCUSSION

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#SEC2)

_REFERENCES

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#BIBL)

Serotonin syndrome is an often severe, potentially life-threatening adverse

drug reaction that may result from inadvertent interactions between drugs

with serotoninergic activity (_1_

(http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#R1-28) ). It

is produced by excessive central and

peripheral activation of serotonin receptors, but other monoaminergic

neurotransmitters may also be involved (_2_

(http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#R2-28) ).

Clinical manifestations are diverse and

nonspecific, which may lead to misdiagnosis. Severity ranges from mild and

inconsequential to rapidly lethal (_1_

(http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#R1-28) ).

Multiple proserotoninergic drugs have been implicated in the causation of

this syndrome (_1_ (http://www.anes

thesia-analgesia.org/cgi/content/full/103/6/1466#R1-28) ). Obvious culprits

include medications that enhance serotonin

activity as their main pharmacodynamic mechanism, such as monoamine oxidase

inhibitors (MAOIs), and selective serotonin-reuptake inhibitors. However, many

other commonly used drugs can activate the serotonin system, including opiates,

lithium, other antidepressants (tricyclics, trazodone, buspirone,

venlafaxine), antiemetics (ondansetron, metoclopramide), antimicrobials

(linezolid,

ritonavir), triptans, sirbutamine, and even dextromethorphan, a frequent

component of over-the-counter cold remedies. Although many of these drugs are

harmless in isolation, their interaction may precipitate unexpected, and

possibly

grave, serotonin toxicity.

We present two cases of severe serotonin syndrome induced by the

introduction of cyclobenzaprine (Flexeril®), a frequently prescribed muscle

relaxant,

into regimens already containing another proserotoninergic medication.

CASE REPORTS _Top

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#top)

_Abstract

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#ABS)

_Introduction

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#BDY) CASE

REPORTS

_DISCUSSION

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#SEC2)

_REFERENCES

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#BIBL)

Case 1

A 70-yr-old woman was admitted for resection of an infected hip arthroplasty.

She had a history of depression, which was being treated with phenelzine

(Nardil®, a nonselective MAOI) 15 mg four times a day for several years. Her

surgery under general anesthesia was uneventful, and cefazolin was continued

for

the hip infection. Postoperatively, she received oral acetaminophen and

oxycodone for pain as needed. On the sixth postoperative day, the patient

complained of muscle spasm in the right leg, and oral cyclobenzaprine 10 mg

three

times per day was prescribed. After the third dose of cyclobenzaprine, the

patient became confused and agitated. She was tremulous, tachycardic, febrile,

and extremely diaphoretic. She was initially oriented to person and place, but

later became delusional and developed frank hallucinations. Investigations

for bacteremia and pulmonary embolism were negative. Cyclobenzaprine and opiates

were stopped. Haloperidol was used to mitigate the agitation with limited

efficacy. The following day, the patient remained delusional, tachycardic, and

hyperthermic. She had labile arterial blood pressure and exhibited multifocal

myoclonus. In view of the severity of the patient’s signs and symptoms, she

was

transferred to the intensive care unit for further evaluation and

management. Her symptoms failed to resolve, and psychiatry and neurology

consultations

were requested. The diagnosis of serotonin syndrome was suspected, leading to

the discontinuation of phenelzine. Over the subsequent 3 days, all her

symptoms progressively resolved. The patient’s depression had previously been

difficult to treat, but had responded well to phenelzine. Accordingly, within

the following month, phenelzine was gradually restarted, and reinitiation of

the drug was without consequences.

Case 2

A 53-yr-old man with a history of multiple low-back surgeries was admitted

for the removal of infected spinal hardware. He had a history of chronic pain

and depression, for which he was receiving duloxetine (Cymbalta®, 60 mg/day),

pregabalin (75 mg twice a day), bupropion (300 mg/day), and oxycodone or

hydromorphone as needed for pain. The patient underwent uneventful removal of

his

spinal hardware under general endotracheal anesthesia. Postoperative pain was

managed with opiates, and his infection was treated with vancomycin. Two days

after the surgery, the patient developed worsening confusion with

hallucinations. On the fifth postoperative day, over the course of a few hours,

he became

very diaphoretic, tachycardic, and markedly agitated. Pronounced tremors,

spontaneous sustained clonus and multifocal myoclonus were noted. Laboratory

studies revealed hypernatremia (154 mEq/L) and lactic acidosis (arterial pH

7.27,

anion gap 20, lactate level 10.1 mmol/L). There was only mild hyperthermia and

no significant increase of his creatine kinase concentration (highest 265

U/L). Because of the extreme severity of his agitation, the patient’s trachea

was

intubated after administration of propofol and vecuronium. He was then

sedated with a continuous infusion of propofol and scheduled IV lorazepam.

Sedation

was withheld at scheduled intervals to allow serial neurological

examinations. He was appropriately rehydrated, and a ß-blocker was used to

ameliorate the

tachycardia.

Upon reviewing the medication list, it became clear that the patient had been

given cyclobenzaprine (10 mg three times per day) very shortly before the

onset of his confusion. His medication regimen also included duloxetine (60

mg/day), which the patient had been taking for the previous 4 mo, and oxycodone

(5

mg every 6 h as needed for pain), which he had also been using for several

weeks before the current hospital admission. Bupropion had not been administered

for more than 60 h. Cyclobenzaprine and duloxetine were stopped, and

cyproheptadine (8 mg via nasogastric tube every 6 h), a serotonin antagonist,

was

administered for 72 h. The patient’s clinical status improved steadily over

the

following days; he was tracheally extubated 2 days later and recovered without

sequelae.

DISCUSSION _Top

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#top)

_Abstract

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#ABS)

_Introduction

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#BDY) _CASE

REPORTS

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#SEC1)

DISCUSSION

_REFERENCES

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#BIBL)

In both of the described patients, the manifestations of serotonin syndrome

(_Table 1_

(http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#T128) )

commenced shortly after the administration of cyclobenzaprine and

resolved after its discontinuation. We postulate that serotonin overactivity

resulted from the interaction of this drug with proserotoninergic medications

already in use, phenelzine in one case and duloxetine in the other.

View this table:

_[in this window]_

(http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466/T128)

_[in a new window]_

(http://www.anesthesia-analgesia.org/cgi/content-nw/full/103/6/1466/T128)

Table 1. Most Common Clinical Manifestations of Serotonin Syndrome

Cyclobenzaprine is indicated for relief of muscle spasm associated with

acute, painful musculoskeletal conditions. Cyclobenzaprine is structurally

related

to the tricyclic antidepressants, and shares many of their central actions,

including noradrenergic enhancement and, probably, augmentation of central

serotonin transmission. Cyclobenzaprine may reduce muscle spasms by modulating

the

effect of descending monoaminergic pathways on the activity of motor neurons

of the ventral horn (_3–5_

(http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#R3-28) ). It

has been argued that cyclobenzaprine has a lower

risk of serious toxicity than tricyclic antidepressants (_6,7_

(http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#R6-28) ),

though the

spectrum of adverse reactions is markedly similar (_6_

(http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#R6-28) ).

Although the package insert of

this product warns against the use of cyclobenzaprine in conjunction with

MAOIs for the potential induction of life-threatening reactions, we did not

find

reports of this complication in the literature. Moreover, the information

provided by the manufacturers does not warn against possible interactions with

other proserotoninergic drugs. Indeed, to our knowledge, this is the first

report describing the association of cyclobenzaprine with serotonin syndrome.

Duloxetine is a recently released selective serotonin and norepinephrine

reuptake inhibitor indicated for the treatment of neuropathic pain and major

depression (_8_

(http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#R8-28) ). Its

use is contraindicated in patients taking MAOIs. Duloxetine has

not been reported to produce serotonin syndrome, but its potential to induce

this complication is likely to be similar to that of other antidepressants

with similar mechanisms of action.

Other drugs (occasional doses of opiates in both cases, recent use of

bupropion in Case 2) may have played a contributory role in the production of

serotonin syndrome in our patients. Patients with refractory chronic pain are

often treated with complex therapeutic regimens that include multiple

medications

with serotoninergic activity. Recognizing which drugs have serotonin

agonistic properties is essential to prevent dangerous interactions. When more

than

one of these medications is used, patients should be closely monitored for

the appearance of early symptoms and signs of serotonin toxicity, and all

proserotoninergic drugs should be stopped as soon as serotonin syndrome is

suspected. Keeping vigilant for this complication is important because its

early

manifestations are nonspecific and may be confused with other causes of

postoperative stress and confusion.

On the basis of our experience, we recommend that cyclobenzaprine and

duloxetine be added to the list of drugs that may cause serotonin syndrome.

Footnotes

Accepted for publication September 14, 2006.

REFERENCES _Top

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#top)

_Abstract

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#ABS)

_Introduction

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#BDY) _CASE

REPORTS

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#SEC1)

_DISCUSSION

_ (http://www.anesthesia-analgesia.org/cgi/content/full/103/6/1466#SEC2)

REFERENCES

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pe=MED)

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(http://www.anesthesia-analgesia.org/cgi/ijlink?linkType=ABST & journalCode=pharmt\

her & resid=38/12/2078)

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