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Overview and Description

Chronic pain and spasticity are commonly encountered medical issues that can have a devastating impact on affected patients.  Previously, chronic pain was defined as a continuation of acute pain beyond a chosen temporal cut-off point.  However chronic pain is now understood to involve a shift in pathogenic mechanisms from an earlier period of acute pain, inflammation and tissue healing to a later period of abnormal, maladaptive changes in neuronal plasticity and sensory processing that develop within the peripheral and central pain pathways.1  Spasticity is a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes during passive range of motion of a limb.2  It is one of several muscle over-activity patterns frequently observed in the upper motor neuron syndrome and can interfere with the patient’s active (e.g. ambulation) and/or passive functioning (e.g. positioning and hygiene).3

The magnitude of pain and/or spasticity the patient is experiencing may appear mild on assessment but can severely impair quality of life and function.  Enteral medications used to treat these problems can often have negative side effects on arousal and cognition due to systemic delivery.  Intrathecal pump delivery systems bypass the blood-brain barrier and deliver medication directly into the cerebrospinal fluid (CSF), allowing for enhanced distribution of the agent to targets in the spinal cord and subsequently reduced dosing with less systemic effects.

The appropriate candidate for intrathecal therapy needs to be psychologically screened and extensively counseled that this treatment modality involves an invasive procedure, represents long-term commitment and although the risks are low, complications due to the pump or catheter malfunction may occur.  The patient typically has undergone a successful intrathecal trial with the desired medication which can be administered as a bolus or continuously via a temporary infusion system in order to be considered for surgical implantation.  Contraindications to implantation of an intrathecal infusion system include presence of infection (e.g. meningitis, ventriculitis, cellulitis or bacteremia), if the pump cannot be implanted 2.5 cm (1 in) or less from the surface of the skin, insufficient body mass to accept pump bulk and weight, or spinal anomalies that complicate placement of the catheter.4  The implantable intrathecal pump system consists of a programmable pump and catheter, both of which are surgically placed under the skin.  The catheter is typically inserted into the intrathecal space at the L3-4 level and is advanced cephalad to approximately the T10 level.  In some instances, it may be advanced to the midthoracic level to have more effect on spasticity in the upper extremities.5,6,7  Following the titration phase of intrathecal therapy, maintenance consists of periodic refilling of the pump reservoir with new medication, troubleshooting any system malfunctions and regularly replacing the pump for battery replenishment.

Although often relegated as an intervention of “last resort,” intrathecal drug delivery can be useful for improving pain and spasticity control, optimizing patient functionality, and minimizing the use of systemic medications in appropriately selected patients.  However, due to its clinical and logistical requirements, intrathecal therapy may be an intervention that is feasible only with larger practices that can commit the necessary staff and resources to support patients’ needs through the trialing, initiation, titration, maintenance and troubleshooting phases.8

Relevance to Clinical Practice

Morphine sulfate (Infumorph®; Baxter Healthcare Corp., Deerfield, IL), ziconotide (Prialt®; Jazz Pharmaceuticals Inc., Palo Alto, CA) and baclofen, which is commercially available as Lioresal® (Novartis Pharmaceuticals, New York, NY) and Gablofen® (Mallinckrodt Pharmaceuticals, St. Louis, MO), are the only medication brands currently approved by the Food and Drug Administration (FDA) for long-term intrathecal infusion (Table 1).  Morphine sulfate and ziconotide are indicated as first-line intrathecal therapies for chronic intractable pain (benign or malignant).  Baclofen is indicated for chronic spasticity of spinal (traumatic spinal cord injury and multiple sclerosis) or cerebral origin (acquired brain injury, cerebral palsy and stroke).  For spasticity of spinal origin, each patient must have previously trialed oral baclofen and either have an insignificant response or intolerable adverse effects at an effective dose.  For spasticity of cerebral origin, current guidelines recommend waiting for at least one year following injury before consideration of pump implant, but this does not always apply.  For all causes of spasticity, intrathecal therapy can be viewed as a legitimate therapeutic alternative to neurosurgical procedures such as dorsal rhizotomy.  No mixed combinations of these medications are currently FDA-approved for long term intrathecal infusion.  However, the Polyanalgesic Consensus Conference (PACC) also considers the combination of morphine plus bupivacaine as a viable option for a first line agent in the treatment of chronic pain.9  For purposes of review, we will only be discussing in detail monotherapy with intrathecal medications that are currently FDA-approved.

Morphine Sulfate

Morphine sulfate predominantly interacts with the mu-receptors in the dorsal horn of the spinal cord to inhibit release of excitatory neurotransmitters (such as glutamate and substance P) and therefore produce analgesia.  It is important to note that it is significantly more hydrophilic than any of the other opioids in clinical use, which allows for prolonged duration of action in the CSF and increased spread above the injection point.10  This can lead to more widespread analgesic benefits but prolonged duration can also be associated with a delay in respiratory depression.11  Intrathecal morphine was initially developed for severe cancer pain but its application has become more widespread in the treatment of chronic pain.12,13  There are many benefits of intrathecal opioid delivery over enteral routes, especially a marked decrease in dosing and reduction in morphine metabolites.  High concentrations of these metabolites may cause cognitive deficits and impair attention and memory.14 Decreased systemic concentrations of opioids can reduce risk of adverse effects to other systems.

Morphine sulfate is commercially available in 10 mg/mL and 25 mg/mL concentrations.  The recommended initial intrathecal dose range in patients with no tolerance to opioids is 0.2 to 1 mg/day.  Intrathecal morphine sulfate trials with a bolus or temporary catheter infusion typically start at 0.2 mg/day for opioid-naïve patients and can be titrated up as indicated over 2-3 days.15  Ranges of dose reported for patients with opioid tolerance vary from 1 to 10 mg/day with some patients receiving doses greater than 20 mg/day.  Several studies have shown that a period of opioid weaning and abstinence prior to trial and implantation may increase chances of success with intrathecal morphine therapy and reduce the need for oral opioid supplementation.16,17

Despite its potential benefits, intrathecal morphine has been associated with several potentially serious safety concerns including respiratory depression, sedation, hypotension, nausea, vomiting, pruritus, urinary retention, hypogonadism, peripheral edema and intrathecal granulomas.  Intrathecal granulomas are an inflammatory mass that can develop at the catheter tip, which may interfere with medication delivery but also lead to serious and possibly irreversible neurological impairment, including paralysis.18  Patients at-risk of intrathecal granuloma will typically present with worsening low back pain while on stable long-term intrathecal dosing, new-onset radiating leg pain, or progressive paraplegia.19  Treatment of intrathecal granulomas includes cessation of drug therapy and/or switch to a lower-risk agent (such as fentanyl) to shrink the mass and possible surgical removal of catheter if refractory and neurologic symptoms remain.20  Withdrawal symptoms may result from abrupt cessation of intrathecal opioids due to catheter disruption, battery failure or human error.  Human error, especially with pump refilling and reprogramming, can also cause drug overdose.  Intrathecal morphine sulfate is contraindicated in patients with history of substance abuse as well as significant pulmonary disease, such as obstructive sleep apnea.21

Ziconotide

Ziconotide, a non-opioid analgesic agent, is the synthetic equivalent of a naturally occurring conopeptide produced by the venomous marine cone snail for prey capture and self-defense.  It is thought to be an antagonist of N-type calcium channels located on the primary nociceptive (A-d and C) afferent nerves of the dorsal horn.22  The efficacy of intrathecal ziconotide has been proven in several double-blinded, placebo-controlled trials in severe chronic cancer pain, non-cancer pain, and acquired immunodeficiency syndrome pain with a significant reduction in pain compared to placebo.23,24,25  Furthermore, safety of long-term infusion has been established in open label multicenter studies.26 Significant adverse events reported with ziconotide were dizziness, confusion, hallucinations, ataxia, abnormal gait, memory impairment, headache, nystagmus, nausea, vomiting and urinary retention.  Due to the potential for hallucinations and other psychiatric events, ziconotide is contraindicated in patients with prior history of psychosis.  Clinically significant abnormalities in creatine kinase levels were reported in some patients warranting periodic monitoring.26  Slow titration and lower doses have been shown to be better tolerated and can reduce the incidence of adverse events.24,25

Ziconotide is commercially available in 25 mcg/mL and 100 mcg/mL solution with the latter requiring dilution with preservative free saline.  A ziconotide naïve pump requires priming as the drug will bind to the internal titanium surface of the pump.  Priming consists of several rinses of the internal surface of the pump with drug prior to filling.  Recommended initial dosing should not be greater than 2.4 mcg/day during both trialing and titration phase after implantation.  Intrathecal delivery rate can be increased in increments up to 2.4 mcg/day (0.1 mcg/hr) at intervals of 2 to 3 times per week based on analgesic efficacy and patient tolerance.  The maximum recommended dose is 19.2 mcg/day (0.8 mcg/hr) though some may tolerate higher doses.  The initial fill solution should be replaced within 14 days.  Diluted ziconotide requires replacement more frequently (within 40 days) than undiluted medication (within 84 days).  Ziconotide, unlike morphine and baclofen, can be discontinued abruptly without evidence of withdrawal in the event of serious neurological or psychiatric disturbance.  No incidences of intrathecal granuloma formation or lethal overdose from ziconotide have been reported to-date.27

Baclofen

Baclofen is a gamma-aminobutyric acid (GABA) B agonist and acts selectively on GABA-B receptors in the brain and spinal cord to inhibit presynaptic excitatory neurotransmitter release and therefore reduce spasticity.28  Bypassing the blood-brain barrier allows dosing to be approximately a hundredfold less than the equivalent oral dose.  Studies have shown that there is a 4:1 gradient of baclofen in the lower vs. upper portions of the spinal cord, which shows preference towards action at the spinal level with reduced cerebral side effects.29  It has been shown to be effective in reducing spasticity caused by cerebral palsy, spinal cord injury, brain injuries, multiple sclerosis and stroke.30  Screening can be performed with an intrathecal bolus (50-100 mg) via lumbar puncture or continuous catheter infusion.  A catheter infusion trial offers the advantage of having the ability to control catheter tip placement and more closely mimics the effects of continuous infusion with implantation, however the risk of complications is increased.

Baclofen is commercially available in 500 mg/mL, 1,000 mg/mL and 2,000 mg/mL concentrations for chronic intrathecal infusion.  Initial starting dose can vary based on the effective trial dose and the duration of relief obtained on that dose.  During the titration phase, the daily dose can be increased in 20-30% increments in patients with spinal cord pathology and 5-15% increments in patients with cerebral pathology only once every 24 hours until desired clinical effect is achieved.  Tolerance and daily maintenance dosing varies widely between individuals and can range from 10 mg/day to well over 1,000 mg/day.  The most common adverse reactions are hypotonia, somnolence, headache, dizziness, nausea, vomiting, urinary retention and peripheral edema.  Inadvertent stoppage may result from malfunction of the system or human error and lead to potentially life-threatening withdrawal syndrome (fever, confusion, hypertonia, multiple organ-system failure).  Overdosing can also occur and potentially lead to confusion, drowsiness, dizziness, respiratory depression seizures, hypotonia, loss of consciousness, coma, multi-organ failure, and death.

Cutting Edge/ Unique Concepts/ Emerging Issues

The latest 2016 PACC guidelines recommend both intrathecal morphine sulfate and ziconotide to be first-line treatments for chronic pain.31  Both agents are recommended by the United States Preventive Services Task Force (USPSTF) for cancer-related pain (Evidence Level I, Grade A) and ziconotide is recommended for active non-cancer-related pain (Evidence Level I, Grade A).  There is less evidence for morphine sulfate in the use of non-cancer-related pain given its high risk of adverse effects and dependence.  These latest guidelines do not separate treatment recommendations based on type of pain as chronic pain patients tend to experience both nociceptive and neuropathic pain.31

For severe spasticity of both spinal and cerebral origins, intrathecal baclofen remains the standard for treatment.  A recent large review of the Product Surveillance Registry (which monitors patients with intrathecal baclofen therapy at 53 registry sites) analyzed 1,743 patients treated over 14 years and showed exit rate from adverse event to be 0.3% and 10-year continuation of therapy rate to be 87.2% in adults and 76.3% in children.32

Intrathecal infusion systems can allow for more individually-tailored dosing regimens such as flex dosing, bolus dosing, and the use of a personal therapy manager device which commands the pump to release a bolus as needed (similar to a patient-controlled analgesia pump).  However, the efficacy of these different regimens and when to utilize them warrants further study. 

Although only monotherapies of morphine, ziconotide and baclofen are currently FDA-approved, several studies have shown the potential benefit of combination therapy in the treatment of chronic pain and spasticity.33,34  There are also several other medications (e.g. hydromorphone, fentanyl, bupivacaine and clonidine) that are used frequently in intrathecal pumps as adjuvant therapy for pain and spasticity management and are readily available through compounding pharmacies, but may soon be approved for chronic intrathecal infusion. 

Bupivacaine, an amide local anesthetic, is the most common adjuvant to intrathecal opioid therapy and can potentially reduce the need for opioid dose escalation, which limits the risk of adverse effects and subsequent granuloma formation.  Use of extra off-label medications has its own risks, as withdrawal from intrathecal clonidine can present with hypertensive crisis and possible cardiomyopathy.35  Intrathecal bupivacaine does not have any documented withdrawal effects but can have adverse effects with excess dosing such as paresthesias and motor weakness.  Although commonly used, combination intrathecal therapy for chronic pain is recommended only after failed treatment with morphine or ziconotide monotherapy per PACC 2016 guidelines.31

Alternative means of infusion into the central nervous system such as intraventricular infusion systems are also beginning to be utilized in the treatment of spasticity and dystonia.36  Another unique area of development to monitor will be the use of nanomedicine and colloidal delivery systems such as polymers and lipids to deliver target substances intrathecally.  Preliminary studies have shown the use of polymers as delivery systems may potentially improve drug pharmacokinetics in CSF with increased efficacy and reduced toxicity with slower clearance from the CSF rather than injection of free molecules and agents.37  For chronic pain patients, small sample studies have also shown early success in with use of dual modality treatment including both intrathecal drug delivery and spinal cord stimulation.38

Gaps in Knowledge/ Evidence Base

More studies regarding chronic intrathecal therapy and pregnancy are necessary to improve guidance for clinical decisions, especially as more patients who initiated therapy as youth reach adulthood.39 Details regarding combination therapy also warrant further study.  Because most of these mixtures are compounded, concentration and quality may vary.40  Knowledge on the effect that drugs in a mixture can have on each other is also limited.41  It is possible that medications when used in combination can have a synergistic effect.  However, mixing may also have negative effects such as drug interactions, increased risk of granuloma formation or reduced stability.  A compound may also precipitate when medications are mixed which can theoretically interfere with motor operation and/or catheter flow.  Regardless, all patients should be monitored closely for pump and catheter malfunction regardless of medication use.  Sudden large dose increases, or loss of therapeutic response suggests a catheter or pump malfunction and requires further workup.

References

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  34. Saulino M, Burton AW, Danyo DA, Frost S, Glanzer J, Solanki DR. Intrathecal ziconotide and baclofen provide pain relief in seven patients with neuropathic pain and spasticity: case reports.  Eur J Phys Rehabil Med. 2009 Mar; 45(1): 61-7.
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  37. Fowler, MJ, Cotter JD, Knight BE, Sevick-Muraca EM, Sandberg DI, Sirianni RW. Intrathecal drug delivery in the era of nanomedicine. Advanced Drug Delivery Reviews. 2020.
  38. Staudt, MD, Patel, S, Hellman A, Platanitis K, DiMarzi M, Khazen O, Argoff CE, Sukul VV, Pilitsis JG. Efficacy of simultaneous usage of spinal cord stimulation and intrathecal therapy for nonmalignant chronic neuropathic pain. World Neurosurg. 2020.
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Original Version of the Topic

Daniel Moon, MD. Intrathecal Agents. 4/11/2016

Author Disclosure

Daniel Moon, MD, MS
Nothing to Disclose

Ryan Hafner, MD
Nothing to Disclose