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Opioid intrathecal therapy offers the advantage of delivering medication directly to the dorsal horn of the spinal cord—increasing potency and reducing the systemic exposure—thus reducing side effects.
Intrathecal therapy for the management of malignant and nonmalignant pain has undergone a paradigm shift in recent years. Gone are the days of positioning the therapy as a salvage treatment for high-dose opioid patients. With careful selection and vigilance, advanced techniques like intrathecal therapy can be implemented in a manner that greatly improves functionality and pain care.
The intrathecal drug delivery system (IDDS) functions as a platform, much as transdermal and intraveneous formulations, to deliver medication as a pharmacologic therapy. Common aliases for intrathecal therapy include “pain pump” or “morphine pump.” Despite these connotations, the intrathecal-targeted delivery of medications describes the platform itself; it does not define the medication employed. Prior to implantation, a successful trial needs to be performed with at least 50% pain reduction without side effects.
The advantages to opioid intrathecal therapy are numerous, including the ability to deliver medications where they commonly work (ie, the dorsal horn of the spinal cord), increasing potency, and reducing the systemic exposure and dose required to achieve the desired pharmacologic effect, thus reducing side effects.1 Table 1 compares systemic and intrathecal drug delivery systems.
The purpose of this review is to reintroduce the technology, dissect the indications and the risks, comment on the efficacy of the therapy, and provide a few case examples.
The mechanics behind intrathecal therapy are very simple: surgically, a catheter is placed in the intrathecal space and tunneled to an implanted reservoir, where the medication is housed. The reservoir has a mechanism to dose the intrathecal space, based on the volume infused (Figure 1).
Recent work into cerebral spinal fluid (CSF) flow dynamics of the intrathecal space has offered an insight into pharmacokinetic modeling. There is very little bulk CSF flow, but rather discrete regions of mixing, with bidirectional cranio-caudal oscillatory movement, with cardiac and pulmonary motors2-6 producing a relatively non-homogenous fluid.7 Further, animal models suggest that dispersion from the catheter tip within the CSF by slow infusion is limited, dependent on the physiochemical properties of the drug, as well as the rate and volume delivered.8-10 In a pilot study of common volumes of drug delivery by slow infusion typical with intrathecal dosing of 0.48 mL/hour, most staining occurred posteriorly, demonstrated by very little anterior and lateral staining.8 This data suggests that site-specific catheter placement congruent with area of pain within the intrathecal space is important for optimal efficacy.
Employing the current IDDS platforms available—as the rate and volume available for delivery is largely fixed—concentration is typically manipulated. This has led to some challenges with intrathecal therapy for nonmalignant pain, and will be addressed later in the review.
As the medication is depleted from the reservoir, it requires replacement. This necessitates a refill procedure, which is commonly performed in the office. Much of the morbidity and mortality associated with intrathecal therapy centers on iatrogenic causes, specifically around the refill and reprogramming of the device.11 The life of the battery within the reservoir typically lasts 7 to 10 years, and although the mechanics behind the deployment of volume from the reservoir differ based on the manufacturer, the refill procedure is largely the same. Let’s consider them separately.
The Synchromed II by Medtronic (Figure 2), is a pump that has a geared mechanism that is programmable with a variety of infusion strategies. It has the ability to have variable programmable dosing strategies, along with a patient therapy manager, which functions as a patient controlled bolus delivery mechanism much like an inpatient patient controlled analgesia (PCA) system. It is magnetic resonance imaging (MRI) compatible, with the advisory to read the pump before and after the scan, without the need to remove medication from the internal tubing or reservoir. If the pump were to malfunction during an MRI, the therapy would have a motor stall without restarting, with the abrupt withdrawal of the therapy, potentially creating loss of analgesia and withdrawl symptoms.
The Prometra pump by Flowonix (Figure 3) is an implantable, programmable pump. It can be used to deliver a volume at different rates and is refilled percutaneously. The accuracy, efficacy, and safety of the Prometra pump was assessed in clinical trials, demonstrating an accuracy of 97.1%, with a 90% confidence interval of 96.2-98.0%.12,13 The Prometra pump uses a valve-gated dose regulation system, as opposed to the peristaltic pump roller system. Studies have demonstrated improved volume delivery accuracy as compared to the Medtronic Synchromed II.12 The pump is MRI compatible after complete removal of the medication from the reservoir. There currently is no PCA dosing strategy available with the Prometra pump, although it appears to be on the horizon.
Recommendations on drug choice, concentration limits, and starting doses were outlined by the Polyanalgesic Consensus Conference (PACC) latest reiteration in 2012.14 A panel of experts on behalf of the International Neuromodulation Society (INS) convened on intrathecal therapy to promote safety and efficacy. The medication tiers were designed based on nociceptive or neuropathic pain (see Tables 2-4).
To date, only two medications are approved by the FDA to treat chronic pain via intrathecal therapy: morphine (Infumorph) and ziconotide (Prialt). Morphine delivered pharmacodynamically works at the opioid receptors within the dorsal horn, while ziconotide, a non-opioid based medication, antagonizes the N-type calcium channels within the dorsal horn.15-16 Medtronic recently released a statement regarding non-labeled drugs used within the Synchromed II pump, reporting a statistically significantly higher incidence of motor stalls when non-labeled medications—as monotherapy or in combination—are employed.17 Multiple studies have commented on stability of medications within the reservoir, and suggest that the medications as monotherapy or in combination should be replaced routinely every 3 to 4 months.18-23 Combination therapy has been demonstrated to slow dose escalation when initiated at onset of intrathecal therapy.24
The indications for intrathecal therapy include chronic intractable pain, which has failed conservative medical care. Conservative care strategies include physical therapy, pharmacotherapy (oral, transdermal, intravenous, or intramuscular), and lesser interventional care. Please refer to Table 5, for a list of indications for intrathecal therapy. With the advances in neurostimulation therapies, intrathecal therapy has been positioned commonly after these strategies, or as an alternative therapy if a patient has relative contraindications to the procedure. In nonmalignant pain patients, this therapy is less often positioned as a salvage therapy to treat patients on high-dose opioid medications. For example, elderly patients who suffers from axial back pain and whom are unresponsive to more conservative therapy or have analgesic benefit with pharmacotherapy but with intolerable side effects, should be considered candidates for intrathecal therapy. In the cancer population, intrathecal therapy has been shown to reduce side effects and improve treatment outcomes, whether curative or palliative in nature, with improvement by Karnofsky Performance Index.1,25
Intrathecal therapy has been demonstrated in many studies to improve pain control and function in both cancer and noncancer patients.26 Intrathecal therapy had level II-2 evidence based for cancer pain and level II-3 evidence for noncancer pain, as described by the United States Preventative Services Task Force criteria for evidence-based medicine,26,27 with a recommendation strength of moderate based on Guayatt’s criteria.28
Adverse consequences of long term opioid therapy are not averted with intrathecal therapy, as endocrinopathic and immunologic sequelae occur.29 Opioid-related side effects specific to intrathecal delivery include endocrinopathy, urinary retention, pruritis, and fluid retention.29 As the device is an implanted therapy, typical perioperative risks are present and should be addressed prior to proceeding. The importance of having a communicative patient during needle placement within the intrathecal space and catheter deployment and positioning is paramount. Common device-related side effects include catheter malfunction, although there have been recent advancements in catheter design that likely will largely eliminate this challenge, and rarely pump “flipping,” which prevents reservoir refill. Biologic-related side effects include infection and seroma.26
As noted, much of the reported morbidity and mortality associated with intrathecal therapy centers on the refill procedure, where medication is deposited within the reservoir and reprogramming occurs.30 Further, depositing the medication inadvertently outside of the reservoir can cause overdose and requires admission and vigilant care. Some experts advocate ultrasound guidance with needle placement to better qualify appropriate needle position when reservoir membrane localization is difficult to determine.31
When concentrations of medications are elevated outside of the PACC recommendations, granulomas may form. A granuloma is a noninfectious collection of cells found at the catheter tip that can progress to be compressive in nature. Granulomagenic medications include all of the commonly employed intrathecal medications, and are commonly associated with opioid strategies.32 There have been no reports of granuloma formation with monotherapy with either ziconotide or fentanyl. If granuloma is suspected secondary to loss of therapy efficacy or new neurologic findings, a plain radiograph should document catheter tip and then a MRI should be performed at that level. Further, a catheter evaluation should be performed prior to revision. Treatment includes cessation of the granulomagenic medication and replacement of catheter. Very rarely is formal neurosurgical decompression required.
A 76-year-old woman presented with axial low back pain that was unresponsive to facet joint treatments. An MRI demonstrated spinals stenosis and lumbar spondylosis with facet arthropathy. Her back pain was most exacerbated when she was laying down flat while trying to sleep. She rated her pain as 9 out of 10 on a numerical rating scale. She had tried a course of hydrocodone (Norco, 5 mg hydrocodone/325 mg acetaminophen up to 4 times daily), and although she reported improvement, she stopped taking the medication due to constipation. The patient also failed other neuropathic pain therapies, including gabapentin at a dose of 100 mg given at night and duloxetine (Cymbalta) 20 mg, because of unsteadiness and sedation. Other oral opioid formulations were tried but stopped due to constipation. She then underwent a trial of morphine—total dose of 0.1 mg/day—and experienced 80% pain relief lasting over 18 hours. She elected to proceed with the implant. Her intrathecal dose is now 0.15 mg/day with no opioid-related side effects; pain score is now 1-2 out of 10.
A 38-year-old woman presented with a history of multiple sclerosis and a cerebrovascular accident with continued right-sided sequelae. She is confined to a wheel chair with pain in her axial back, with upper and lower extremity pain on her right side. She reported minimal pain control, and described her pain as aching, burning. She had failed multiple neuropathic pain medications with an attempt to titrate to effect, including gabapentin at 300 mg three times daily, amitriptyline 100 mg at night, oxcarbazepine (Trileptal) 150 mg twice daily, duloxetine 90 mg daily, and topiramate (Topamax) 200 mg at night, along with multiple short-acting opioid regimens with upward titration to daily dose of 300 morphine equivalents. She underwent a trial with ziconotide 2 mcg, and her pain went from 8 out of 10 to 1 out of 10. She subsequently underwent intrathecal implant and flex dosed with bolus delivery of ziconotide per day to dose of 2 mcg/day. The patient continues to report minimal pain (on the order of 1-2/10) with very infrequent pain exacerbations.
Intrathecal therapy is an important component of the armamentarium to treat pain in patients who that continue to have intractable pain despite conservative efforts. When employed vigilantly and selectively, intrathecal therapy is overwhelmingly helpful. Indications include those patients who cannot tolerate systemic opioid delivery despite analgesic benefit, and in those with uncontrolled pain despite appropriate systemic dosing attempts.
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