Pharmacokinetics and pharmacodynamics of intrathecal baclofen therapy
Heetla, Herre Wigger
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of Intrathecal Baclofen Therapy
P R O E F S C H R I F T
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op maandag 26 maart 2018 om 16.15 uur
door
Herre Wigger Heetla geboren op 20 mei 1982
Prof. dr. R.J.M. Groen Prof. dr. M.J. Staal † Copromotor Dr. J.H. Proost Beoordelingscommissie Prof. dr. J.H.B. Geertzen Prof. dr. S.M. Peerdeman Prof. dr. J.M.A. van Gerven
Chapter 1. General introduction and outline 9
Chapter 2. Clinical relevance of pharmacological and physiological data in intrathecal baclofen therapy
Archives of Physical Medicine and Rehabilitation (2014), 95: 2199-2206
23
Chapter 3. Incidence and management of tolerance in intrathecal baclofen therapy
Spinal Cord (2009), 47: 751–756
47
Chapter 4. Tolerance to continuous intrathecal baclofen infusion can be reversed by pulsatile bolus infusion
Spinal Cord (2010), 48: 483–486
63
Chapter 5. A pharmacokinetic–pharmacodynamic model for intrathecal baclofen in patients with severe spasticity
British Journal of Clinical Pharmacology (2015), 81:1: 101–112
75
Chapter 6. Improved gait performance in a patient with HSP after a continuous ITB test infusion and subsequent pump implantation
Archives of Physical Medicine and Rehabilitation (2015), 96: 1166-9
103
Chapter 7. The usefulness of qualitative and quantitative tests in measuring the effect of a continuous ITB test-infusion in ambulatory patients with spasticity
Submitted for publication
113
Chapter 8. Summary and discussion 127
Chapter 9. Nederlandse samenvatting 141
Appendices List of abbreviations Dankwoord Curriculum vitae List of publications 151 153 155 157
General introduction and outline
1
INTRODUCTION
Spasticity is derived from the Greek word spasticos (σπαστικός) and spaon (σπάω, to draw out, stretch).1 The term was first used by Good in 1829 to describe excessive muscular
action.1 However, the most commonly used definition of spasticity is from Lance:
“Spasticity is a motor disorder characterized by a velocity dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyper-excitability of the stretch reflex as one component of the upper motor neuron syndrome.” 2
This definition describes spasticity as one of the symptoms of the upper motor neuron (UMN) syndrome. The UMN syndrome is caused by a disruption of the descending motor pathways (the UMN) between the motor cortex and the spinal cord. These pathways control the spinal reflexes, which become hyperactive after a lesion to the UMN.3 The
UMN syndrome results in negative and positive symptoms. The negative symptoms are characterized by muscle weakness (paresis), loss of dexterity, and fatigability.4 The positive
symptoms are characterized by spasticity, hyperactive tendon reflexes, clonus and flexor spasms.4 The symptoms do not always occur in combination and depend on the site and
nature of the lesion.
Recently the definition by Lance has been criticized, being too narrow and it was suggested that spasticity should be used as an umbrella term for all positive symptoms of the UMN syndrome.5 In this thesis however, the classical definition of Lance is used.
Pathophysiology of spasticity
A spinal reflex is the interaction between an afferent sensory neuron to an efferent motor neuron within the spinal cord. The sensory neurons detect change (e.g. in muscle length) and transmit this signal to the motor neurons, which respond with muscle contraction. Spinal reflexes are under supraspinal control by the pre- and primary motor cortex, by means of the pyramidal and parapyramidal fibers. The pyramidal fibers (the corticospinal tract) are involved in voluntary movement. The parapyramidal fibers have an inhibitory and excitatory control on spinal reflexes. The main inhibitory tract is the dorsal reticulospinal tract, which is under facilitary control from the motor cortex. The main excitatory tract is the medial reticulospinal tract.3
The UMN syndrome results from lesions to pyramidal and especially parapyramidal fibers. Isolated lesions to the pyramidal tract do not often result in spasticity, but only in a reduction in muscle tone and reflexes.3 Spasticity arises when the parapyramidal fibers
cortex, or to the dorsal reticulospinal tract in the spinal cord.3 The loss of inhibitory control
leads to hyperactive spinal reflexes, accounting for most of the positive UMN symptoms.6
After the loss of supraspinal control, secondary changes at cellular level in the spinal cord below the lesion further contribute to hyperactivity of the spinal reflexes.7 The hyperactive
reflexes are the result of (a) an increased gain in the stretch reflex networks (i.e. from a given sensory input, the motor response is greater), and (b) a decreased threshold in the stretch receptors (i.e. the stretch reflex can be triggered with a smaller stimulus).5
Symptoms of upper motor neuron pathology
The symptoms and severity of the UMN syndrome depend on both the site and the nature of the lesion. In the next paragraph spasticity and other positive symptoms of the UMN syndrome will be reviewed.
Spasticity is a form of hypertonia. Hypertonia is defined as an abnormally increased
resistance to muscle stretch. Spasticity is characterized by a velocity dependent hypertonia. This means the hypertonia increases with the speed of movement, which is the result of the hyper-excitability of the stretch reflex. It should be distinguished from hypertonia due to dystonia and rigidity, which are not velocity dependent and are caused by lesions of the basal ganglia.8 During physical examination of patients with spasticity, there is a direct
relationship between the speed of stretching the muscle and the magnitude of resistance. Spasticity causes invalidating movements, especially if spasticity occurs in combination with other UMN symptoms, like muscle weakness. Spasticity may also result in a continued shortened position of muscles, which in turn may result into secondary soft tissue changes and contractures.4, 6 Spasticity can be painful, especially if it results in a permanent state of
flexion, which may give rise to contractures.4
Disinhibition of existing spinal reflexes causes flexor- and extensor spasms, which are disinhibited normal reflexes, like the withdrawal reflex after painful stimuli.6 However, in
patients with an UMN syndrome, very small stimuli (e.g. passive movements or touching the skin) may already cause these spasms. Damage of the UMN may also result in primitive
reflexes. These primitive reflexes (such as the Babinski sign) normally disappear during the
first year of life, but may return, for instance as a symptom of lesions in the UMN.6
Another phenomenon belonging to UMN pathology is clonus. Clonus consists of a series of involuntary rhythmic muscular contractions and relaxations, mostly seen in the ankle, which is also caused by disinhibition of spinal reflexes.
1
The clasp knife phenomenon is a clinical sign which appears if spastic muscles are beingstretched. It is characterized by an increased muscle tone in either flexion or extension, with sudden relaxation as the muscle continues to be stretched repetitively. This phenomenon is based on the fact that spasticity is not only velocity dependent, but also length dependent.6
The initial hypertonia slows down the movement. Due to the slowing movement and the lengthening of the muscles, hypertonia may disappear suddenly.
Epidemiology of spasticity
Spasticity is related to disorders affecting the (para)pyramidal system. The damage may be acute, due to stroke, spinal cord injury (SCI), traumatic brain injury (TBI) or cerebral palsy (CP), or may be progressive over a number of years, like multiple sclerosis (MS) or hereditary spasticity. The incidence of spasticity in these various disorders is variable. Spasticity appears in more than 34-80% of all patients with MS9, 10, in 65-78% of patients with SCI11, and in
20-38% of patients suffering from a stroke.12, 13
The burden for the patient
The different symptoms of spasticity may cause a wide range of functional problems, which may have a negative influence on the various activities of daily living.12 Spasticity of the lower
extremities has a large impact on mobility, such as walking and making transfers.4 Spasticity
of the upper extremities may cause difficulties with feeding and self-care. Inactivity due to spasticity may lead to decubitus and or contractures. Involuntary movements, spasms and hypertonia might disturb sleep, or might cause pain and difficulties in daily care. Adductor spasms f.i. frequently cause problems with the handling of urinary catheters and may prevent putting on pants.4
Treatment of spasticity
It is important to pay attention to the prevention of trigger factors for spasticity (f.i. pain, infections and constipation) in all patients with spasticity.9 Other non-pharmacological
treatments consist of physical therapy, such as stretching, and repetitive transcranial magnetic stimulation, a non-invasive therapy stimulating the cerebral cortex by means of electromagnetic induction.14 Stretching of affected muscles is thought to prevent
contractures, although its effect has been questioned with respect to the long term-consequences.15, 16
Pharmacological treatments can be categorized in central and local acting agents. Central acting agents consist of different oral spasmolytics, mostly used for generalized spasticity. Oral baclofen was the first effective drug for spasticity and still is the most widely used treatment option, followed by tizanidine and gabapentin.9
Local acting agents can be injected into isolated muscles or nerves, to achieve a local effect. The most commonly used agent is Botulinum toxin, a reversible treatment, with a duration of effect of several weeks to months.9 Phenol or alcohol injections, leading to axonal
damage, and surgical interventions are other less frequently used focal therapies.9, 17
Intrathecal baclofen therapy
Baclofen is a potent gamma-aminobutyric acid (GABA)-B agonist and binds to the GABA-B receptors in the dorsal root ganglion and the spinal grey matter.18, 19 Baclofen seems to
achieve its effect by the increase of GABA activity, leading to a reduction of the stretch reflex in patients with spasticity.19 Although baclofen acts on the central nervous system
(CNS), its concentration in the cerebrospinal fluid (CSF) after oral administration is very low, because baclofen does not cross the blood-brain barrier effectively.20 In 1984, Penn and
Kroin bypassed the blood-brain barrier by injecting baclofen directly into the CSF, using
a subcutaneous programmable pump connected to an intrathecal lumbar drain.21 This
intrathecal baclofen (ITB) therapy resulted in an improved effect and much higher baclofen concentrations in the CSF, as compared to oral baclofen therapy (25 – 100 mg), with a fraction of the oral dose (50 – 1000 µg).22 ITB is a local therapy and has less side-effects as
compared to (systemic) oral baclofen, which may induce drowsiness and sleepiness, related to its inhibitory effects on the CNS.23 Since its introduction in 1984, ITB has shown good
efficacy in patients with spasticity.24-26
Indications for ITB therapy
In the past three decades, ITB therapy has shown to be effective for spasticity of both spinal and cerebral origin, not responding to oral spasmolytics.27, 28 A survey of more than 1000 ITB
pump implantations showed the following underlying diseases: CP 44%, SCI 22%, TBI 9%, anoxic brain injury 3% and other pathologies, including MS, 22%.29 ITB has also shown to
be effective in treating generalized dystonia30, hereditary spasticity31 and spasticity due to
stroke.32
Candidates for ITB therapy can be divided into ambulatory and non-ambulatory patients. Ambulatory patients still have the ability to walk (with or without assistive devices). Non-ambulatory patients lost the functional ability of their legs and are often bedridden or confined to a wheelchair. In both groups a reduction of spasticity is the main goal of ITB therapy. In the ambulatory patient group ITB therapy may also result in functional improvement.33
1
ITB test-infusionITB therapy is considered if oral spasmolytics have limited efficacy and/or too much side effects.9 The implantation of an ITB pump for spasticity and the related hospitalization is
costly, but has proven to be cost-effective in patients who do not respond to less invasive treatments.34, 35 It is recommended that possible candidates initially receive a test-infusion
prior to implantation, to evaluate the effect and tolerability of ITB.36, 37 A test-infusion can
also help to manage expectations of the patient and their caregivers.36, 38
The ITB test-infusion is performed during a hospital admission of several days, using an external intrathecal catheter to administer test doses of baclofen. Clinical effects and possible adverse events are closely monitored during this period. ITB is mostly administered as a 25 – 100 µg bolus, which provides an effect for several hours.22, 39 Continuous
test-infusion can be used to titrate the optimal dose more precisely, for instance in ambulatory patients with a narrow therapeutic window in between a decrease of muscle tone and functional gain.40
ITB pump implantation
A successful test-infusion normally leads to implantation of a permanent subcutaneous ITB pump-system. Surgery is performed under general anesthesia. During surgery a one- or two-piece spinal catheter is introduced in the spinal canal via a Tuohy-needle, usually at mid lumbar level, in the midline.24 The tip of the infusion catheter is usually positioned near
the 10th thoracic vertebra (Th10), close to the spinal cord segments of the lower limbs. The
distal end of the catheter is subcutaneously connected to a programmable pump, which is positioned in a subcutaneous pocket in the abdominal wall.24 Postoperative complications
can be divided into wound-related and device-related complications. Wound infections occur with a frequency varying from 3 to 41% and occur more frequently in children as compared to adults.41, 42 Catheter complications (dislocation, fracture, disconnection) are
the most common device-related complications with an incidence of 10 – 40%.42-44
After ITB pump implantation the patient will be controlled with regular intervals, mostly once every 3 months, to evaluate the effect of ITB and to check and/or adapt the pump settings. The initial ITB infusion rate per day is based on the optimal dose determined during test-infusion.24 Dose alterations can be made using a Personal Digital Assistant (PDA) with
a wireless connection to the implanted ITB pump. Every 2-3 months the pump needs to be refilled with baclofen using a special sterile needle. The average life time of the pump battery is 4-5 years, after which the device needs to be replaced.45
Unsolved problems and unmet needs
Since its introduction in 1984, ITB has proven to be a potent and effective therapy, able to treat severe spasticity from various causes. A number of studies has shown its indications, clinical effect and safety.24-26 Over the years an increasing number of patients with severe
spasticity, dependent from ITB, have shown an increasing amount of clinical problems, especially related to maintaining the beneficial effect on the long-term.
One of these problems is the unexplained ITB dose increase over time in some patients. Most patients show a gradual increase of the ITB dose over the year(s) after pump implantation, before finally reaching a stable level of infusion.46 However, some patients show a very
rapid increase of the baclofen dose, to maintain a satisfactory clinical response.47 This
phenomenon is known as tolerance.48 Although tolerance has been described previously
in ITB, its etiology and management has not been studied in more detail so far. In clinical practice, ITB infusion regimens are just adapted based on clinical experience. Until now, there is no evidence-based pharmacological guideline to structure the infusion regimens of ITB infusion.49
Irrespective the known efficacy, little is known about the mechanism of action, the pharmacokinetics (PK; how is baclofen spread over the body ) and the pharmacodynamics (PD; how does the body react to baclofen) of ITB therapy. The general lack of pharmacokinetic-pharmacodynamic (PKPD) data of ITB therapy is caused by the difficulty of collecting CSF samples with baclofen in humans. A better knowledge of the PKPD of ITB would improve the understanding and management of dosing problems with ITB, including the issues of drug tolerance.
Finally, another important puzzle is the application of ITB in ambulatory patients. Studies on the effect of ITB on ambulatory function in patients with spasticity, still able to walk, showed mixed results.33, 40, 50, 51 These variable data have restricted the use of ITB in ambulatory
patients with spasticity, which could be a missed opportunity to improve functional abilities in these patients.40, 51 Therefore, more data are needed to get a better understanding of the
1
AIMS AND OUTLINE OF THE THESIS
The primary aim of this thesis is to investigate and describe the pharmacology of ITB, collecting human pharmacokinetic (PK) and pharmacodynamic (PD) data.
The secondary aim is to evaluate the efficacy of ITB in ambulatory patients, focusing on how to measure the effect on various clinical domains, like spasticity, strength and ambulatory function.
The current state of knowledge on the pharmacology of ITB therapy is reviewed in chapter 2. Since there were no data on the incidence of tolerance in the ITB population, the medical records of all patients treated with ITB therapy between 1991-2005 in the University Medical Center Groningen (UMCG) were reviewed. The results of this review are reported in chapter 3, addressing both the details about tolerance, and the different regimens that were used to overcome baclofen tolerance. The hypothesis that pulsatile bolus infusion could be effective in lowering the daily ITB dose in patients with tolerance was studied and presented in chapter 4. In chapter 5 the sampling of PK and PD data after an ITB test-infusion is described. These data were used to develop the first PKPD model for intrathecal baclofen in humans. In chapter 6 the possible benefit of ITB in ambulatory patients is illustrated, as we describe the effect of ITB-therapy on gait performance during the test-infusion and after pump-implantation in a patient with hereditary spasticity. The objective of the study presented in chapter 7 was to determine which qualitative and quantitative tests on the domains of spasticity, strength, ambulatory function and the patient’s personal impression are useful in measuring the effect of a continuous ITB test-infusion in ambulatory patients with spasticity. In chapter 8 the thesis is summarized and discussed.
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28. McIntyre A, Mays R, Mehta S, Janzen S, Townson A, Hsieh J, et al. Examining the effectiveness of intrathecal baclofen on spasticity in individuals with chronic spinal cord injury: A systematic review. J Spinal Cord Med. 2014 Jan;37(1):11-8.
29. Stempien L, Tsai T. Intrathecal baclofen pump use for spasticity: A clinical survey. Am J Phys Med Rehabil. 2000 Nov-Dec;79(6):536-41.
30. Albright AL, Barry MJ, Shafton DH, Ferson SS. Intrathecal baclofen for generalized dystonia. Dev Med Child Neurol. 2001 Oct;43(10):652-7.
31. Dan B, Cheron G. Intrathecal baclofen normalizes motor strategy for squatting in familial spastic paraplegia: A case study. Neurophysiol Clin. 2000 Feb;30(1):43-8.
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34. Postma TJ, Oenema D, Terpstra S, Bouma J, Kuipers-Upmeijer H, Staal MJ, et al. Cost analysis of the treatment of severe spinal spasticity with a continuous intrathecal baclofen infusion system. Pharmacoeconomics. 1999 Apr;15(4):395-404.
35. Sampson FC, Hayward A, Evans G, Morton R, Collett B. Functional benefits and cost/benefit analysis of continuous intrathecal baclofen infusion for the management of severe spasticity. J Neurosurg. 2002 Jun;96(6):1052-7.
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37. Albright AL. Intrathecal baclofen for childhood hypertonia. Childs Nerv Syst. 2007 Sep;23(9):971-9.
38. Boster AL, Bennett SE, Bilsky GS, Gudesblatt M, Koelbel SF, McManus M, et al. Best practices for intrathecal baclofen therapy: Screening test. Neuromodulation. 2016 Aug;19(6):616-22.
39. 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(4):363-5.
40. Phillips MM, Miljkovic N, Ramos-Lamboy M, Moossy JJ, Horton J, Buhari AM, et al. Clinical experience with continuous intrathecal baclofen trials prior to pump implantation. PM R. 2015 Oct;7(10):1052-8.
41. Haranhalli N, Anand D, Wisoff JH, Harter DH, Weiner HL, Blate M, et al. Intrathecal baclofen therapy: Complication avoidance and management. Childs Nerv Syst. 2011 Mar;27(3):421-7. 42. Vender JR, Hester S, Waller JL, Rekito A, Lee MR. Identification and management of intrathecal
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1
47. Sahuquillo J, Muxi T, Noguer M, Jodar R, Closa C, Rubio E, et al. Intraspinal baclofen in the treatment of severe spasticity and spasms. Acta Neurochir (Wien). 1991;110(3-4):166-73. 48. Stevens CW, Yaksh TL. Potency of infused spinal antinociceptive agents is inversely related to
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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 ITBtherapy, 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 modeling
An 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 concentrationand 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 ofthe 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 beinteresting 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.
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