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 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, 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 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.
- Rose, M. Chronic Pain Syndromes: Current Concepts and Treatment Strategies. CME Resource. 2014; 139(4): 57-104.
- Lance JW. Symposium synopsis. Chicago: Yearbook Medical, c1980. Spasticity: disordered motor control. pp 485-94.
- Mayer NH and Herman RM. Phenomenology of Muscle Overactivity in the Upper Motor Neuron syndrome. Eur Med Phys. 2004; 40(2): 85-110.
- SYNCHROMED® II infusion system patient manual. Manufactured by Medtronic, Inc. Minneapolis, MN 55432.
- 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.
- Burns AS and Meythaler JM. Intrathecal baclofen in tetraplegia of spinal origin: efficacy for upper extremity hypertonia. Spinal Cord. 2001; 39: 413-419.
- 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.
- 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.
- 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.
- Cosgrave D, Shanahan E, Conlon N. Intrathecal opioids. ATOTW. 2017; 347: 1-6.
- Hindle A. Intrathecal opioids in the management of acute postoperative pain. Continuing Education in Anaesthesia Critical Care & Pain. 2008; 8(3): 81-85.
- Onofrio B, Yaksh T. Long-term relief produced by intrathecal morphine infusion in 53 patients. J Neurosurg. 1990; 72: 200-209.
- Penn R, Paice J. Chronic intrathecal morphine for intractable pain. J Neurosurg. 1987; 67: 182-187.
- 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.
- Knight KH, Brand FM, Mchaourab AS, Veneziano G. Implantable intrathecal pumps for chronic pain: Highlights and updates. Croatian Medical Journal. 2007; 48: 22-34.
- 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.
- 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.
- 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.
- Miele, VJ, Price KO, Bloomfield S, Hogg J, Bailes JE. A review of intrathecal morphine therapy related granulomas. European Journal of Pain. 2012: 10(3): 251.
- Hassenbusch, S, Burchiel, K, Coffey RJ, Cousins MJ, Deer T, Hahn MB, Du Pen S, Follett KA, Krames E, Rogers JN, Sagher O, Staats PS, Wallace M, Willis KD. Management of intrathecal catheter-tip inflammatory masses: A consensus statement. Pain Med. 2002; 3(4): 313-323.
- Pope, JE, Deer TR, Bruel BM, Falowski S. Clinical uses of intrathecal therapy and its placement in the pain care algorithm. PAIN Practice. 2016: 16(8): 1092-1106.
- PRIALT® drug labeling. Manufactured by Jazz Pharmaceuticals, Inc. Palo Alto, CA 94304.
- 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.
- 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.
- 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.
- 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.
- Pope JE, Deer TR, Amirdelfan K, McRoberts WP, Azeem N. The pharmacology of spinal opioids and ziconotide for the treatment of non-cancer pain. Current Neuropharmacology. 2017; 15(2): 206-216.
- Davidoff RA, Hackman JC. GABA: Presynaptic actions. Plenum Press, c1985. Neurotransmitter Actions in the Vertebrate Nervous System. pp 3-32.
- Kroin JS, Penn RD. Cerebrospinal fluid pharmacokinetics of lumbar intrathecal baclofen. Parthenon Publishing, c1991. Parental drug therapy in spasticity and Parkinson’s disease. pp 66-77.
- Francisco GE, Saulino MF, Yablon SA, Turner M. Intrathecal Baclofen Therapy: An Update. PM&R. 2009 Sept; 1(9): 852-858.
- Deer TR, Pope JE, Hayek S, et al. The polyanalgesic consensus conference (PACC): Recommendations on intrathecal drug infusion systems best practices and guidelines. Neuromodulation. 2017; 20(2): 96-132.
- Schiess MC, Eldabe S, Konrad P, Molus L, Spencer R, Stromberg K, Weaver T, Plunkett R. Intrathecal baclofen for severe spasticity: Longitudinal data from the product surveillance registry. Neuromodulation. 2020; 23(7): 996-1002.
- 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.
- 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.
- Noon K, Wallace M, Furnish T. Intrathecal medication withdrawal. Challenging Cases and Complication Management in Pain Medicine. 2017; 203-209.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Original Version of the Topic
Daniel Moon, MD. Intrathecal Agents. 4/11/2016
Daniel Moon, MD, MS
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Ryan Hafner, MD
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