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Cyproheptadine for Intrathecal Baclofen Withdrawal Jay M. Meythaler, MD, JD, James F. Roper, MD, MS, Robert C. Brunner, MD ABSTRACT. Meythaler JM, Roper JF, Brunner RC. Cyproheptadine for intrathecal baclofen withdrawal. Arch Phys Med Rehabil 2003;84:638-42.

Objective: To evaluate the efficacy of cyproheptadine in the management of acute intrathecal baclofen (ITB) withdrawal.

Design: Descriptive case series.

Setting: University hospital with a comprehensive in- and outpatient rehabilitation center.

Participants: Four patients (3 with spinal cord injury, 1 with cerebral palsy) with implanted ITB infusion pumps for treatment of severe spasticity, who had ITB withdrawal syndrome because of interruption of ITB infusion.

Interventions: Patients were treated with 4 to 8mg of cyproheptadine by mouth every 6 to 8 hours, 5 to 10mg of diazepam by mouth every 6 to 12 hours, 10 to 20mg of baclofen by mouth every 6 hours, and ITB boluses in some cases.

Main Outcome Measures: Clinical signs and symptoms of ITB withdrawal of varying severity were assessed by vital signs (temperature, heart rate), physical examination (reflexes, tone, clonus), and patient report of symptoms (itching, nausea, headache, malaise).

Results: The patients in our series improved significantly when the serotonin antagonist cyproheptadine was added to their regimens. Fever dropped at least 1.5°C, and heart rate dropped from rates of 120 to 140 to less than 100bpm. Reflexes, tone, and myoclonus also decreased. Patients reported dramatic reduction in itching after cyproheptadine. These changes were associated temporally with cyproheptadine dosing.

Discussion: Acute ITB withdrawal syndrome occurs frequently in cases of malfunctioning intrathecal infusion pumps or catheters. The syndrome commonly presents with pruritus and increased muscle tone. It can progress rapidly to high fever, altered mental status, seizures, profound muscle rigidity, rhabdomyolysis, brain injury, and death. Current therapy with oral baclofen and benzodiazepines is useful but has variable success, particularly in severe cases. We note that ITB withdrawal is similar to serotonergic syndromes, such as in overdoses of selective serotonin reuptake inhibitors or the popular drug of abuse 3,4-methylenedioxymethamphetamine (Ecstasy).

We postulate that ITB withdrawal may be a form of serotonergic syndrome that occurs from loss of ␥-aminobutyric acid B receptor–mediated presynaptic inhibition of serotonin.

Conclusion: Cyproheptadine may be a useful adjunct to baclofen and benzodiazepines in the management of acute ITB withdrawal syndrome.

From the Department of Physical Medicine & Rehabilitation, University of Alabama School of Medicine and the University of Alabama Spain Rehabilitation Center, Birmingham, AL. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated.

Reprint requests to Jay M. Meythaler, MD, JD, Dept of Physical Medicine & Rehabilitation, University of Alabama School of Medicine, R157, 619 6th Ave S, Birmingham, AL 35249-7330, e-mail: Jmeythal@uab.edu.

0003-9993/03/8405-7961$30.00/0 doi:10.1016/S0003-9993(03)00105-9

Arch Phys Med Rehabil Vol 84, May 2003

Key Words: Baclofen; Cyproheptadine; Hyperpyrexia, malignant; Infusion pumps, implantable; Muscle spasticity; Neuroleptic malignant syndrome; Receptors, GABA-B; Rehabilitation; Serotonin; Serotonin syndrome; Withdrawal symptoms. © 2003 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation NTRATHECAL BACLOFEN (ITB) PUMPS are used widely for the management of spastic hypertonia in patients with Ispinal cord injury (SCI), cerebral palsy (CP), traumatic brain injury (TBI), multiple sclerosis, and other disorders.1-7 The delivery system consists of a subcutaneously placed, self-contained, abdominal pump, with a reservoir attached to an intraspinal catheter. The pump is programmable to deliver various rates of medication via a catheter that enters at the lumbar spinal level into the subarachnoid space of the spinal canal. The central nervous system (CNS) side effects of oral baclofen, such as drowsiness or confusion, appear to be minimized with intrathecal administration.1-3,5,8 The intrathecal delivery method allows for much higher levels of baclofen and concentrates the medication in the cerebrospinal fluid (CSF) within the spinal cord and brainstem at much higher levels than those attainable via the oral route.1,5,8 Abrupt withdrawal of ITB therapy can result in a fulminant, life-threatening syndrome that starts with pruritic symptoms, increased spasticity, and a return of muscle stretch reflexes.9-12 This may be followed by a high fever, altered mental status, seizures, and profound muscle rigidity. The most severe cases can progress to rhabdomyolysis, hepatic and renal failure, disseminated intravascular coagulation, brain injury, and death.6,9-12 The molecular and cellular mechanisms of ITB withdrawal are not well understood. Baclofen, 4-amino-3 (p-chlorophenyl) butyric acid, is structurally similar to ␥-aminobutyric acid (GABA). Baclofen binds to presynaptic mono- and polysynaptic GABAB receptors within the brainstem, the dorsal horn of the spinal cord, and other CNS sites.8,13 In long-term ITB therapy, there is some receptor accommodation to baclofen during the first year after starting therapy, if not longer.1-7 Acute baclofen withdrawal may result in widespread disinhibition of GABAB-modulated pathways.9,14-17 The highest priority in the management of acute ITB withdrawal is the reinstitution of intrathecal baclofen by any means appropriate.9,11,12 If this is problematic, and it often is, oral baclofen, intravenous benzodiazepines such as diazepam, and intravenous dantrolene sodium are used for withdrawal.9 However, in the most severe cases, even these measures have sometimes failed.9,11 Recently, Coffey et al9 explicated the important observation that ITB withdrawal syndrome shares some characteristics with, but is distinct from, several other acute, life-threatening, neurologic syndromes, such as autonomic dysreflexia (AD), neuroleptic malignant syndrome (NMS), and malignant hyperthermia (MH). Other severe conditions associated with multiple-organ system failure, such as sepsis, status epilepticus, and other toxic, metabolic, or immune-mediated disorders, may resemble acute ITB withdrawal syndrome. The reader is referred to table 1 of the study by Coffey9 for more details. As

CYPROHEPTADINE FOR INTRATHECAL BACLOFEN WITHDRAWAL, Meythaler Table 1: Ashworth Scale and PSFS Grading30,31 Ashworth Scale 1 No increase in tone 2 Slight increase in tone, giving a “catch” when affected part is moved in flexion or extension 3 More marked increase in tone, but affected part easily flexed 4 Considerable increase in tone; passive movement difficult 5 Affected part rigid in flexion or extension PSFS 0 No spasms 1 Mild spasms induced by stimulation 2 Infrequent full spasms occurring less than once per hour 3 Spasms occurring more than once per hour 4 Spasms occurring more than 10 times per hour

Coffey9 asserted, correct differential diagnosis before initiating treatment is crucial, because the management of each of these life-threatening neurologic syndromes is quite different.

Interestingly, ITB withdrawal syndrome shares some characteristics with serotonergic syndromes,18-20 such as are seen in overdoses of selective serotonin reuptake inhibitors (SSRIs) or the popular drug of abuse 3,4-methelenedioxymethamphetamine (MDMA, or Ecstasy) (see table 1). Serotonin syndromes are often confused with NMS.18-20 It is reasonable, therefore, to consider whether serotonin antagonists may be useful in the management of ITB withdrawal syndrome. We present a series of 4 cases in which the potent serotonin antagonist cyproheptadine was used with apparent benefits in the management of acute ITB withdrawal.

METHODS Case 1 A 32-year-old man with a history of CP and spastic tetraplegia, previously treated with ITB for 16 consecutive months, was admitted for ITB pump removal because of a chronic pressure ulcer over the pump and a pocket infection. To reduce the possibility of ITB withdrawal, the ITB dose had been tapered from 420␮g/d (simple continuous infusion) to 200␮g/d during 14 days before admission. Concurrently, oral baclofen had been titrated to 15mg 3 times daily. On admission, oral baclofen was increased to 20mg 3 times daily, and oral diazepam to 5mg twice daily was started. Pump removal on hospital day 1 was uneventful. On postoperative day 2, the patient developed a low-grade fever (37.8°C), tachycardia (heart rate⫽142bpm), hyperreflexia, clonus, and worsening hypertonia. His average lower-extremity Ashworth Scale score changed from 2 to 4, and the Penn Spasm Frequency Score (PSFS) went from 0 to 4 (table 1). Two 50mg oral doses of diphenhydramine had no effect on pruritus. When 4mg of cyproheptadine by mouth every 6 hours was added, the patient reported dramatic relief of pruritus, his temperature returned to normal within 1 hour, and his tachycardia resolved. Low-grade fever and mild tachycardia consistently returned approximately 1 hour before the next dose of cyproheptadine was due, and both consistently were resolved during the hour after the dose of cyproheptadine was given. Tone, reflexes, and clonus cycled similarly. ITB withdrawal signs and symptoms resolved com-

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pletely during the following 3 days. The patient was discharged in good condition, on oral baclofen and diazepam, on postoperative day 12.

Case 2 A 49-year-old woman with T5 complete paraplegia because of traumatic SCI enjoyed good control of spasticity for 34 months after ITB pump placement. She began to experience intermittent severe pruritus and increased spasticity, consistent with episodic baclofen withdrawal. A kinked catheter was discovered by radiographic studies. Symptoms were worse in the evenings and better in the mornings, after she slept supine in bed: her Ashworth score would change from 1 to 3, and her PSFS would go from 1 to 3. The patellar and Achilles’ deep tendon reflexes would return by midday. A 25mg dose of diphenhydramine by mouth every 6 hours provided no relief of pruritus. When 4mg of cyproheptadine by mouth 3 times daily was added, the patient reported dramatic relief of itching, anxiety, and malaise. She was maintained on oral cyproheptadine, baclofen, and diazepam, until her intrathecal catheter was replaced. After reinstitution of intrathecal baclofen, cyproheptadine was tapered uneventfully.

Case 3 A 45-year-old man with C4-5 tetraplegia and spastic hypertonia had been treated successfully with ITB for 38 months, until he presented to an emergency department with fever, hyperpyrexia, a return of deep tendon reflexes, and spasticity.

One month earlier, his Ashworth score had been 1 (on a 1–5 scale) for both arms and legs, and his PSFS was 1 (on a 0 – 4 scale). He was admitted with a diagnosis of urosepsis. Approximately 4 hours after admission, he had a cardiopulmonary arrest and was resuscitated. He was transferred to an intensive care unit, where he had fever (41.7°C), tachycardia, hypotension (blood pressure⫽84/36), and muscle rigidity. He received intravenous antibiotics and pressors. He developed rhabdomyolysis and disseminated intravascular coagulation (creatine phosphokinase, 4064U/L; urine myoglobin, 4064␮g/L; platelets, 31,000). The following morning, the ITB team was consulted. On initial evaluation, the patient was febrile (39.5°C), unresponsive, and spastic. It was determined that he had a probable ITB pump stall. An 8mg dose of cyproheptadine every 6 hours by nasogastric tube was started concurrently with the first ITB bolus. Fever and spasticity resolved within 2 hours of the first ITB bolus and cyproheptadine dose. His Ashworth score dropped to 1, and his PSFS dropped to 0 during the same time. Radiographic studies confirmed that the catheter tip was in the intrathecal space at the T6 level. The catheter was patent, and CSF was easily withdrawn from the lateral pump access port. Subsequent radiographic and telemetric studies showed that the pump had resumed functioning normally (intermittent periodic bolus protocol, 100␮g baclofen every 4h). The patient became more stable hemodynamically but continued to be marginally responsive. The patient died because of pulmonary complications 2 months after his initial presentation.

Case 4 For 6 years, a 44-year-old man with T4 complete SCI and severe lower-extremity spasticity was treated successfully with an ITB pump. The patient’s bilateral lower-limb tone had acutely increased from 2 to 4 on the Ashworth score, his PSFS had increased almost 2 points, and he experienced a return of patellar and Achilles’ deep tendon reflexes. The patient experienced episodes of increased spasticity and itching intermittently during 13 months, raising the suspicion of intermittent Arch Phys Med Rehabil Vol 84, May 2003

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CYPROHEPTADINE FOR INTRATHECAL BACLOFEN WITHDRAWAL, Meythaler Table 2: Comparison of ITB Withdrawal and Serotonin Syndromes ITB Withdrawal

Serotonin Syndrome

Mechanism Clinical setting

Abrupt decrease in CNS GABAB transmission One to 3 days after abrupt cessation of ITB

Mental status

Dysphoria, anxiety; may progress to delirium and coma in severe cases Hyperthermia Tachycardia Hypotension Increased muscle stretch reflexes and tone; may progress to rigidity in severe cases Pruritus; seizures in some cases

Temperature Heart rate Blood pressure Muscle activity Other features

Acute overload of CNS serotonin transmission Hours after initiation of excessive serotonin release and/or blockade of serotonin reuptake Confusion; may progress to delirium and coma in severe cases Hyperthermia Tachycardia Hypotension Increased muscle stretch reflexes and tone, myoclonus Autonomic instability, convulsions

Adapted from Coffey et al.9

kinking of the intrathecal catheter. However, multiple fluoroscopic catheter studies were negative. Various intrathecal bolus regimens were tried unsuccessfully in attempts to overcome the possible intermittent kinking. After the patient presented to the clinic with particularly severe spasticity and itching, he was readmitted to the hospital for repeat intrathecal catheter dye study and possible catheter revision. Admission laboratory studies revealed a urinary tract infection (UTI) and an elevated creatine kinase level of 744U/L (reference range, 35–250U/L).

On admission, the patient was started on an oral antibiotic, 4mg of cyproheptadine by mouth every 6 hours for treatment of UTI, and 5mg of diazepam by mouth every 6 hours and 20mg of baclofen by mouth every 6 hours for ITB withdrawal syndrome. Subsequently, his spasticity and itching improved. An intrathecal catheter dye study revealed a positionally dependent narrowing of the intrathecal catheter. The catheter was replaced, and 2 days later ITB was restarted (simple, continuous infusion, initially 450␮g/d; advanced to 550␮g/d). Cyproheptadine and oral baclofen were discontinued, and diazepam was tapered to 2.5mg by mouth twice daily. The patient was discharged with good control of spasticity and with resolution of his previous symptoms of baclofen withdrawal.

DISCUSSION ITB is the standard of care in the treatment of intractable spastic hypertonia.1-8 It is used after the failure of oral agents but before ablative procedures.1-8 However, in our experience, acute ITB withdrawal syndrome occurs with an almost universal onset of symptoms that include pruritus, a return of deep tendon reflexes, and an increase in spastic hypertonia (table 2).

Medical management of this syndrome includes oral baclofen, benzodiazepines, dantrolene sodium, and, when possible, the reinstitution of ITB therapy as soon as possible.9,12 This management sometimes has been less than completely successful, particularly in advanced cases, and has resulted in mortality.9 Acute ITB withdrawal is similar in some respects to AD, MH, and NMS.9 This similarly can cause diagnostic and treatment confusion during the critical initial hours after presentation.9 Although their presentations may be similar, these neurologic syndromes are distinct entities with significantly different treatment approaches.9-12 The ITB withdrawal syndrome also shares many characteristics with serotonin syndrome.19-21 Patients with either of these neurologic syndromes often report pruritus as an initial symptom. Subsequently, they may develop increased muscle tone, hyperreflexia, clonus, muscle rigidity, dysautonomia, hyperpyrexia, and seizures.9,18-21 In severe cases, rhabdomyolysis, disseminated intravascular coagulation, and even death have Arch Phys Med Rehabil Vol 84, May 2003

occurred.22,23 We believe that these similarities, unlike those with AD, MH, and NMS, may reflect a common underlying mechanism, possibly resulting from excess serotonin.

The most common causes of serotonin syndrome are overdoses of SSRIs or MDMA.19,20 MDMA is a potent releaser of serotonin from presynaptic vesicles and an inhibitor of serotonin reuptake.18-20 Excessive serotonin is associated with increased muscle tone and muscle stretch reflexes and is often associated with spastic hypertonia.19-21 Treatment of serotonin syndrome with benzodiazepines and dantrolene sodium has not been completely successful.20 Although dantrolene sodium may help reduce the amount of rhabdomyolysis, it has been unsuccessful in reducing dysautonomia, seizures, or hyperpyrexia in serotonin syndrome.9,19-21 The use of benzodiazepines, dantrolene sodium, or dopamine agonists is largely based on the data obtained from NMS.19,20 However, NMS is caused by dopamine blockade and/or reduced transmission to the hypothalamus.19,20,24 Intrathecally delivered baclofen is unlikely to affect dopaminergic pathways. ITB is concentrated in the CSF within the spinal subarachnoid space in the thoracolumbar and sacral spinal areas immediately after delivery.8 Lower levels of ITB reach the brainstem and cerebellum, in which there are significant concentrations of serotonergic neurons. But unless there is retrograde flow of CSF, such as that noted with a ventricular peritoneal shunt, it is unlikely that any significant amount of intrathecally delivered baclofen reaches the dopaminergic pathways in the brain.

Some success has been reported with the use of propranolol in the treatment of NMS and serotonin syndrome.19-21 Interestingly, propranolol has also been useful in treating acute central fever associated with dysautonomia in TBI.25 However, in 1 case of acute ITB withdrawal in a series recently reported,9 propranolol was not useful in reducing the fever or other symptomatology in the acute stages of ITB withdrawal (patient 3, table 39). Benzodiazepines, ITB, dantrolene sodium, and gabapentin were also not effective.9 This patient had a temperature of 41.0°C (105.8°F) or greater, sustained for several hours before dying. It may be that acute ITB withdrawal syndrome in some patients progresses beyond all aid, including intrathecal boluses of baclofen, before treatment can be initiated.

The patient described earlier developed acute ITB withdrawal syndrome after a cervicopleural shunt was placed to reduce a dissecting cervical syrinx, which likely had prevented ITB from reaching the upper cervical-brainstem region.9 Review of this case and observations of similarities in general between acute ITB withdrawal and serotonin syndrome led us

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CYPROHEPTADINE FOR INTRATHECAL BACLOFEN WITHDRAWAL, Meythaler Table 3: Patient Summary of Case Series Patient

Age and Sex

1

32y male

CP with spastic hypertonia

16mo

Pump removal (nonhealing pressure ulcer)

2

49y female

SCI T5 paraplegia (complete)

34mo

3

45y male

SCI C5 tetraplegia (complete)

38mo

Kinked intrathecal catheter (intermittent) Possible pump malfunction

4

44y male

SCI T4 paraplegia (complete)

72mo

Condition

ITB Duration

Reason for ITB Interruption

Kinked intrathecal catheter (intermittent)

Presentation Pruritus, increased muscle tone, lowgrade fever, tachycardia Intermittent pruritus, increased muscle tone Mental status changes, high fever, tachycardia, spasticity Pruritus, spasticity

to postulate that serotonin blockade with cyproheptadine should be used to alleviate the symptoms of acute ITB withdrawal.

Cyproheptadine is perhaps the most potent serotonin antagonist currently available for human use.19,26 It also has antihistaminic and anticholinergic characteristics. Cyproheptadine has been used in the treatment of cold urticaria, atopic dermatitis, Cushing’s syndrome secondary to pituitary disorders, and anorexia. It has been reported to antagonize the effects of SSRI antidepressants such as fluoxetine and paroxetine. The major side effect is drowsiness. Paradoxical excitation may occur, more often in children. Cyproheptadine in both oral and intrathecal delivery appears to reduce spastic hypertonia in both animals and humans.27,28 We postulate that GABA, via GABAB receptors, inhibits the release of serotonin at the level of the brainstem. There may be accommodation of the serotonergic pathway to this long-term inhibition. When this inhibition is abruptly removed, the system may swing toward excessive release of serotonin, resulting in a “serotonin syndrome.”

The clinical findings reported above are consistent with GABA having a role in the inhibition of serotonin release. In humans, the interaction of serotonin and GABA has never been described in the neurologic literature, but recently there has been a description of the interaction of serotonin and GABA pathways in mammals.29 Initially, this could contribute to the commonly seen reduction in spastic hypertonia after the initiation of ITB therapy. Accommodation would be consistent with the generally increasing dosages of ITB required for the first 12 to 18 months after the initiation of therapy,1-8 and the acute ITB withdrawal syndrome tends to be more severe for those who have been treated with ITB for several years.

In 2 patients (see table 3; patients 1, 2) who were conscious, cyproheptadine provided immediate relief from the pruritic symptoms associated with acute ITB withdrawal. In 1 patient (see table 3, patient 1) there was a dramatic drop in fever, pulse, temperature, and pruritic symptoms, which again became elevated 1 hour before the dose was due and dropped 1 hour later consistently over a 2-day dosing period. There was a reduction in tone noted in all 4 patients approximately 1 hour after the first dose of cyproheptadine. This is consistent with other studies27,28 that indicate that cyproheptadine was associated with a decrease in spastic hypertonia. In 2 patients (see table 3; patients 1, 4) there was a significant reduction in the fever of central origin. Despite concerted efforts, patient 4 sustained severe brain injury from complications of this severe case of ITB withdrawal and probable sepsis, and subsequently died.

Cyproheptadine is generally available as tablets (4mg) or syrup (2mg/mL). In cases of severe ITB withdrawal, we have

Severity of ITB Withdrawal

Response to Cyproheptadine

Moderate

Relief of pruritus, vital signs normalized

Mild

Relief of pruritus, decreased muscle tone Improvement in fever, spasticity

Severe

Moderate

Notes

Deceased 2mo after onset (pulmonary complications)

Improvement in pruritus, spasticity

started cyproheptadine in 8mg doses every 6 hours. More recently, we have started to use the medication within 48 hours of a suspected ITB withdrawal, to attenuate the symptoms of withdrawal.

CONCLUSION Cyproheptadine appears to be a useful adjunct in the medical management of ITB withdrawal syndrome. We postulate that the GABAB agonist baclofen, in addition to other actions that it may have, inhibits the release of serotonin, possibly through a presynaptic mechanism, and that the serotonin pathways accommodate to this inhibition over time. In this model, abrupt withdrawal of baclofen’s inhibition of serotonin pathways would result in an acute serotonin syndrome, which could be a component, perhaps even the definitive component, of acute ITB withdrawal syndrome. The cases presented here show that, at the very least, cyproheptadine, used in conjunction with baclofen and diazepam, is associated with significant improvement in the management of the signs and symptoms of acute ITB withdrawal syndrome. It also appears to help prevent syndrome progression when administered early. Further research at the clinical and basic science levels is likely to shed more light on the basis of cyproheptadine’s effects, as well as on the mechanism of ITB withdrawal itself.

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