Intrathecal Agents

Author(s): Daniel Moon, MD

Originally published:04/11/2016

Last updated:04/11/2016

1. 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

2. 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) and cerebral origin (acquired brain injury, cerebral palsy and stroke).  No combinations of these medications are currently FDA approved for long term intrathecal infusion.  However, the Polyanalgesic Consensus Conference 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.

Medication Mechanism of Action Indication Potential Advantages Potential Risks                       
Morphine
Sulfate
μ-receptor agonist in the dorsal horn of the spinal cord Chronic pain Marked decrease in systemic concentrations of metabolites that may impair cognition Sedation, hypotension, nausea, vomitting pruritus, urinary retention, hypogonadism, peripheral edema, respiratory depression and intrathecal granulomas
Ziconotide Antagonist of N-type calcium channels located on the primary nociceptive (A-δ and C) afferent nerves of the dorsal horn of the spinal cord Chronic pain Can be discontinued abruptly without evidence of withdrawal in the event of a serious adverse reaction Dizziness, confusion, hallucinations, ataxia, abnormal gait, memory impairment, headache, nystagmus, nausea, vomiting, urinary retention and elevated creatinine kinase
Baclofen γ-aminobutyric acid (GABA) B receptor agonist in the spinal cord Spasticity Bypassing blood-brain barrier allows dosing to be approximately a hundredfold less than the equivalent oral dose Hypotonia, somnolence, headache, dizziness, urinary retention, peripheral edema, nausea, vomiting, confusion, drowsiness, dizziness, respiratory depression, seizures, intrathecal granulomas, loss of consciousness

 

Morphine Sulfate

Morphine sulfate predominantly interacts with the m-receptors in the dorsal horn of the spinal cord to produce analgesia.  It is important to note that it is significantly more water soluble than any of the other opioids in clinical use, which enables rapid diffusion and clearance in the CSF (half-life 42-136 minutes).10  Intrathecal morphine was initially developed for severe cancer pain, but its application has become more widespread in the treatment of chronic pain.11,12There 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.13 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.  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.14,15

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 can not only interfere with medication delivery but lead to serious neurological impairment, including paralysis.16 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.

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.17 The efficacy of intrathecal ziconotide has been proven in several double-blinded, placebo-controlled trials in severe chronic cancer pain, noncancer pain, and acquired immunodeficiency syndrome pain with a significant reduction in pain compared to placebo.18,19,20 Furthermore, safety of long term infusion has been established in open label multicenter studies.21 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.21 Slow titration and lower doses have been shown to be better tolerated and can reduce the incidence of adverse events.19,20

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.

Baclofen

Baclofen stimulates g-aminobutyric acid (GABA) B receptors in the spinal cord to reduce spasticity.  Bypassing the blood-brain barrier allows dosing to be approximately a hundredfold less than the equivalent oral dose.  It has been shown to be effective in reducing spasticity caused by cerebral palsy, spinal cord injury, brain injuries, multiple sclerosis and stroke.22Screening 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, 1000 mg/mL and 2000 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 1000 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 and coma.

3. CUTTING EDGE/UNIQUE CONCEPTS/EMERGING ISSUES

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 warrants further study.  Although only monotherapy of morphine, ziconotide and baclofen is currently FDA approved, several studies have shown the potential benefit of combination therapy in the treatment of chronic pain and spasticity.23,24 There are also several other medications (e.g. hydromorphone, fentanyl, bupivacaine and clonidine) that are used frequently in intrathecal pumps and readily available through compounding pharmacies that may soon be approved for chronic intrathecal infusion.  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.25

4. 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.26 Details regarding combination therapy also warrant further study.  Because most of these mixtures are compounded, concentration and quality may vary.27 Knowledge on the effect that drugs in a mixture can have on each other is also limited.28 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(s).  Sudden large dose increases or loss of therapeutic response suggests a catheter or pump malfunction and requires further workup.

REFERENCES

  1. Rose, M. Chronic Pain Syndromes: Current Concepts and Treatment Strategies.  CME Resource 2014; 139(4): 57-104.
  2. Lance JW. Symposium synopsis.  Chicago: Yearbook Medical, c1980.  Spasticity: disordered motor control.  pp 485-94.
  3. Mayer NH and Herman RM. Phenomenology of Muscle Overactivity in the Upper Motor Neuron syndrome.  Eur Med Phys 2004; 40(2): 85-110.
  4. SYNCHROMED® II infusion system patient manual. Manufactured by Medtronic, Inc.  Minneapolis, MN 55432.
  5. Meythaler JM, Guin-Renfroe S, Grabb P, Hadley MN. Long-term continuously infused intrathecal baclofen for spastic-dystonic hypertonia in traumatic brain injury: 1-yr experience. Arch Phys Med Rehabil 1999; 80: 13-19.
  6. Burns AS and Meythaler JM. Intrathecal baclofen in tetraplegia of spinal origin: efficacy for upper extremity hypertonia.  Spinal Cord 2001; 39: 413-419.
  7. Grabb PA, Guin-Renfroe S, Meythaler JM. Midthoracic catheter tip placement for intrathecal baclofen administration in children with quadriparetic spasticity. Neurosurgery 1999; 45: 833-837.
  8. Saulino M, Kim PS, Shaw E. Practical considerations and patient selection for intrathecal drug delivery in the management of chronic pain.  J Pain Res. 2014 Nov 10; 7: 627-38.
  9. Deer TR, Smith HS, Cousins M, et al. Consensus guidelines for the selection and implantation of patients with noncancer pain for intrathecal drug delivery. Pain Physician. 2010; 13(3): E175-E213.
  10. INFUMORPH® drug labeling. Manufactured by Baxter Healthcare Corp.  Deerfield, IL 60015.
  11. Onofrio B, Yaksh T. Long-term relief produced by intrathecal morphine infusion in 53 patients. J Neurosurg. 1990; 72: 200-209.
  12. Penn R, Paice J. Chronic intrathecal morphine for intractable pain. J Neurosurg. 1987; 67: 182-187.
  13. Chauvin M, Samii K, Schermann JM, Sandouk P, Bourdon R, Viars P. Plasma pharmacokinetics of morphine after intramuscular, extradural and intrathecal administration. Br J Anaesth. 1982; 54(8): 843-847.
  14. Hamza M, Doleys D, Wells M, et al. Prospective study of 3 year follow-up of low-dose intrathecal opioids in the management of chronic nonmalignant pain. Pain Med. 2012; 13(10): 1304-1313.
  15. Grider JS, Harned ME, Etscheidt MA. Patient selection and outcomes using a low-dose intrathecal opioid trialing method for chronic nonmalignant pain. Pain Physician. 011; 14(4): 343-351.
  16. Coffey R, Burchiel K. Inflammatory mass lesions associated with intrathecal drug infusion catheters: report and observations on 41 patients. Neurosurgery. January 2002; 50: 79-87.
  17. PRIALT® drug labeling. Manufactured by Jazz Pharmaceuticals, Inc.  Palo Alto, CA 94304.
  18. Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, Fisher R, Bryce DA, Mangieri EA, Luther RR, Mayo M, McGuire D, Ellis D. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 2004 Jan 7; 291(1): 63-70.
  19. Rauck RL, Wallace MS, Leong MS, Minehart M, Webster LR, Charapata SG, Abraham JE, Buffington DE, Ellis D, Kartzinel R; Ziconotide 301 Study Group. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain.  J Pain Symptom Manage. 2006 May; 31(5):393-406.
  20. Wallace MS, Charapata SG, Fisher R, Byas-Smith M, Staats PS, Mayo M, McGuire D, Ellis D; Ziconotide Nonmalignant Pain Study 96-002 Group. Intrathecal ziconotide in the treatment of chronic nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial.  Neuromodulation. 2006 Apr; 9(2):75-86.
  21. Wallace MS, Rauck R, Fisher R, Charapata SG, Ellis D, Dissanayake S; Ziconotide 98-022 Study Group. Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial.  Anesth Analg. 2008 Feb; 106(2): 628-37.
  22. Francisco GE, Saulino MF, Yablon SA, Turner M. Intrathecal Baclofen Therapy: An Update.  PM&R 2009 Sept; 1(9): 852-858.
  23. Wallace MS, Kosek PS, Staats P, Fisher R, Schultz DM, Leong M. Phase II, open-label, multicenter study of combined intrathecal morphine and ziconotide: addition of ziconotide in patients receiving intrathecal morphine for severe chronic pain.  Pain Med. 2008 Apr; 9(3): 271-81.
  24. 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.
  25. Turner M, Nguyen HS, Cohen-Gadol AA. Intraventricular baclofen as an alternative to intrathecal baclofen for intractable spasticity or dystonia: outcomes and technical considerations.  J Neurosurg Pediatr. 2012 Oct; 10(4): 315-9.
  26. Morton CM, Rosenow J, Wong C, Kirschner KL. Intrathecal Baclofen Administration During Pregnancy: A Case Series and Focused Clinical Review.  PM&R.  2009 November; 1(11): 1025-1029.
  27. Farid R, Murdock FA, Bonnett A, Mawhinney TP, Chance D, Waters JK, Hewett JE. Quality of Intrathecal Baclofen from Different Sources.  PM&R 2012 March; 4(3): 182-189.
  28. Rudich Z, Peng P, Dunn E, McCarney C. Stability of clonidine-hydromorphone mixture from implanted intrathecal infusion pumps in chronic pain patients.  J Pain Symptom Manage.  2004 Dec; 28(6): 599-602.

Author Disclosure

Daniel Moon, MD:

Company Type Received Role
Medtronic USA Grant (to Institution) Recipient Physician
Advanced Studies
in Medicine
Honorarium Speaker
Neurovations Honorarium Speaker

Related Articles