Description

Intrathecal route of drug administration is well established in anesthesia and pain management. For anesthesia and acute postoperative pain management, drugs are usually administered by lumbar puncture. For chronic pain management, special devices, including pumps, are used. A variety of therapeutic substances can be delivered by the intrathecal route. These include conventional drugs, biologicals, and genetically engineered encapsulated cells. Delivery of neurotrophic factors into the cerebrospinal fluid by intrathecal administration is less invasive and allows access to a much wider area of the central nervous system through cerebrospinal fluid circulation pathways. However, diffusional and cellular barriers to penetration into surrounding neural tissue and significant clearance of the cerebrospinal fluid into the venous and lymphatic circulation are also limiting. Implantation of genetically engineered encapsulated cells producing ciliary neurotrophic factor in the spinal subarachnoid space is an example of gene delivery into the central nervous system via this route and overcomes some of the limitations of direct injection.

Pharmacokinetics of drugs administered intrathecally. Drug distribution in CSF in vivo is highly variable even with identical drug dosage and method of administration mode. Because there are gaps in the layer of pia mater lining the CNS surface, the continuity of the leptomeningeal space with the perivascular spaces extending into the brain parenchyma provides a route for drug transport deep into the brain via CSF. One important factor is that CSF pulsatility varies from patient to patient and may lead to differences in drug distribution. Medical image-based computational fluid dynamics has been used to construct a patient-specific model to quantify drug transport as a function of a spectrum of physiological CSF pulsations and helps in adjusting the infusion variables and reducing the risk of drug toxicity (20). Besides active pumping of CSF into the periarterial spaces, solute transport from the latter to the brain parenchyma where neuronal uptake and axonal transport occur are important processes that determine the outcome of molecules in an intrathecal bolus following administration (27). More than 1% of the intrathecally administered dose of macromolecules and nanoparticles can be delivered to CNS, which is a biologically significant amount.

Guidelines for intrathecal drug administration consider drug-specific kinetics of tissue uptake, which determine the speed of drug dispersion and influence tissue targeting (34). There are limitations of this analysis in that the parameters are obtained from a healthy subject in supine position. Nevertheless, this approach can help physicians to select clinical infusion parameters for their patients and guides optimization of treatment algorithms, which are personalized for an individual patient’s anatomy and disease.

Intrathecal injection of cationic liposome. DNA complexes can produce significant levels of therapeutically relevant gene expression within the central nervous system. In experimental studies on rats, genetically modified cells were implanted in the lumbar subarachnoid space, and the expression of beta-endorphin for pain relief from these cells could be controlled by the systemically administered dexamethasone. The application of this technique might provide a new therapeutic approach to various neurologic diseases.

Intrathecal antisense oligonucleotides for CNS disorders. These are large molecules that do not cross the blood-brain barrier, which limits their application for CNS disorders. This can be overcome by direct introduction into the CSF. An example of this is nusinersen, a splice modulating antisense oligonucleotide with a phosphorothioate backbone, which is approved for the treatment of spinal muscular atrophy. Following intrathecal delivery, neurons take up an antisense oligonucleotide with a phosphorothioate backbone efficiently and distribute it throughout the brain and the spinal cord, with eventual passage to other tissues as well (06).

Advantages of intrathecal therapy. The advantages are as follows:

	• Drugs can bypass the blood-brain barrier.
	• Systemic side-effects of several other drugs can be avoided if they are given in smaller doses for localized action in the nervous system.
	• Approximately one tenth of the intravenous dose of an opioid is needed for relief of pain when administered epidurally and one hundredth is needed when administered intrathecally. This technique reduces adverse effects.
	• Intrathecal pump regulates the infusion rate throughout the day to eliminate the peaks and troughs in plasma drug levels as seen with oral administration of a drug.
	• Intrathecal analgesic administration by an implanted pump can be continued in an ambulatory setting with patient-controlled analgesia.

Complications are rare when recommended techniques are followed. Adverse effects may be due to either the drug or the procedure for administration of the drug. Postlumbar puncture headaches may occur as with lumbar puncture done for any other indication. Extradural hematoma and infections may occur with implanted devices such as catheters and pumps for drug administration. No specific catheter implantation characteristics are associated with the occurrence of complications. The complication rate can be reduced by careful surgical technique during implantation. Staphylococcus epidermidis meningitis developing after insertion of an intrathecal baclofen pump can be successfully treated by intrathecal coadministration of vancomycin and baclofen. Failure of the intrathecal drug delivery system after radiation therapy in patients with pain is a rare complication but is not a reason for denying therapeutic radiation to these patients (19). However, the delivery system should be checked after radiation therapy if the patient has increased pain or analgesic requirement.

Adverse effects due to intrathecally administered drugs and biologicals. These include the following:

• The most well-known adverse effect with intrathecal therapy is drug-induced aseptic or chemical meningitis due to direct irritation of the meninges by the drug. This usually resolves on discontinuation of the drug. Chemical meningitis accounts for half of the serious complications of an intrathecal injection of methylprednisolone.

Other reported complications of intrathecal administration of drugs include transverse myelitis, cauda equina syndrome, lumbar radiculitis, and urinary retention.

	• Reactions to preservative solutions can produce arachnoiditis. The intrathecal administration of solutions preserved with benzyl alcohol has been shown to increase the risk of adverse neurologic events. Spinal injection should not contain any preservatives (such as benzyl alcohol or polyethylene glycol).
	• Granulomatous masses can develop at the tip of the intrathecal catheter of the morphine infusion systems.
	• Respiratory depression can occur with intrathecal opioids, but kappa receptor agonists produce analgesia with little or no respiratory depression. The mechanism of adverse effects after spinal administration is distinctly different for morphine, as morphine is water soluble compared to more lipid-soluble opioids. The systemic absorption of morphine after intrathecal or epidural administration is slow, resulting in long duration of analgesia and low plasma concentrations, whereas lipid-soluble opioids are rapidly absorbed into the circulation and redistributed to the brain. Loss of opioid tolerance due to delayed intrathecal pump refill may lead to development of severe respiratory depression; therefore, refilling pumps in these patients should be done properly when their pumps are completely empty (30).
	• High concentrations of local anesthetics in the cerebrospinal fluid are neurotoxic.
	• Pruritus is a frequent and annoying side effect of intrathecal opioids, but the mechanism is not clear. Several drugs, including antihistamines, nonsteroid antiinflammatory drugs, and droperidol, have been tried for pruritus associated with intrathecal opioids.

Complications of intrathecal administration of drugs not meant to be given by this route of administration. Severe neurologic complications have been reported to be associated with inadvertent administration of methadone by means of implanted intrathecal catheters to a group of patients.

Some safeguards that should be used to hinder the use of certain intrathecal drugs include:

	• Cytotoxic drugs should be given only by appropriately trained staff.
	• Intrathecal drugs should be administered in a designated area (eg, an operating theater).
	• Drugs for intrathecal use should be delivered directly from the pharmacy to the point of use and shipped separately from other drugs.
	• Cytotoxic drugs should be delivered to, and stored in, such a designated area.

Contraindications. Absolute contraindications for intrathecal drug delivery systems are:

• Systemic infection or infection at the implantation site • Allergies to materials in the implant • Intravenous drug abuse • Psychosis

Relative contraindications are:

• Cachexia with muscle wasting and loss of body fat • Anticoagulation or active bleeding • Opioid addiction

Clinical applications

	• Intrathecal approach, with various types of implanted pumps, is approved by the FDA administration into the CSF of morphine for cancer pain, ziconotide for neuropathic pain, and baclofen for spasticity.
	• Other applications include anticancer agents for lymphomatous meningitis.
	• Complications of long-term intrathecal therapy may be related to pumps or catheters placed in the intrathecal space that may malfunction or get obstructed, requiring invasive intervention for correction.

Intrathecal approach, with various types of implanted pumps, is well recognized for administration into the cerebrospinal fluid of morphine for cancer pain and baclofen for spasticity. Various agents that are available for intrathecal administration are shown in Table 1. Most of these are for the relief of pain. The first randomized trial comparing comprehensive medical pain management with and without use of an implantable intrathecal drug delivery system showed that with this method of drug delivery pain was better controlled, toxicity was less, and overall survival was increased (32). The use of intrathecal analgesia has now extended from the inpatient to the ambulatory practice. A Cochrane review found improvement in pain and functioning in patients with chronic noncancer pain who received permanent intrathecal drug delivery systems (35). However, no conclusions were drawn regarding long-term effectiveness of this technology as compared with other treatments. Investigational drugs given by intrathecal route are shown in Table 2.

Table 1. Drugs Available for Intrathecal Administration

Baclofen
	Indication(s)
		• Spasticity • Dystonia related to complex regional pain syndrome
Local anesthetics (lidocaine, bupivacaine tetracaine)
	Indication(s)
		• Postoperative pain
NMDA antagonist (ketamine)
	Indication(s)
		• Postoperative pain • Neuropathic pain
Alpha-2 agonist (clonidine)
	Indication(s)
		• Postoperative pain • Neuropathic pain • Cancer pain • Control of bladder hyperreflexia
Morphine sulfate
	Indication(s)
		• Cancer pain
µ opioid receptor agonist (alfentanil, buprenorphine, etc.)
	Indication(s)
		• Postoperative pain • Cancer pain
Kappa opiate receptor agonist (butorphanol)
	Indication(s)
		• Postoperative pain • Cancer pain
Intrathecal ziconotide
	Indication(s)
		• Neuropathic pain
Anticancer agents (cytarabine liposome injection)
	Indication(s)
		• Lymphomatous meningitis
Intrathecal papaverine in combination with spinal cord hypothermia
	Indication(s)
		• Reduces the incidence of permanent injury to the spinal cord from clamping of aorta during surgical procedures. Intrathecal papaverine dilates spinal arteries and prevents spasm due to hypothermia.
Intrathecal nusinersen
	Indication(s)
		• Spinal muscular atrophy

Table 2. Investigational Drugs Administered by Intrathecal Route

Intrathecal administration of methylprednisolone
	• Postherpetic neuralgia
		- Some studies have shown it to be effective, whereas others show lack of efficacy. This method has not been tested adequately in clinical trials to draw any conclusions. An experimental study of intrathecal methylprednisolone in dogs has shown dose-dependent intrathecal inflammatory reactions from formulations comparable to those used in humans, indicating that the continued use of this method in humans is not recommended (29).
Intrathecal administration of fentanyl for relief of pain
	• Chronic fentanyl intrathecal infusion via implanted catheter, and pump is used for relief of cancer pain.
Intrathecal nicardipine administration
	• Vasospasm due to subarachnoid hemorrhage
		- This approach was shown to relieve vasospasm.
Intrathecal liposomal neostigmine
	• Postoperative pain
		- Provides prolonged spinal antinociception, and permits the safe administration of a relatively large dose because the drug is gradually released from the liposomal depot.
Intrathecal autologous mesenchymal stem cell therapy
	• Amyotrophic lateral sclerosis
		-A phase 1 trial was conducted to study the safety of intrathecal delivery of autologous mesenchymal stem cells to the cerebrospinal fluid of patients with amyotrophic lateral sclerosis.
Intrathecal injection of autologous MSC-NTF cells in patients with amyotrophic lateral sclerosis
	• Amyotrophic lateral sclerosis
		-A phase 2 randomized, double-blind, placebo-controlled multicenter trial is evaluating the safety and efficacy of transplantation of autologous mesenchymal stem cells (MSCs) secreting neurotrophic factors in patients with amyotrophic lateral sclerosis.

Several earlier efforts to deliver neurotrophic factors to the spinal cord in amyotrophic lateral sclerosis patients have been abandoned. Currently several trials are assessing the intrathecal delivery of stem cells, some of which have been modified to secrete neurotrophic factors.

Intrathecal chemotherapy. This is used for treatment of meningeal carcinomatosis. This topic is discussed in more detail in the MedLink Neurology article on leptomeningeal metastasis. Chemotherapeutic agents that have been administered include methotrexate and cytosine arabinoside. Intrathecal chemotherapy is effective for meningeal involvement in lymphoma.

Although frequency of systemic side effects is low with intrathecal administration of methotrexate, high-dose therapy requires close monitoring when performed in combination with trimethoprim-sulfamethoxazole therapy and proton pump inhibitors as well as nonsteroidal antiinflammatory drug administration because of delay in excretion and enhancement of toxicity (36). An analysis of patients with CNS lymphoma treated by intrathecal methotrexate showed that in patients who could not tolerate high-dose methotrexate, prognosis was better in those treated with continuous intrathecal methotrexate likely due to stable concentration of methotrexate in the cerebrospinal fluid (26).

Intrathecal pain therapy. Several analgesics including morphine have been administered intrathecally, but intrathecal morphine is rarely used in lumbar spine surgery. A randomized trial showed that a single intraoperative (prior to closure of the incision) intrathecal injection of 0.2 mg of morphine safely reduces postoperative pain following lumbar fusion (13).

Intrathecal drug delivery systems with opioid plus bupivacaine is a safe and efficient route for expeditious pain relief and decreased oral morphine equivalents in patients with cancer pain (33). Targeted intrathecal drug delivery (TIDD), using a combination of intrathecal bupivacaine with an opioid through a catheter, is often used in postlaminectomy patients with refractory chronic low back pain. A retrospective comparative analysis of consecutive patients with lumbar postlaminectomy syndrome who received targeted intrathecal drug delivery with a combination of bupivacaine/hydromorphone or bupivacaine/fentanyl showed similar relief (01). Low-dose intrathecal fentanyl leads to a lower rate of opioid escalation and may be safer than hydromorphone.

One of the uses of intrathecal morphine is for pain relief in cancer patients. Approximately 5% of cancer patients require interventions or the direct delivery of opioids to the central nervous system. Patients with unmanageable side effects of opioids may benefit from the intrathecal administration, as approximately one hundredth of the intravenous dose of an opioid is needed when administered intrathecally. Approximately, 10% to 20% of patients with cancer pain fail to obtain adequate relief from conventional medical management and may benefit from intrathecal opioid administration. According to consensus-based guidelines for intrathecal drug delivery systems in the treatment of cancer pain, a much wider application of intrathecal therapy is recommended to provide meaningful analgesia (12). High concentrations of morphine in CSF have been found following chronic infusion of morphine; the high concentrations correlate with the infusion dose and the proximity of the sampling site to the infusion site with no effects on CSF chemistry (39).

Ziconotide is used for the treatment of chronic intractable pain, including pain associated with cancer and neuropathic pain. Safety and tolerability of intrathecal ziconotide for severe chronic pain has been investigated in long-term trials and is an option for patients with severe, refractory chronic pain.

Intrathecal baclofen is considered effective for the treatment of dystonia related to complex regional pain syndrome, but a double-blind study failed to show that varying the infusion rate at a fixed daily dose had any effect on the efficacy and safety of intrathecal baclofen (37).

The Polyanalgesic Consensus Conference concluded that intrathecal therapy is a viable and relatively safe option for the treatment of cancer, as well as noncancer pain (11). However, continuous research and expert opinions are needed to improve the pharmacokinetic and pharmacodynamic models of intrathecal drug delivery to improve safety and efficacy.

Intrathecal therapy for spasticity. A retrospective study of records of children with dyskinetic cerebral palsy treated by intrathecal administration of baclofen showed that dystonia, spasticity, and pain were reduced (15). Sitting, communication, and fine motor function improved as well.

Intrathecal drug delivery using implanted devices. Various pumps can be implanted for long-term repeated delivery of drugs to the neuraxis. Only a few intrathecal drug delivery devices are commercially available for intrathecal use in the United States or Europe. Most of these are composed of soft silicone and a relatively fixed design based on dimensions and properties of the thecal sac and use a Tuohy needle for penetration. These catheters are durable and easy to use but lack steerability or targeted intrathecal fixation. Advances in intrathecal catheter design, access techniques, imaging, and understanding of the spinal cord neurophysiology are anticipated in the next decade (25).

For relief of cancer pain, life expectancy of the patient is an important consideration, because of the cost of the hardware and surgical implantation. A trial with a single bolus of the drug given by lumbar puncture should be used to determine the response to medication prior to implantation. Follow-up observation following implantation of the pump is still required, as some patients who respond to the analgesic in the initial trial may not obtain pain relief in the long term (04). However, a longitudinal study of long-term intrathecal drug administration for chronic nonmalignant pain by implanted systems with an average follow-up of 13.5 years showed that this approach has the potential to be a solution for life-long pain management in appropriately selected patients (14).

Surgery for implantation of intrathecal drug delivery devices. Details of surgical techniques for implantation of pumps for intrathecal drug delivery and tips for avoiding complications are described in detail elsewhere (09).

In cachectic patients with insufficient musculature and fatty tissue to support an implanted pump, the lumbar intrathecal catheter can be tunneled subcutaneously to the anterolateral abdomen and connected to a subcutaneous injection port (38). If continuous infusion of a drug is required, an external pump can be connected to the subcutaneous port using a noncoring needle.

Complications of long-term intrathecal therapy using devices. Most of the therapy-related safety issues associated with intrathecal drug delivery are due to inadequate patient monitoring, inflammatory granuloma at catheter tip, wound healing, dosing errors, pump fills or refills, and interaction with concomitant systemic medications. These complications can be prevented by adequate clinician training and implementation of best practices (28).

Complications of long-term intrathecal therapy may be related to pumps or catheters placed in the intrathecal space that may malfunction or get obstructed, requiring invasive intervention for correction. The most bothersome complication is infection. Cancer patients receiving cytotoxic therapies are particularly susceptible to infectious complications because they are immunocompromised. The incidence of infectious complications varies from 2% to 8% and frequently requires prolonged antibiotics and device revision or removal (16).

Chronic headache due to loss of CSF may occur in patients with an implanted drug delivery pump. Radioisotope cisternography may be a useful diagnostic procedure to determine the exact location of CSF leak (10). Spinal fluid leak can be stopped with a blood patch, but if it fails, epidural fibrin glue can be used (17).

Catheter-tip masses are a complication of implantable drug-delivery device usage in less than 3% of all patients with intrathecal catheters (23). These require removal to prevent neurologic complications. In 1 case, air trapped within an arachnoid cyst at the tip of the catheter due to long-term use of intrathecal morphine led to lower extremity paresis, which recovered after surgical decompression (03).

CSF analysis should be performed in patients chronically treated by intrathecal infusion who develop a rapid increase in pain, usually due to aseptic arachnoiditis. In a patient who developed pain after long-term treatment with intrathecal morphine infusion, the symptoms resolved on switch to ziconotide (07).

Migration of intrathecal catheter 5 months following placement for management of pain due to arachnoiditis and extensive epidural scarring and manifested by reduction of pain relief has been reported in 1 patient requiring repositioning of the catheter (02). High-resolution 3D CT with volume rendering technique is a noninvasive method that can identify complications of intrathecal drug delivery devices such as catheter obstruction, displacement, or leakage more precisely than axial CT and fluoroscopy (24). In a retrospective study of patients who required surgery for complications associated with removal of the intrathecal catheter, retained catheter was the cause of complications in half of the cases and persistent cerebrospinal fluid leak was the next most common complication that required an external drainage system (18).