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Baclofen toxicity in a patient with subclinical renal insufficiency
Baclofen Toxicity in a Patient With Subclinical Renal Insufficiency Mindy L. A&en, MD, Mark Dietz, MD, Fletcher
McDowell, MD, Henn Kutt, MD, PhD
ABSTRACT. Aiaen ML, Dietz M, McDowell F, Kutt H. Baclofen toxicity in a patient wlth subclinical renal insufficiency. Arch Phys Med Rehabil 1994;75:109-11. l Baclofen, a centrally acting y-aminobutyric acid agonist is a commonly used pharmacotherapy for spasticity of spinal origin. It is primarily excreted by glomerular filtration with a clearance proportional to creatinine clearance. We describe a 39.year-old quadriplegic woman who, over a 16-week period, developed clinical signs of baclofen toxicity confirmed by progressively rising serum baclofen levels while on a conventional stable dosing regimen. During this period blood urea nitrogen and creatinine concentrations were normal and stable (9mg/dL and O.Smg/dL, respectively). However, creatinine clearance values were consistently low (55 to 6OmAnin), suggesting renal insufficiency as the underlying cause. After a decrease in baclofen dosage, evidence of baclofen toxicity resolved. Clinicians should be alert to signs of evolving baclofen toxicity even in patients on an apparently stable regimen. Baclofen dosage adjustments based on systemic baclofen level may play a role in optimizing the clinical management of spa&city. 0 1994 by the American Congress of Rehabilitution Medicine and the American Academy of Physical Medicine and Rehubilitution Spastic@ is a common complication of spinal cord disease; it is substantially a result of hyperactivity in alpha and gamma mediated reflex arcs. y-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the spinal cord, producing effects through presynaptic inhibition of primary
afferents.’ Baclofen is a centrally acting GABA agonist that represents the cornerstone of pharmacotherapy for spasticity of spinal cord origin. Its effects include activation of GABAB receptors in primary sensory afferents, enhancement of Renshaw cell activity, and depression of fusimotor responses.’ Conventional use of baclofen consists of gradually increasing the oral doses taken by the patients while monitoring symptoms and side effects, and then maintaining a stable optimal dosage when the desired clinical response is achieved. Assays of baclofen plasma concentration do not play a role in traditional practice, and creatinine clearance generally is not measured before baclofen is prescribed. The following case report describes a patient with normal urea nitrogen and creatinine blood concentrations who developed gradually evolving signs of baclofen toxicity with rising baclofen plasma blood levels over a 16-week period, while on a stable baclofen-dosing regimen. CASE REPORT The patient was a previously healthy 39-year-old woman who suffered a cervical spinal injury in a motor vehicle accident, rendering her quadriplegic with a complete C5 motor and sensory level. (Frankel A). After C5-6 posterior bone fusion stabilization, her course was complicated by progressive painful dysesthesias involving all extremities, recurrent paroxysmal flexor spasms, urinary Prom the Synergen Corporation, Denver, CO; and Cornell University Medical College, Burke Rehabilitation Hospital, White Plains, NY, Submitted for publication November 10. 1992. Accepted in revised form March 24, 1993. No commercial party having a direct or indirect interest in the subject matter of this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Mindy L. Aisen, MD, Cornell University Medical College, Burke Rehabilitation Hospital, 785 Mamaroneck Avenue, White Plains, NY 10605. 0 1994 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation OOO3-9993/94/7501-0038$3.00/O
infections, and weight loss. She was transferred to The Burke Rehabilitation Center 6 weeks after injury. Medications were baclofen 15mg three times daily and amitriptyline 25mg every night, for treatment of spasticity and pain, and ciprofloxacin 25Omg twice daily for cystitis. Blood pressure was 120180. She weighed 62.7kg. Physical examination was notable for a complete C5 level motor and sensory quadriplegia, hyperactive reflexes, and bilateral Babinski signs. She complained of spontaneous burning dysesthesias and experienced violent flexor spasms involving trunk, arms, and legs after minor tactile stimulation. Initial laboratory values were unremarkable, including serum creatinine of 0.8mg/dL. During the subsequent 8 weeks, the patient experienced recurrent pain, urinary infections, and a pulmonary embolus. Her systemic medical complications subsided and she was placed on a stable regimen of methenamine mandelate lg four times daily, warfarin sodium 5mg every day, amitriptyline 150mg every night, and baclofen 15mg four times daily. Persistent disabling flexor spasms then prompted a gradual increase in baclofen dosage to 30mg four times daily in the next 4 weeks. Spasticity correspondingly diminished; spontaneous flexor spasms decreased in frequency from 3 per hour to 0 per hour, and average Ashworth’ score (table) dropped from four to two in each limb. Five days after the last dosage increment, she agreed to participate in an experimental protocol designed to assess baclofen pharmacokinetics and pharmacodynamics in patients receiving a stable baclofen regimen. The protocol was also designed to help define baclofen’s therapeutic window, as toxic and therapeutic serum baclofen levels are not well established. Medication compliance was assessed by the hospital’s nursing staff, which documented all drug consumption. To evaluate the relationship between blood level and clinical effect, clinical assessment of spasticity was performed immediately before obtaining a morning predose trough blood sample on a monthly basis. Spasticity was assessed using the Ashworth Scoring System (table). The patient was asked to report the number of spontaneous spasms noted in the hour before evaluation. Blood was separated and plasma frozen. Sample analysis was performed at the conclusion of a 16-week study period. Serum baclofen concentrations were measured using a high performance liquid chromatography procedure based on the techniques of Harrison and colleagues3 and Wuis and coworkers4 Baclofen was extracted from plasma using Bondelut C- 18 minicolumns. P-chlorophenylalanine served as the internal standard.
Arch Phys Med Rehabil Vol75, January 1994
BACLOFEN TOXICITY, Aisen
110
The eluate was then chromatographed with an analytical C-18 column using acetonitril with phosphate buffer as the mobile phase, in a ratio that was adapted to the individual C-18 main column. The peaks were detected with an ultraviolet detector set at a wavelength of 220nm. The assay was linear over a cover of 25 to 1,25Ong/mL in plasma. The between days covariance of the assay was 6% to 8%. Monthly CBC, electrolytes, serum creatinine, liver function tests, and blood urea nitrogen were obtained, as were 24-hour urine collections to measure creatinine excretion. Although all serum laboratory values were within normal limits including a stable serum creatinine of 0.8mg/dL, creatinine clearance consistently ranged between 55 to 6OmIJmin during the study period. The patient’s weight remained stable during the study interval. The patient was maintained on a stable 30mg four times daily regimen after 6 weeks, her average Ashworth score decreased from 2 to 1.5; at week 10 she exhibited normal tone (Ashworth = 1) in all limbs, and all spontaneous spasms ceased. Approximately 14 weeks after entering the study the patient reported episodic fatigue and nocturnal confusion. Ten days later she developed asymptomatic hypotension with a supine blood pressure of 80150. Baclofen toxicity was suspected and the dosage was tapered, with resolution of symptoms of toxicity and a generalized increase in hypertonicity. Throughout this time she remained anesthetic and paralyzed in all dermatomes and myotomes below C5. Subsequent plasma analysis showed a steady rise in baclofen level throughout the 16-week interval (fig).
I 0
2
4
6
10
12
14
16
10
20
WEEK
Baclofendose increasedto 30 mg qid (1.91 m&&lay)
Trough serum baclofen levels measured over a 1Cweek period while on a stable (3Omg four times daily) dosing regimen. Comedications: methenamine mandelate, lgm four times daily; wafarin sodium, 5mg every day; amitryptiline, 15Omg every night.
DISCUSSION This patient experienced gradually evolving baclofen toxicity while on a stable conventional dosing regimen. Baclofen undergoes first-order elimination kinetics at therapeutic doses; the elimination half-life for baclofen has been previously reported to range from 2 to 6.8 hours, with an average of 3.5 hours.5-g As this patient’s dosing interval was 6 hours, the predicted steady state should have occurred within 30 hours. Baclofen is primarily excreted by glomerular filtration and its clearance is proportional to creatinine clearance.4 Baclofen excretion was presumably impaired because of renal insufficiency, which was apparent only by creatinine clearance measurement. (The normal range values of serum creatinine may have been related to decreased muscle mass). A reduction in glomerular filtration rate has been described in the spinal injured population.” Renal dysfunction could be related to recurrent urinary infections and reflux. An auto-
nomic basis for the observed renal impairment is less likely. Though the kidneys receive a substantial sympathetic supply, and renal denervation experimentally acutely increases sodium and water excretion”3’2 denervation alone has not been shown to produce a sustained effect on renal function. Definition of the Ashworth Spasticity Scale Ashworth score 1 2 3 z
Degree of Muscle Tone No increase in tone Slight increase; a catch noted when limb is quickly extended or flexed Marked increase in tone, but affected part easily moved Considerable increase in tone, passive movement difficult Affected limb rigid in flexion or extension
(Data from Ashworth?)
Arch Phys Med Rehabil Vol75, January 1994
A previous repo@ details the development of baclofen toxicity in a chronic paraplegic with ibuprofen induced renal dysfunction; as renal function declined, signs of baclofen toxicity ensued. Our patient received methanamine mandelate warfarin sodium, and amitriptyline as comedications, none of which have been reported to reduce glomerular filtration. Extensive literature review produced no evidence that urinary acidification (by methenamine mandelate) influences baclofen excretion. In a previous study of baclofen pharmacokinetics and dynamics it was shown that although there is wide variability in optimal dosage and corresponding serum levels between individuals, a clear correlation exists between serum levels and clinical control of spasticity within individuals.‘4 Earlier reports indicate that cerebrospinal fluid (CSF) penetration of baclofen is limited, showing maximal CSF: serum ratios of 1: 1000 in patients on an oral regimen? This patient showed clinical signs and laboratory confirmation of rising serum baclofen levels over a 16-week period while on a stable baclofen dose. Baclofen dosage adjustment based on creatinine clearance and systemic baclofen concentration monitoring could potentially optimize spastic@ treatment of the spinal cord injured population. Clinicians should be alert to signs of evolving baclofen toxicity, even in patients who seem to have stabilized on a baclofen regimen. References 1. Davidoff RA. Antispasticity drugs: mechanisms of action. Neurology 1985;17:107-16. 2. Ashworth B. Preliminary trial of carisoprodel in multiple sclerosis. Practitioner 1964;192:540-2. 3. Harrison PM, Tonkin AM, McLean AJ. Determination of 4-amino3-liquid (p-chlorophenyl) butyrin acid baclofen in plasma by bighperformance chromatography, J Chromatogr 1985;339:424-8.
BACLOFEN TOXICITY, Aisen 4. Wuis EW, Dirks MJM, Termond EFS, et al. Plasma and urinary excretion kinetics of oral baclofen in healthy subjects. Eur J Clin Pharmacol 1989;37:181-4. 5. Faigle JW, Keberle H. The chemistry and kinetics of Lioresal. Postgrad Med 1 1972;48(Suppl):9-13. 6. Peterson GM, McLean S, Millingen KS. Food does not affect the bioavailability of baclofen. Med J Aust 1985;142:689-90. 7. Kochak GM, Rakhit A, Wagner WE, et al. The pharmacokinetics of baclofen derived from intestinal infusion. Clin Pharmacol Ther 1985;38:251-7. 8. Andrew P, Wood KL. Systemic baclofen stimulates gastric motility and secretion via a central action in the rat. Br J Pharmacol 1986:89:461-7. 9. Knutsson E, Lindblum U, Martensson A. Plasma and cerebrospinal fluid levels of baclofen at optimal therapeutic responses in spastic paresis. J Neurosci 1974;23:473-84.
111
10. Ragnarrson KT, Krebs M, Naftchi NE, et al. Effects of head-up tilt on glomerular filtration rate and renal plasma flow in spinal man. In: Naftchi NE, editor. Spinal cord injury. New York SP Medical and Scientific Books, 1982:233-40. 11. Thompson IM, Zatzman M. The influence of denervation on renal function. J Ural 1962;88:117-9. 12. Barger AC, Herd JA. Renal vascular anatomy and distribution of flow. In: Grloff J, Berliner RW, editors. Renal Physiology. Washington, DC, American Physiological Society, 1973:249-313. 13. Dahlin PA, George J. Baclofen toxicity associated with declining renal clearance after ibuprofen. Drug Intel1 Clin Pharmacol 1984;18:805-8. 14. Aisen ML, et al. Clinical and pharmacokinetic aspects of high dose oral baclofen therapy. J Am Paraplegia Sac 1992;15:211-6.
Arch Phya Mod RehabH Vol75,
January IW4
McDowell, MD, Henn Kutt, MD, PhD
ABSTRACT. Aiaen ML, Dietz M, McDowell F, Kutt H. Baclofen toxicity in a patient wlth subclinical renal insufficiency. Arch Phys Med Rehabil 1994;75:109-11. l Baclofen, a centrally acting y-aminobutyric acid agonist is a commonly used pharmacotherapy for spasticity of spinal origin. It is primarily excreted by glomerular filtration with a clearance proportional to creatinine clearance. We describe a 39.year-old quadriplegic woman who, over a 16-week period, developed clinical signs of baclofen toxicity confirmed by progressively rising serum baclofen levels while on a conventional stable dosing regimen. During this period blood urea nitrogen and creatinine concentrations were normal and stable (9mg/dL and O.Smg/dL, respectively). However, creatinine clearance values were consistently low (55 to 6OmAnin), suggesting renal insufficiency as the underlying cause. After a decrease in baclofen dosage, evidence of baclofen toxicity resolved. Clinicians should be alert to signs of evolving baclofen toxicity even in patients on an apparently stable regimen. Baclofen dosage adjustments based on systemic baclofen level may play a role in optimizing the clinical management of spa&city. 0 1994 by the American Congress of Rehabilitution Medicine and the American Academy of Physical Medicine and Rehubilitution Spastic@ is a common complication of spinal cord disease; it is substantially a result of hyperactivity in alpha and gamma mediated reflex arcs. y-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the spinal cord, producing effects through presynaptic inhibition of primary
afferents.’ Baclofen is a centrally acting GABA agonist that represents the cornerstone of pharmacotherapy for spasticity of spinal cord origin. Its effects include activation of GABAB receptors in primary sensory afferents, enhancement of Renshaw cell activity, and depression of fusimotor responses.’ Conventional use of baclofen consists of gradually increasing the oral doses taken by the patients while monitoring symptoms and side effects, and then maintaining a stable optimal dosage when the desired clinical response is achieved. Assays of baclofen plasma concentration do not play a role in traditional practice, and creatinine clearance generally is not measured before baclofen is prescribed. The following case report describes a patient with normal urea nitrogen and creatinine blood concentrations who developed gradually evolving signs of baclofen toxicity with rising baclofen plasma blood levels over a 16-week period, while on a stable baclofen-dosing regimen. CASE REPORT The patient was a previously healthy 39-year-old woman who suffered a cervical spinal injury in a motor vehicle accident, rendering her quadriplegic with a complete C5 motor and sensory level. (Frankel A). After C5-6 posterior bone fusion stabilization, her course was complicated by progressive painful dysesthesias involving all extremities, recurrent paroxysmal flexor spasms, urinary Prom the Synergen Corporation, Denver, CO; and Cornell University Medical College, Burke Rehabilitation Hospital, White Plains, NY, Submitted for publication November 10. 1992. Accepted in revised form March 24, 1993. No commercial party having a direct or indirect interest in the subject matter of this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Mindy L. Aisen, MD, Cornell University Medical College, Burke Rehabilitation Hospital, 785 Mamaroneck Avenue, White Plains, NY 10605. 0 1994 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation OOO3-9993/94/7501-0038$3.00/O
infections, and weight loss. She was transferred to The Burke Rehabilitation Center 6 weeks after injury. Medications were baclofen 15mg three times daily and amitriptyline 25mg every night, for treatment of spasticity and pain, and ciprofloxacin 25Omg twice daily for cystitis. Blood pressure was 120180. She weighed 62.7kg. Physical examination was notable for a complete C5 level motor and sensory quadriplegia, hyperactive reflexes, and bilateral Babinski signs. She complained of spontaneous burning dysesthesias and experienced violent flexor spasms involving trunk, arms, and legs after minor tactile stimulation. Initial laboratory values were unremarkable, including serum creatinine of 0.8mg/dL. During the subsequent 8 weeks, the patient experienced recurrent pain, urinary infections, and a pulmonary embolus. Her systemic medical complications subsided and she was placed on a stable regimen of methenamine mandelate lg four times daily, warfarin sodium 5mg every day, amitriptyline 150mg every night, and baclofen 15mg four times daily. Persistent disabling flexor spasms then prompted a gradual increase in baclofen dosage to 30mg four times daily in the next 4 weeks. Spasticity correspondingly diminished; spontaneous flexor spasms decreased in frequency from 3 per hour to 0 per hour, and average Ashworth’ score (table) dropped from four to two in each limb. Five days after the last dosage increment, she agreed to participate in an experimental protocol designed to assess baclofen pharmacokinetics and pharmacodynamics in patients receiving a stable baclofen regimen. The protocol was also designed to help define baclofen’s therapeutic window, as toxic and therapeutic serum baclofen levels are not well established. Medication compliance was assessed by the hospital’s nursing staff, which documented all drug consumption. To evaluate the relationship between blood level and clinical effect, clinical assessment of spasticity was performed immediately before obtaining a morning predose trough blood sample on a monthly basis. Spasticity was assessed using the Ashworth Scoring System (table). The patient was asked to report the number of spontaneous spasms noted in the hour before evaluation. Blood was separated and plasma frozen. Sample analysis was performed at the conclusion of a 16-week study period. Serum baclofen concentrations were measured using a high performance liquid chromatography procedure based on the techniques of Harrison and colleagues3 and Wuis and coworkers4 Baclofen was extracted from plasma using Bondelut C- 18 minicolumns. P-chlorophenylalanine served as the internal standard.
Arch Phys Med Rehabil Vol75, January 1994
BACLOFEN TOXICITY, Aisen
110
The eluate was then chromatographed with an analytical C-18 column using acetonitril with phosphate buffer as the mobile phase, in a ratio that was adapted to the individual C-18 main column. The peaks were detected with an ultraviolet detector set at a wavelength of 220nm. The assay was linear over a cover of 25 to 1,25Ong/mL in plasma. The between days covariance of the assay was 6% to 8%. Monthly CBC, electrolytes, serum creatinine, liver function tests, and blood urea nitrogen were obtained, as were 24-hour urine collections to measure creatinine excretion. Although all serum laboratory values were within normal limits including a stable serum creatinine of 0.8mg/dL, creatinine clearance consistently ranged between 55 to 6OmIJmin during the study period. The patient’s weight remained stable during the study interval. The patient was maintained on a stable 30mg four times daily regimen after 6 weeks, her average Ashworth score decreased from 2 to 1.5; at week 10 she exhibited normal tone (Ashworth = 1) in all limbs, and all spontaneous spasms ceased. Approximately 14 weeks after entering the study the patient reported episodic fatigue and nocturnal confusion. Ten days later she developed asymptomatic hypotension with a supine blood pressure of 80150. Baclofen toxicity was suspected and the dosage was tapered, with resolution of symptoms of toxicity and a generalized increase in hypertonicity. Throughout this time she remained anesthetic and paralyzed in all dermatomes and myotomes below C5. Subsequent plasma analysis showed a steady rise in baclofen level throughout the 16-week interval (fig).
I 0
2
4
6
10
12
14
16
10
20
WEEK
Baclofendose increasedto 30 mg qid (1.91 m&&lay)
Trough serum baclofen levels measured over a 1Cweek period while on a stable (3Omg four times daily) dosing regimen. Comedications: methenamine mandelate, lgm four times daily; wafarin sodium, 5mg every day; amitryptiline, 15Omg every night.
DISCUSSION This patient experienced gradually evolving baclofen toxicity while on a stable conventional dosing regimen. Baclofen undergoes first-order elimination kinetics at therapeutic doses; the elimination half-life for baclofen has been previously reported to range from 2 to 6.8 hours, with an average of 3.5 hours.5-g As this patient’s dosing interval was 6 hours, the predicted steady state should have occurred within 30 hours. Baclofen is primarily excreted by glomerular filtration and its clearance is proportional to creatinine clearance.4 Baclofen excretion was presumably impaired because of renal insufficiency, which was apparent only by creatinine clearance measurement. (The normal range values of serum creatinine may have been related to decreased muscle mass). A reduction in glomerular filtration rate has been described in the spinal injured population.” Renal dysfunction could be related to recurrent urinary infections and reflux. An auto-
nomic basis for the observed renal impairment is less likely. Though the kidneys receive a substantial sympathetic supply, and renal denervation experimentally acutely increases sodium and water excretion”3’2 denervation alone has not been shown to produce a sustained effect on renal function. Definition of the Ashworth Spasticity Scale Ashworth score 1 2 3 z
Degree of Muscle Tone No increase in tone Slight increase; a catch noted when limb is quickly extended or flexed Marked increase in tone, but affected part easily moved Considerable increase in tone, passive movement difficult Affected limb rigid in flexion or extension
(Data from Ashworth?)
Arch Phys Med Rehabil Vol75, January 1994
A previous repo@ details the development of baclofen toxicity in a chronic paraplegic with ibuprofen induced renal dysfunction; as renal function declined, signs of baclofen toxicity ensued. Our patient received methanamine mandelate warfarin sodium, and amitriptyline as comedications, none of which have been reported to reduce glomerular filtration. Extensive literature review produced no evidence that urinary acidification (by methenamine mandelate) influences baclofen excretion. In a previous study of baclofen pharmacokinetics and dynamics it was shown that although there is wide variability in optimal dosage and corresponding serum levels between individuals, a clear correlation exists between serum levels and clinical control of spasticity within individuals.‘4 Earlier reports indicate that cerebrospinal fluid (CSF) penetration of baclofen is limited, showing maximal CSF: serum ratios of 1: 1000 in patients on an oral regimen? This patient showed clinical signs and laboratory confirmation of rising serum baclofen levels over a 16-week period while on a stable baclofen dose. Baclofen dosage adjustment based on creatinine clearance and systemic baclofen concentration monitoring could potentially optimize spastic@ treatment of the spinal cord injured population. Clinicians should be alert to signs of evolving baclofen toxicity, even in patients who seem to have stabilized on a baclofen regimen. References 1. Davidoff RA. Antispasticity drugs: mechanisms of action. Neurology 1985;17:107-16. 2. Ashworth B. Preliminary trial of carisoprodel in multiple sclerosis. Practitioner 1964;192:540-2. 3. Harrison PM, Tonkin AM, McLean AJ. Determination of 4-amino3-liquid (p-chlorophenyl) butyrin acid baclofen in plasma by bighperformance chromatography, J Chromatogr 1985;339:424-8.
BACLOFEN TOXICITY, Aisen 4. Wuis EW, Dirks MJM, Termond EFS, et al. Plasma and urinary excretion kinetics of oral baclofen in healthy subjects. Eur J Clin Pharmacol 1989;37:181-4. 5. Faigle JW, Keberle H. The chemistry and kinetics of Lioresal. Postgrad Med 1 1972;48(Suppl):9-13. 6. Peterson GM, McLean S, Millingen KS. Food does not affect the bioavailability of baclofen. Med J Aust 1985;142:689-90. 7. Kochak GM, Rakhit A, Wagner WE, et al. The pharmacokinetics of baclofen derived from intestinal infusion. Clin Pharmacol Ther 1985;38:251-7. 8. Andrew P, Wood KL. Systemic baclofen stimulates gastric motility and secretion via a central action in the rat. Br J Pharmacol 1986:89:461-7. 9. Knutsson E, Lindblum U, Martensson A. Plasma and cerebrospinal fluid levels of baclofen at optimal therapeutic responses in spastic paresis. J Neurosci 1974;23:473-84.
111
10. Ragnarrson KT, Krebs M, Naftchi NE, et al. Effects of head-up tilt on glomerular filtration rate and renal plasma flow in spinal man. In: Naftchi NE, editor. Spinal cord injury. New York SP Medical and Scientific Books, 1982:233-40. 11. Thompson IM, Zatzman M. The influence of denervation on renal function. J Ural 1962;88:117-9. 12. Barger AC, Herd JA. Renal vascular anatomy and distribution of flow. In: Grloff J, Berliner RW, editors. Renal Physiology. Washington, DC, American Physiological Society, 1973:249-313. 13. Dahlin PA, George J. Baclofen toxicity associated with declining renal clearance after ibuprofen. Drug Intel1 Clin Pharmacol 1984;18:805-8. 14. Aisen ML, et al. Clinical and pharmacokinetic aspects of high dose oral baclofen therapy. J Am Paraplegia Sac 1992;15:211-6.
Arch Phya Mod RehabH Vol75,
January IW4