Pharmacokinetics and pharmacodynamics of intrathecal baclofen therapy
Heetla, Herre Wigger
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2018
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Heetla, H. W. (2018). Pharmacokinetics and pharmacodynamics of intrathecal baclofen therapy. Rijksuniversiteit Groningen.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
Clinical relevance of pharmacological
and physiological data in
intrathecal baclofen therapy
Archives of Physical Medicine and Rehabilitation 2014;95:2199-206
H.W. Heetla M.J. Staal J.H. Proost
ABSTRACT
Objective: To review all pharmacological and physiological data available on intrathecal
baclofen (ITB) therapy and to evaluate its use in clinical practice and future research.
Data Sources: PubMed was searched for relevant anatomic, physiological, and
pharmacological data available on ITB.
Study Selection: All currently available data on ITB pharmacokinetics (PKs) and
pharmacodynamics (PDs) in both human and animal studies were reviewed and combined with the anatomy and physiology of the intrathecal space and cerebrospinal fluid flow.
Data Extraction: Only 4 studies reported PK data on ITB in humans. More studies reported
PD data on ITB; however, none were combined with PK data. More detailed data on PK could be gathered from studies using an animal model.
Data Synthesis: ITB does not spread equally over the intrathecal space after injection, but
it diffuses according to a concentration gradient. ITB distribution can be influenced by the location of the catheter tip and by changing the infusion mode.
Conclusions: The pharmacological and physiological data on ITB can be used to support
decisions in clinical practice concerning drug concentration, infusion regimens, localization of the catheter tip, and management of tolerance; however, some strategies have little evidence in humans.
2
INTRODUCTION
Baclofen is widely used for the treatment of spasticity. It is a muscle relaxant with its primary site of action in the spinal cord, acting as an agonist of the inhibitory gamma aminobutyric acid, type B (GABA-B) receptor. The uptake of baclofen across the blood-brain barrier is limited. Therefore, high oral doses are needed to achieve a therapeutic effect, often causing central nervous system side effects ( e.g. drowsiness, sleepiness).1 In 1984, Penn and
Kroin bypassed the blood-brain barrier in 2 patients by infusing baclofen directly into the cerebrospinal fluid (CSF) using a subcutaneously located programmable pump connected to an intrathecal lumbar drain. Intrathecal baclofen (ITB) therapy needs much lower doses (range 50 – 1000 µg/d) than oral administration (range 25 – 100 mg/d), resulting in fewer side effects.2 The long-term effects and safety of ITB therapy have been proven extensively
in the last 2 decades.2-5 However, the pharmacologic basics of ITB therapy have not been
studied extensively.
METHODS
To evaluate its use in clinical practice, PubMed was used to review all currently available pharmacokinetic (PK) and pharmacodynamic (PD) data on ITB in both human and animal studies and the physiological basics of CSF flow and intrathecal anatomy. Only 4 studies reported PK data on ITB in humans. More studies reported PD data on ITB; however, none were combined with PK data. More detailed data on PKs could be gathered from studies using an animal model. The clinical implications of these data were evaluated, especially its use to support decisions in daily practice related to drug concentration, infusion regimens, localization of the catheter tip, and treatment of tolerance.
RESULTS
Anatomy of the spinal canal and CSF flow
The spinal cord extends from the medulla oblongata to the level of the first lumbar vertebra. The human spinal cord is approximately 38±3 cm long, has a volume of 20±3 mL in adults, and is surrounded by the pia mater.6 The spinal canal is the compartment between the
arachnoid and pia mater. The spinal canal is approximately 58±3 cm long, and it is filled with CSF surrounding the brain and spinal cord.6 Most of the CSF is produced by the choroid
replace the entire CSF volume (±150 mL) 3 times a day.7,8 The spinal CSF volume is 81±13
mL, and is divided over the cervical (19±4 mL), thoracic (37±8 mL), and lumbosacral (25±7 mL) spinal canal.6
The CSF moves from the lateral ventricles, through the third and fourth ventricle, and into the subarachnoid space around the brain and spinal cord. The CSF does not move in a 1-directional manner ( e.g. blood) but is moved in a pulsatile pattern, synchronous with the contractions of the heart. During each systole, blood is pumped into the cerebral arteries causing an increase of the intracranial volume. Because both blood and brain are less compressible, some CSF will be forced in a caudal direction into the spinal canal, which is expandable because it is not constricted by the skull. During the diastole, the CSF flow reverses in a rostral way. In a recent human physiological model, it has been calculated that because of this process only 0.5 to 2 mL of CSF is displaced with every heartbeat.9 At
the spinal level, pulsations from the spinal arteries contribute to these pulsatile waves as well.10 Because the driving force of these pulsatile movements starts in the skull, its effect
decreases caudally, resulting in a limited CSF flow at the lumbar/low thoracic level. When injected at this level, most of the drug remains around the injection site, creating a higher drug concentration gradient along the spinal cord than the high thoracic level injections.11
This concentration gradient is important to understand the variation in clinical effect of ITB.
CSF absorption takes place by a 1-way flow through the arachnoid villi in the dura of the superior sagittal sinus. However, animal data suggest that CSF absorption also takes place at the spinal level because arachnoid villi have been found along the nerve roots in the spinal cord in various animals, where they account for up to 25% to 50% of the total clearance from the intrathecal space.12,13
Drug distribution depends not only on CSF flow but also on baricity. Baricity refers to the density of a fluid (i.e. baclofen) compared with the density of another fluid (e.g. human CSF). The density of baclofen ranges from 0.99836 mg/mL (1000 µg/mL) to 0.99971 mg/mL (2000 µg/mL), which is lower than the CSF density (1.00049 - 1.0007 mg/mL).14 Therefore, baclofen
behaves like a hypobaric compound causing distribution against gravity.
Pharmacology of ITB
The pathophysiology of spasticity and dystonia is complex and caused by alterations to various spinal mechanisms. One of these is the loss of inhibitory mechanisms, which can cause a hyperexcitability of the stretch reflex because of increased sensory neuron and motoneuron excitability.15
2
Baclofen is a potent GABA-B agonist and binds to the inhibitory GABA-B receptor. During ITB therapy, baclofen is infused directly into the CSF where it binds to GABA-B receptors in the dorsal root ganglion and spinal gray matter, especially in lamina I and II of the dorsal horn of the spinal cord.16,17 It is believed that baclofen achieves its antispastic effect by presynaptic
inhibition and postsynaptic hyperpolarization of the dorsal horn neurons, which causes an inhibition of neurotransmitter release and a reduction in motoneuron excitability, leading to a reduction of the stretch reflex in patients with spasticity.17 Baclofen exists as a racemic
mixture, but the therapeutic effect is mostly attributed to the L-enantiomer.18 There are no
major differences in PKs between both enantiomers.19
PK data
All PK data on ITB in humans are derived from 4 studies.20-23 The reported PK parameters
have been summarized in table 1. All studies used different doses of ITB and sampled CSF at varying distances from the infusion location causing a large variability of the reported PK data. The most important conclusions with respect to the PK data in table 1 are as follows: 1) The intrathecal life of ITB ranges from 1 to 5 hours, roughly the same as the plasma half-life of baclofen (3 – 4 h)20-22,24; 2) CSF clearance is thought to take place by bulk flow of the
CSF and its constituents through the arachnoid villi. As in animal models, spinal clearance (6.6 – 13.8 mL/h) accounts for up to 25% to 50% of the total CSF clearance (22 mL/h).7,12,13,25
However, the reported baclofen clearance rates (29.9 – 41mL/h) are higher, suggesting an additional clearance route. It might be possible that some baclofen is cleared from the spinal tissue via the blood and/or lymphatic system7; 3) The distribution volume (the apparent
volume of the theoretical compartment in which baclofen is dissolved) is higher than the spinal CSF volume, indicating distribution into spinal tissue as well, which seems logical because its receptors are located within the myelum.21,22 Baclofen is a slightly hydrophilic
compound (partition coefficient octanol/water 0.1); therefore, it has difficulties passing the lipophilic membranes of the cells aligning the spinal canal.26 Therefore, most baclofen will
remain in the CSF. The total spinal CSF volume is 81 mL, from which 62 mL is found at the thoracic and lumbosacral levels, where baclofen is mostly injected.6 Two studies reported
Figure 1. ITB concentration time curves from 3 ITB PK studies: (A and C) ITB concentration at the infusion location after different boluses of ITB; (B) ITB concentration 0 to 4 vertebral levels below the infusion location of 4 different boluses in 4 different patients. Data from Muller, Sallerin-Caute, and Kroin.20-22
2
Table 1. Summar y of intrathecal baclof en phar macokinetic studies in humans
Study Infusion (mo de) N Dose (μg) Vd (ml) CL (ml / h) T½ (min) CSS (ng / ml) Deliv er y (spinal le vel) Sampling (spinal le vel) M uller et al 20 continuous 8 50 –1,200 / 24h. NA NA NA 130 - 950 Pump * NA bolus 3 200 – 600 NA NA 270 † NA NA NA Saller in-Caut e et al 21 bolus 4 75 – 140 119 36 54-300 NA T6 – T11 T10 – L3 Kr oin et al 22 bolus 2 50 85 35 101 NA T12 – L2 T12 – L2 bolus 5 100 86 41 82 NA T12 – L2 T12 – L2 continuous 10 96 – 600 / 24h. NA 29.9 NA 76 – 1240 pump * side -por t * Albr ight et al 23 continuous 43 70 –1,395 / 24h. NA NA NA 200 – 20,000 pump * side -por t * Abbr eviations: CL, clearance; C max , maximum concentration; C SS , lumbar st eady-stat
e concentration; NA, not applicable;
Tmax, time of maximum concentration;
T½ , half-lif e; V d , v olume of distr ibution. * D eliv er
y and sampling happened using the pump
, wher
eas the cathet
er tip le vel is unk no wn. † Calculat ed fr om the g raph.
Only 3 studies have reported detailed time-concentration data after bolus infusion of ITB (figure 1).20-22 Two of these studies (see figure 1A and C) used the same catheter for
both infusion and sampling, which may have caused error in the sample data. These time-concentration curves represent the disappearance of ITB as measured at the catheter tip, which explains why the upswing of the curves is missing. The peak concentration of baclofen (1.5 – 107 µg/mL) shows a large variation.20,21 None of the studies attempted to fit their data
in a PK model. However, the biphasic elimination of most curves (fast concentration drop in the beginning, slower drop at the end) suggests that a multicompartment model could be helpful to describe the time-concentration profiles of baclofen.
Concentration gradient of ITB
The pulsatile flow of CSF causes a concentration gradient of all its constituents along the spinal canal. Unfortunately, very little data on this concentration gradient of ITB are published. The only human data show a mean lumbar to cisternal drug ratio of 4.1:1 (range, 2 – 8.7) after 48 hours of continuous ITB infusion.22 These data suggest a decrease in baclofen
concentration of 50% to 89% along the total spinal canal (58±3 cm), which is a decrease in ITB concentration of about 0.9% to 1.5% per centimeter. Detailed examination of the spinal ITB concentration gradient has only been performed in a pig model.11 The spinal
canal of the pig is comparable with the human spinal canal with regard to the anatomy and dimensions and CSF formation rate. If a pig is placed in an upright position, the results from this animal model can possibly be comparable with the ITB distribution in humans. Figure 2 shows the ITB concentration gradients along the pig spinal canal after 8 hours of infusion at 3 different ITB regimens: a 40 µg/h and 2000 µg/h continuous infusion regimen and a 2000 µg/h bolus infusion regimen.11 During both continuous infusion regimens, most
baclofen remains around the catheter tip in pigs, especially in the 40 µg/h group, which is most similar to the infusion delivery rate in humans (4 – 20µg/h). In this group, no baclofen could be measured at 5 cm above the catheter tip. Comparing the two 2000 µg/h infusion regimens, the bolus infusion demonstrated an increased distribution compared with a continuous infusion. After bolus infusion, baclofen was detected in 52% of the CSF samples at a distance of 10 cm from the tip, whereas this was the case in only 14% of the samples after continuous infusion at 10 cm from the tip. Peak concentrations were also higher at 5- and 10-cm distance from the catheter tip during bolus infusions (see figure 2).
2
Figure 2. Comparison of rostral CSF peak concentrations after 3 different ITB infusion regimens in pigs.11 The concentration at the injection location is set at 100%.
PD data
Several methods are described to monitor the PDs of ITB. The most widely used method to assess spasticity is the Modified Ashworth Scale (MAS).27 It grades muscle tone on a scale
from 0 to 5 and has been proven to be a good indicator of effectiveness of ITB.28 However,
recently, the MAS has been criticized for its reliability and validity in measuring spasticity because it is unable to detect slight changes in spasticity.29 Other clinical tests, such as the
Penn Spasm Frequency Scale (measures the number of spontaneous spasms) and Reflex Scale (measures reflex intensity), are less often used and suffer from the same disadvantages as the MAS. More advanced neurophysiological tests (e.g. H-reflex and fiberglass casts) to measure spasticity are used only in research methodologies because of their complexity.21,30
Table 2 summarizes the human PD data of ITB.2,21,28,30-35 All data were assessed after lumbar
bolus injections and showed the latency of effect to be between 30 and 120 minutes. The maximal clinical effect of an ITB bolus demonstrated great variability, averaging between 4 and 6 hours. The duration of the effect varied from 6 to 8 hours after single boluses delivered in the lumbar area. During continuous ITB therapy, the baclofen is infused at a much slower rate, resulting in a longer latency of onset (6 – 8h) and a later maximum effect (12 – 24h).31
Table 2. Summar y of intrathecal baclof en phar macodynamic studies Study Cause Deliv er y (mo de) N Dose (μg) M easur emen t La tenc y of onset (hours) M aximum E ff ec t (hours) D ur ation of eff ec t (hours) Penn et al 2 SCI bolus 2 5 – 50 MA S <1 1 – 7 6 – 8 M uller et al 31 var ious bolus 30 50 – 500 SFS / M AS 1 1 – 12 8 – 48 continuous 25 Var ious SFS / M AS 6 – 8 12 – 24 NA Ziersk i et al 32 var ious bolus 44 10 – 300 SFS / M AS 1 – 2 NA 4 – 24 Albr ight et al 33 CP bolus 23 25 – 100 MA S <2 4 >8 var ious bolus 6 25 MA S <2 4 >8 50 MA S <2 8 >8 100 MA S <2 4 >8 Saller in-Caut e et al 20 var ious bolus 4 75 – 136 MA S 1 NA 9 – 16 M eythaler et al 34
traumatic brain injur
y bolus 11 50 MA S <1 4 6 M eythaler et al 28 str ok e bolus 22 50 MA S <1 6 >6 SFS <1 4 >6 RS <1 6 >6 Scheinber g et al 35 CP bolus 1 50 MA S 2 4 6 1 50 MA S 1 4 8 Pohl et al 30 CP bolus 13 100 Fibr eglass cast / M AS 0.5 – 1 3.5 – 4.5 2 – 8.5 Abbr eviations: CP , cer ebral palsy ; M AS, M odified A sh w or th S
cale; NA, not applicable; RS, R
eflex S
cale; SCI, spinal cor
d injur y; SFS, P enn Spasm F requenc y S cale;
TBI, traumatic brain injur
2
PK-PD modelingAn interesting approach to predict the clinical effect after ITB infusion is PKPD modeling. PKPD models connect drug concentrations to a particular clinical effect. A well-designed model is able to predict the time-effect profile after drug administration. However, because of the lack of adequate PKPD data on ITB, these models are not yet available.
DISCUSSION
Location of the catheter tip
An important clinical issue is the location of the catheter tip because it determines the center of the concentration gradient. The pig model demonstrated that continuous infusion at a low speed (40 µg/h) will spread no baclofen beyond a 5-cm distance of the catheter tip.11
Irrespective of this concentration gradient, it is clear that the highest concentration of ITB is found around the tip. Therefore, the tip of the catheter should ideally be located as close as possible to the targeted spinal cord level. Theoretically, it should be placed near the lumbar enlargement (Th11 – L1) for spasticity in the lower extremities and around the cervical enlargement (C3 – Th2) for spasticity in the upper extremities. There has been discussion about the optimal catheter tip location in patients who experience both upper- and lower-extremity spasticity. One study reported that increasing baclofen dosages infused from a lower position of the catheter tip (Th10) to provide an effect on spastic upper extremities, resulted in hypotonia of the lower extremities.36
Another option is to place the catheter tip at a midthoracic (Th6) level, which effectively decreased the upper-extremity spasticity without loss of effect on the lower extremities in patients with spasticity of both cerebral and spinal origin.37-39 Only 1 study directly compared
midthoracic (Th6 – 7) with lowthoracic (Th12) localization of the catheter tip placement and found a greater relief of spasticity of the upper extremities in patients with a midthoracic catheter tip without a loss of effect on the lower extremities.37 Midthoracic-infused baclofen
seems to achieve its effects on the lower extremities by reaching a sufficient concentration at the lower spinal levels. The alternative explanation might be a local inhibiting effect on the GABA-B receptors on the descending pyramidal axons. The concentration gradient of ITB is influenced by the pulsatile CSF movements, which are stronger at the rostral/midthoracic area than the caudal area of the spinal canal. Baclofen injected at a rostral level may therefore show an increased distribution compared with an injection at the lumbar level, possibly explaining the sufficient lumbar concentrations after midthoracic ITB infusion. Theoretically, this may also increase cerebral baclofen concentrations and associated side effects after midthoracic and lower cervical infusion of ITB; however, this has not been reported so far.40
It would be an interesting option to infuse baclofen at both the cervical and caudal enlargement using 2 catheters or a double lumen catheter; however, this is not possible with the currently available catheters.
Considering the importance of the catheter tip location on the effect of ITB, migration of the catheter tip should be ruled out in a patient demonstrating a sudden drop in clinical effect. Another concern is the formation of catheter tip granulomas in patients receiving chronic intrathecal infusions, especially opioids.41 This occurs less frequently in patients
who receive baclofen; however, a few cases have been reported in the literature.41,42
Because the formation of a mass around the catheter tip can alter the local CSF flow and drug distribution, this complication should also be considered if there is a sudden drop of response to ITB therapy. Furthermore, there have been no studies on the potential influence of other anatomic variations ( e.g. those because of postinfectious, posttraumatic, or postsurgery changes) that could affect the flow and concentration gradient of baclofen in the spinal canal.
Recently, intraventricular baclofen (IVB) infusion has been suggested as an alternative delivery route.43 In small case series, IVB appears to be as effective and to have similar complications
as ITB.44,45 It has been suggested that baclofen can increase GABA-B-mediated inhibition at
the premotor and supplementary motor cortex in patients with dystonia.46 IVB might also
play a role in the treatment of patients who suffered from multiple revisions. 45 However,
caution is needed because high cerebral concentrations of ITB might be associated with increased side effects. Furthermore, obstruction of CSF flow might induce regional toxic effects of ITB.45 Therefore, the role of IVB needs to be clarified in larger prospective studies,
especially because long term effects and safety are unknown.
Infusion mode
Altering the mode of infusion is perhaps the most important tool for clinicians to influence the distribution of ITB in spinal CSF. Most implantable ITB pumps offer the following three infusion modes.
Continuous infusion
The baclofen is infused at a constant speed. This is the initial infusion mode in most ITB patients. It takes about 5 times the half-life for a drug’s concentration to reach a steady state after infusion is started, which is approximately 24 hours for baclofen. Evaluation of dose changes should take place after steady-state concentrations have been reached. Although the steady-state concentration shows a positive correlation with daily ITB dose (figure 3), the strength of the correlation varies considerably between studies.20,22 One study in
2
children was not able to demonstrate a correlation between the steady-state concentration and dose after long-term ITB.23 However, in this study, CSF was sampled from the infusion
catheter, which is likely to influence the samples with baclofen from this catheter.
Figure 3. Results of 2 studies which measured the correlation between the daily continuous ITB dose and steady-state baclofen concentrations in the lumbar CSF after at least 24 hours of infusion.20,22
Flex-mode infusion
The baclofen is infused continuously but with varying speeds over the day, resulting in higher and lower dose periods. Flex mode is often used to tailor the ITB dose to periods of higher and lower spasticity during the day. However, one should bear in mind that switching between different infusion speeds will take several hours to reach a new steady-state concentration of ITB. This relatively long adaptation period limits the practical use of flex-mode infusion. Flex-mode infusion cannot be used effectively to lower daily ITB dose in tolerant patients (as subsequently shown).47
Bolus infusion
The baclofen dose is divided in a number of bolus doses, which are administered during the day. Because the ITB pump cannot be stopped completely, there is always a low basal rate of continuous infusion between the boluses. Based on the previously referred pig study, bolus infusion seems to achieve a better ITB distribution in the CSF of the spinal canal.11 This
distribution may deliver the ITB more effectively, leading to a lower daily ITB dose.48 The
optimal number of boluses per day has not been established so far. Four patients were previously described with tolerance to ITB and were switched to a 6 times per day bolus infusion regimen.48 The pump was programmed to deliver the lowest continuous dose
possible in between boluses (minimal infusion rate, 72 µg/d). The bolus dose was calculated as follows48:
bolus dose = (total daily dose - 10%) - minimal infusion rate
6
The total continuous daily dose was lowered by 10% to avoid high peak concentrations. Using this regimen, the ITB dose was stabilized in all 4 patients.48 Another study effectively
switched patients to a bolus regimen of 4 times per day (every 6h; basal rate, 4.6 µg/h) after they had shown a lack of response.49 With the currently available data, bolus infusion
regimens seem to offer the best chance to reduce tolerance.
Finally, it is important to gradually alter a daily ITB dose independent of the ITB infusion regimen. ITB therapy can trigger seizures, especially during the ITB test infusion.50-52 Seizures
have been associated with rapid dose changes, overdose, and withdrawal.36,51,52 Patients
with structural brain disease or multiple sclerosis seem to be more susceptible.51-53
Concentration and infusion speed
ITB concentration varies between 500 and 3000 µg/mL. Using higher concentrations is not recommended because pharmacy compounded baclofen at a concentration of 4000 µg/ mL has been shown to cause catheter tip masses caused by precipitation of baclofen.42
However, ITB concentrations also determine the speed of infusion. For some spinal anaesthetics it was demonstrated that a faster injection provided a better distribution.54
Although there is no evidence that this is true for ITB, this could be because of the greater kinetic energy imparted to the infusate, causing it to spread further away from the injection site.11 Because the CSF volume at the level of injection consists of only a few milliliters, a
small volume of the drug might already create local CSF flow. This theory might explain why bolus infusion achieves better distribution.11 The infusion speed has a negative correlation
with concentration if the same dose is administered. This implies that adjusting the concentration of ITB in the pump might change the clinical effect. A more variable infusion speed in future pumps could offer the clinician more control over ITB kinetics by increasing the distribution of a lower concentration of baclofen when the catheter tip is not located
2
immediately adjacent to the targeted spinal cord level. However, the limited volumes of the current ITB pumps (20 – 40 mL) would lead to shorter times between refills if lower concentrations of ITB are used. However, no published data support these hypotheses.
Baricity
Baclofen behaves as a hypobaric compound when infused into the CSF, causing it to distribute against gravity.14 Changing the baricity theoretically could offer a tool to influence
baclofen distribution. It has been tried in a pig model, where baclofen was mixed in saline containing 7.5% dextrose, making it hyperbaric to pig CSF.55 By using this hyperbaric drug
solution, caudal drug distribution was increased and rostral distribution decreased in pigs that were placed in an upright position.55 This study supports the idea that drug distribution
might be either increased or decreased by the use of a hyperbaric solution, depending on the position of the subject. However, the possible influence of baricity is not used in humans so far.
Tolerance
The development of tolerance is a problem during long-term ITB therapy.56,57 Although
definitions of tolerance vary between studies, it is reported to occur in 1% to 20% of all ITB patients.3,47,57-59 Tolerance is defined as an escalation of the dose required to produce a
previously obtained effect or by a decreasing effect produced by the same given dose of the drug.60 It is associated with a return of spasticity and increased side effects. Increases in
the ITB dose during the first 12 to 18 months of ITB therapy should be considered a result of careful individual dose titration, associated in part to a reduction of other oral antispasticity medications. This should not be diagnosed as tolerance.48,57,59,61 Tolerance in ITB therapy is
thought to be induced by a reduction in the total number of GABA-B-receptors62 and by
pre- and postsynaptic desensitization of the remaining GABA-B receptors after prolonged ITB administration.63 It has been demonstrated that the G-protein coupled kinases 4 and 5
desensitize GABA-B-receptor mediated responses by forming protein complexes with one of the two GABA-B-receptor subunits (type 1) and the plasma membranes.64
Tolerance should be considered after exclusion of other causes of reduced drug effectiveness, such as technical problems with the delivery system (pump, catheter), improper drug composition, and progression of the underlying disease. Tolerance in ITB therapy has been treated by drug holidays. During these drug holidays, varying from a few days up to 2 months, ITB therapy was lowered or stopped. The patient was then treated with another antispasticity medication, usually intrathecal morphine (0.25 – 2 mg/d).3,56,65,66 Although the
exact mechanism is unclear, the GABA-B-receptors are thought to resensitize during the absence of baclofen. As a result, ITB therapy may be restarted at a lower (30% - 80%) dose than
before the drug holiday; however, a dose increase may reappear because of new receptor desensitization.3,56,65,66 During a drug holiday, the patient has to be monitored carefully
because abrupt withdrawal of baclofen may cause a baclofen withdrawal syndrome with serious complications, which make drug holidays not the preferred therapy for the treatment of tolerance.67 In patients with baclofen withdrawal syndrome it is essential to restore
GABA-mimetic drugs, either by restoring ITB administration or by infusion of benzodiazepines.67
Treatment with oral cyproheptadine, a serotonin antagonist, has been shown to be a useful adjunct in the management of baclofen withdrawal syndrome, possibly because baclofen withdrawal syndrome shows similarities with acute serotonin syndrome.68 As previously
discussed, switching the pump from continuous to bolus infusion mode appears to be a promising method to treat ITB tolerance.48 Although switching a patient from continuous
to bolus infusion has not been reported to cause baclofen withdrawal syndrome so far, it remains important to monitor the patient carefully.
Study limitations
This article reviews all available PK and PD data on ITB. However, the number of studies is limited, especially on human ITB PK data. Furthermore, most studies have considerable differences in study protocols, which make it difficult to compare the studies. Animal studies can be used to fill this gap of knowledge, especially because of the practical and ethical limitations related to CSF sampling in humans. Animal studies need to be considered with care because they cannot be directly compared with humans because of differences in anatomy and physiology. Hopefully, a radiotracer with ITB will be developed in the near future, which would offer clinicians a safer and easier tool to gather in vivo information about ITB distribution in humans.
Conclusion
In the 2 decades after the introduction of ITB therapy, most of the research has focused on its efficacy and safety in multiple indications. With an increasing number of patients being treated with ITB therapy, research needs to deepen our basic understanding of this effective therapy. Future research should produce more human PKPD data on ITB and a better understanding of normative ITB distribution and its spinal concentration gradient. The hardware of ITB pumps should be improved, focusing on a higher degree of customization (e.g. with a variable bolus infusion rate). Furthermore, double lumen catheters with the possibility to deliver ITB at different spinal levels would be an interesting tool as well. Improved insight into the basics of ITB therapy, especially the relation between PK and PD of ITB, would also improve the short- and long-term outcomes of ITB treatment. Future
2
research should also focus on the promising effects of bolus infusion of ITB. It would be interesting to compare bolus infusions with continuous infusion in a randomized controlled trial, looking for differences in the incidence of tolerance between these 2 regimens.
Overall, ITB has been proven to be efficacious in the treatment of severe spasticity. More insight into the PKs and PDs of ITB is necessary to improve its applicability in clinical practice.
REFERENCES
1. Meythaler JM, Clayton W, Davis LK, Guin-Renfroe S, Brunner RC. Orally delivered baclofen to control spastic hypertonia in acquired brain injury. J Head Trauma Rehabil 2004;19:101-8. 2. Penn RD, Kroin JS. Intrathecal baclofen alleviates spinal cord spasticity. Lancet 1984;1:1078. 3. Coffey JR, Cahill D, Steers W, et al. Intrathecal baclofen for intractable spasticity of spinal origin:
results of a long-term multicenter study. J Neurosurg 1993;78:226-32.
4. Azouvi P, Mane M, Thiebaut JB, Denys P, Remy-Neris O, Bussel B. Intrathecal baclofen administration for control of severe spinal spasticity: functional improvement and long-term follow-up. Arch Phys Med Rehabil 1996;77:35-9.
5. Albright AL, Gilmartin R, Swift D, Krach LE, Ivanhoe CB, McLaughlin JF. Long-term intrathecal baclofen therapy for severe spasticity of cerebral origin. J Neurosurg 2003;98:291-5.
6. Edsbagge M, Starck G, Zetterberg H, Ziegelitz D, Wikkelso C. Spinal cerebrospinal fluid volume in healthy elderly individuals. Clin Anat 2011;24:733-40.
7. Edsbagge M, Tisell M, Jacobsson L, Wikkelso C. Spinal CSF absorption in healthy individuals. Am J Physiol Regul Integr Comp Physiol 2004;287:R1450-5.
8. Grant R, Condon B, Lawrence A, et al. Human cranial CSF volumes measured by MRI: sex and age influences. Magn Reson Imaging 1987;5:465-8.
9. Linninger AA, Xenos M, Sweetman B, Ponkshe S, Guo X, Penn R. A mathematical model of blood, cerebrospinal fluid and brain dynamics. J Math Biol 2009;59:729-59.
10. Nakamura K, Urayama K, Hoshino Y. Lumbar cerebrospinal fluid pulse wave rising from pulsations of both the spinal cord and the brain in humans. Spinal Cord 1997;35:735-9.
11. Bernards CM. Cerebrospinal fluid and spinal cord distribution of baclofen and bupivacaine during slow intrathecal infusion in pigs. Anesthesiology 2006;105:169-78.
12. Bozanovic-Sosic R, Mollanji R, Johnston MG. Spinal and cranial contributions to total cerebrospinal fluid transport. Am J Physiol Regul Integr Comp Physiol 2001;281:R909-16.
13. Kido DK, Gomez DG, Pavese AM Jr, Potts DG. Human spinal arachnoid villi and granulations. Neuroradiology 1976;11:221-8.
14. Hejtmanek MR, Harvey TD, Bernards CM. Measured density and calculated baricity of custom-compounded drugs for chronic intrathecal infusion. Reg Anesth Pain Med 2011;36:7-11. 15. Nielsen JB, Crone C, Hultborn H. The spinal pathophysiology of spasticityefrom a basic science
point of view. Acta Physiol (Oxf ) 2007;189:171-80.
16. Li Y, Li X, Harvey PJ, Bennett DJ. Effects of baclofen on spinal reflexes and persistent inward currents in motoneurons of chronic spinal rats with spasticity. J Neurophysiol 2004;92:2694-703. 17. Yang K, Wang D, Li YQ. Distribution and depression of the GABA(B) receptor in the spinal dorsal
horn of adult rat. Brain Res Bull 2001;55:479-85.
18. Olpe HR, Demieville H, Baltzer V, et al. The biological activity of dand l-baclofen (Lioresal). Eur J Pharmacol 1978;52:133-6.
2
19. Mandema JW, Heijligers-Feijen CD, Tukker E, De Boer AG, Danhof M. Modeling of the effect siteequilibration kinetics and pharmacodynamics of racemic baclofen and its enantiomers using quantitative EEG effect measures. J Pharmacol Exp Ther 1992;261: 88-95.
20. Muller H, Zierski J, Dralle D, Krauß D, Mutschler E. Pharmacokinetics of intrathecal baclofen. In: Muller H, Zierski J, Penn RD, editors. Local spinal therapy of spasticity. Berlin: Springer-Verlag; 1988. p 223-6.
21. Sallerin-Caute B, Lazorthes Y, Monsarrat B, Cros J, Bastide R. CSF baclofen levels after intrathecal administration in severe spasticity. Eur J Clin Pharmacol 1991;40:363-5.
22. Kroin JS, Penn RD. Cerebrospinal fluid pharmacokinetics of lumbar intrathecal baclofen. In: Lakke JPWF, Delhaas EM, Rutgers AWF, editors. Parenteral drug therapy in spasticity and Parkinson’s disease. Carnforth (UK): Parthenon Publishing; 1992. p 67-78.
23. Albright AL, Thompson K, Carlos S, Minnigh MB. Cerebrospinal fluid baclofen concentrations in patients undergoing continuous intrathecal baclofen therapy. Dev Med Child Neurol 2007;49:423-5.
24. Knutsson E, Lindblom U, Martensson A. Plasma and cerebrospinal fluid levels of baclofen (Lioresal) at optimal therapeutic responses in spastic paresis. J Neurol Sci 1974;23:473-84. 25. Rubin RC, Henderson ES, Ommaya AK, Walker MD, Rall DP. The production of cerebrospinal fluid
in man and its modification by acetazolamide. J Neurosurg 1966;25:430-6.
26. Leisen C, Langguth P, Herbert B, Dressler C, Koggel A, Spahn- Langguth H. Lipophilicities of baclofen ester prodrugs correlate with affinities to the ATP-dependent efflux pump P-glycoprotein: relevance for their permeation across the blood-brain barrier? Pharm Res 2003;20:772-8.
27. Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther 1987;67:206-7.
28. Meythaler JM, Guin-Renfroe S, Brunner RC, Hadley MN. Intrathecal baclofen for spastic hypertonia from stroke. Stroke 2001;32: 2099-109.
29. Fleuren JF, Voerman GE, Erren-Wolters CV, et al. Stop using the Ashworth Scale for the assessment of spasticity. J Neurol Neurosurg Psychiatry 2010;81:46-52.
30. Pohl M, Rockstroh G, Ruckriem S, et al. Time course of the effect of a bolus dose of intrathecal baclofen on severe cerebral spasticity. J Neurol 2003;250:1195-200.
31. Muller H, Zierski J, Dralle D, Hoffmann O, Michaelis G. Intrathecal baclofen in spasticity. In: Muller H, Zierski J, Penn RD, editors. Local spinal therapy of spasticity. Berlin: Springer-Verlag; 1988. p 155-214.
32. Zierski J, Muller H, Dralle D, Wurdinger T. Implanted pump systems for treatment of spasticity. Acta Neurochir Suppl (Wien) 1988; 43:94-9.
33. Albright AL, Cervi A, Singletary J. Intrathecal baclofen for spasticity in cerebral palsy. JAMA 1991;265:1418-22.
34. Meythaler JM, DeVivo MJ, Hadley M. Prospective study on the use of bolus intrathecal baclofen for spastic hypertonia due to acquired brain injury. Arch Phys Med Rehabil 1996;77:461-6. 35. Scheinberg A, O’Flaherty S, Chaseling R, Dexter M. Continuous intrathecal baclofen infusion for
children with cerebral palsy: a pilot study. J Paediatr Child Health 2001;37:283-8.
36. Meythaler JM, Steers WD, Tuel SM, Cross LL, Haworth CS. Continuous intrathecal baclofen in spinal cord spasticity. A prospective study. Am J Phys Med Rehabil 1992;71:321-7.
37. Grabb PA, Guin-Renfroe S, Meythaler JM. Midthoracic catheter tip placement for intrathecal baclofen administration in children with quadriparetic spasticity. Neurosurgery 1999;45:833-6. 38. Meythaler JM, McCary A, Hadley MN. Prospective assessment of continuous intrathecal infusion
of baclofen for spasticity caused by acquired brain injury: a preliminary report. J Neurosurg 1997;87: 415-9.
39. Burns AS, Meythaler JM. Intrathecal baclofen in tetraplegia of spinal origin: efficacy for upper extremity hypertonia. Spinal Cord 2001;39: 413-9.
40. McCall TD, MacDonald JD. Cervical catheter tip placement for intrathecal baclofen administration. Neurosurgery 2006;59:634-40.
41. Coffey RJ, Burchiel K. Inflammatory mass lesions associated with intrathecal drug infusion catheters: report and observations on 41 patients. Neurosurgery 2002;50:78-86.
42. Deer TR, Raso LJ, Coffey RJ, Allen JW. Intrathecal baclofen and catheter tip inflammatory mass lesions (granulomas): a reevaluation of case reports and imaging findings in light of experimental, clinicopathological, and radiological evidence. Pain Med 2008;9:391-5.
43. Albright AL, Ferson SS. Intraventricular baclofen for dystonia: techniques and outcomes. Clinical article. J Neurosurg Pediatr 2009; 3:11-4.
44. Rocque BG, Albright AL. Intraventricular versus intrathecal baclofen for secondary dystonia: a comparison of complications. Neurosurgery 2012;70(2 Suppl Operative):321-5. discussion 325-6. 45. Turner M, Nguyen HS, Cohen-Gadol AA. Intraventricular baclofen as an alternative to intrathecal
baclofen for intractable spasticity or dystonia: outcomes and technical considerations. J Neurosurg Pediatr 2012;10:315-9.
46. Siebner HR, Dressnandt J, Auer C, Conrad B. Continuous intrathecal baclofen infusions induced a marked increase of the transcranially evoked silent period in a patient with generalized dystonia. Muscle Nerve 1998;21:1209-12.
47. Heetla HW, Staal MJ, Kliphuis C, van Laar T. The incidence and management of tolerance in intrathecal baclofen therapy. Spinal Cord 2009;47:751-6.
48. Heetla HW, Staal MJ, van Laar T. Tolerance to continuous intrathecal baclofen infusion can be reversed by pulsatile bolus infusion. Spinal Cord 2010;48:483-6.
49. Schiess M, Oh I, Stimming E, et al. Prospective 12-month study of intrathecal baclofen therapy for poststroke spastic upper and lower extremity motor control and functional improvement. Neuromodulation 2011;14:38-45.
2
50. Meythaler JM, Guin-Renfroe S, Law C, Grabb P, Hadley MN. Continuously infused intrathecalbaclofen over 12 months for spastic hypertonia in adolescents and adults with cerebral palsy. Arch Phys Med Rehabil 2001;82:155-61.
51. D’Aleo G, Rifici C, Kofler M, Sessa E, Saltuari L, Bramanti P. Seizure after intrathecal baclofen bolus in a multiple sclerosis patient treated with oxcarbazepine. Neurol Sci 2011;32:293-5.
52. Schuele SU, Kellinghaus C, Shook SJ, Boulis N, Bethoux FA, Loddenkemper T. Incidence of seizures in patients with multiple sclerosis treated with intrathecal baclofen. Neurology 2005;64: 1086-7. 53. Kofler M, Kronenberg MF, Rifici C, Saltuari L, Bauer G. Epileptic seizures associated with intrathecal
baclofen application. Neurology 1994;44:25-7.
54. Hocking G, Wildsmith JA. Intrathecal drug spread. Br J Anaesth 2004;93:568-78.
55. Flack SH, Bernards CM. Cerebrospinal fluid and spinal cord distribution of hyperbaric bupivacaine and baclofen during slow intrathecal infusion in pigs. Anesthesiology 2010;112:165-73. 56. Abel NA, Smith RA. Intrathecal baclofen for treatment of intractable spinal spasticity. Arch Phys
Med Rehabil 1994;75:54-8.
57. Akman MN, Loubser PG, Donovan WH, O’Neill ME, Rossi CD. Intrathecal baclofen: does tolerance occur? Paraplegia 1993;31: 516-20.
58. Dario A, Scamoni C, Picano M, Casagrande F, Tomei G. Pharmacological complications of the chronic baclofen infusion in the severe spinal spasticity. Personal experience and review of the literature. J Neurosurg Sci 2004;48:177-81.
59. Koulousakis A, Kuchta J. Intrathecal antispastic drug application with implantable pumps: results of a 10 year follow-up study. Acta Neurochir Suppl 2007;97:181-4.
60. Stevens CW, Yaksh TL. Potency of infused spinal antinociceptive agents is inversely related to magnitude of tolerance after continuous infusion. J Pharmacol Exp Ther 1989;250:1-8.
61. Nielsen JF, Hansen HJ, Sunde N, Christensen JJ. Evidence of tolerance to baclofen in treatment of severe spasticity with intrathecal baclofen. Clin Neurol Neurosurg 2002;104:142-5.
62. Kroin JS, Bianchi GD, Penn RD. Intrathecal baclofen down-regulates GABAB receptors in the rat substantia gelatinosa. J Neurosurg 1993; 79:544-9.
63. Wetherington JP, Lambert NA. GABA(B) receptor activation desensitizes postsynaptic GABA(B) and A(1) adenosine responses in rat hippocampal neurones. J Physiol 2002;544:459-67.
64. Kanaide M, Uezono Y, Matsumoto M, et al. Desensitization of GABA(B) receptor signaling by formation of protein complexes of GABA(B2) subunit with GRK4 or GRK5. J Cell Physiol 2007;210: 237-45. 65. Vidal J, Gregori P, Guevara D, Portell E, Valles M. Efficacy of intrathecal morphine in the treatment
of baclofen tolerance in a patient on intrathecal baclofen therapy (ITB). Spinal Cord 2004;42:50-1. 66. Plassat R, Perrouin Verbe B, Menei P, Menegalli D, Mathe JF, Richard I. Treatment of spasticity
with intrathecal baclofen administration: long-term follow-up, review of 40 patients. Spinal Cord 2004;42:686-93.
67. Coffey RJ, Edgar TS, Francisco GE, et al. Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome. Arch Phys Med Rehabil 2002;83:735-41.
68. Meythaler JM, Roper JF, Brunner RC. Cyproheptadine for intrathecal baclofen withdrawal. Arch Phys Med Rehabil 2003;84:638-42.
