Intrathecal drug delivery represents an advanced modality for refractory chronic pain patients as well as intractable spasticity. This article reviews the advantages and indications for intrathecal therapy, as well as recommendations for proper patient selection using a multidisciplinary team to provide a global assessment of the impact of chronic pain on the patient’s well-being. The goals and expectations of trialing are discussed alongside advantages and disadvantages of several trialing techniques. A discussion of outcomes is presented for patients with chronic pain due to both malignant and nonmalignant causes.
Key points
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Intrathecal drug delivery allows continual administration of analgesics directly to their site of action within the cerebrospinal fluid (CSF), providing pain relief to patients who are intolerant or refractory to other routes of administration.
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Success with intrathecal therapy requires careful patient selection, an understanding of the pain mechanisms, and reasonable patient expectations.
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A trial of intrathecal drug therapy often precedes implant of the intrathecal drug delivery system. The trialing period enables both patient and physician to assess efficacy and immediate side effects of the intrathecal analgesia.
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Sustained improvement in both pain score and functional measures have been demonstrated when intrathecal drug delivery is used for both neuropathic and nociceptive pain.
Introduction
Intrathecal drug delivery systems represent an important therapeutic strategy for a subset of refractory chronic pain patients. Only morphine and the N-type calcium channel blocker ziconotide are Food and Drug Administration (FDA) approved for intrathecal administration, although a much wider variety of agents are currently in use for both nociceptive or neuropathic pain conditions.
The continuous administration of analgesics via the intrathecal route results in higher subarachnoid drug concentrations and can achieve improved pain scores while mitigating many of the side effects seen with systemic administration of these same medications. Quality-of-life measures and overall health care utilization costs are decreased in select patients when intrathecal drug delivery is compared with conventional medical management alone, underscoring the importance of this route of delivery in an increasingly cost-conscious health care arena.
Introduction
Intrathecal drug delivery systems represent an important therapeutic strategy for a subset of refractory chronic pain patients. Only morphine and the N-type calcium channel blocker ziconotide are Food and Drug Administration (FDA) approved for intrathecal administration, although a much wider variety of agents are currently in use for both nociceptive or neuropathic pain conditions.
The continuous administration of analgesics via the intrathecal route results in higher subarachnoid drug concentrations and can achieve improved pain scores while mitigating many of the side effects seen with systemic administration of these same medications. Quality-of-life measures and overall health care utilization costs are decreased in select patients when intrathecal drug delivery is compared with conventional medical management alone, underscoring the importance of this route of delivery in an increasingly cost-conscious health care arena.
Indications
Although intrathecal drug delivery systems have been widely used for treating intractable pain due to various malignancies, the delivery of neuraxial opiates for chronic nonmalignant pain states continues to gain favor in parallel with a growing body of evidence supporting their use. By delivering opiates in close proximity to their site of action on the dorsal horn of the spinal cord, analgesia is achieved at doses much lower than when these same medications are administered systemically. Additionally, adverse effects are often mitigated and concerns about opiate diversion and analgesic compliance are attenuated when medications are administered via an implanted drug delivery system. Newer intrathecal delivery systems are capable of providing patient-controlled analgesia on demand via a personal therapy manager.
Although opiates have multiple established routes of delivery, the recent discovery of the nonopiate analgesic ziconotide necessitates direct administration into the CSF and has efficacy exclusively via the intrathecal route. As ziconotide use increases so will the number of patients with intrathecal drug delivery systems. Although outside of the scope of this discussion, intrathecal drug delivery systems are also widely used in the treatment of spasticity in both pediatric and adult populations.
Consideration of the administration of intrathecal analgesics is typically reserved for those patients who fail, or are unable to tolerate, conservative treatment modalities, including opiate and nonopiate pharmacotherapy, as well as nonpharmacological adjuncts, such as interventional procedures or physical modalities. A pain diagnosis should be well established, classifying the pain as either nociceptive or neuropathic, and serve to guide the selection of intrathecal agents. Additionally, the pain should be chronic and present throughout most of the day, necessitating round-the-clock analgesic dosing. The source of the pain should not be easily correctable via an alternative intervention or any alternative surgical treatment should be deemed to pose a greater risk than treatment of the condition with intrathecal analgesics.
The development of intolerable side effects precluding the use of oral opiates represents a subset of patients who may achieve analgesic benefit from these same agents when administered directly into the CSF. This includes patients who achieve substantial pain relief from oral opiates but develop intolerable sedation, constipation, and other adverse effects. On administration of these same agents into the intrathecal space, many patients achieve analgesia while avoiding the adverse cognitive and gastrointestinal side effects ( Box 1 ).
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An established pain diagnosis has been made classifying the symptoms as neuropathic, nociceptive, or mixed.
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The pain complaint should be chronic or both chronic and progressive in nature owing to either a malignant or nonmalignant cause.
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Pain should be present throughout nearly the entire day.
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Patients have failed to achieve analgesia with conservative nonpharmacologic modalities
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Patients who are refractory or intolerant to orally administered analgesics
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Corrective treatment addressing the pain generator is not warranted.
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Surgical contraindications to implanting prosthetic hardware and accessing the intrathecal space are absent (eg, bacteremia or anticoagulation).
Patient selection
Judicious patient selection is perhaps the most important strategy for achieving lasting success with continuous intrathecal drug therapy and involves multidisciplinary decision making with the input of interventionalists, mental health professionals, patients and their caregivers. Several stepwise algorithms to identify candidates for consideration of intrathecal drug delivery have been suggested, all with a focus on evaluating and optimizing the multiple comorbidities on which chronic pain has an impact.
First, pain practitioners identify patients, establish a pain diagnosis, and determine that more conservative options have been exhausted. Second, intrathecal drug delivery is presented to patients and expectations, comprehension, and support networks are assessed. Because administration of analgesics via the intrathecal route offers pain control, rather than pain elimination, realistic expectations should be set by practitioners and anticipated outcomes quantified among patients. Third, patients are evaluated and treated for psychological comorbidities that may be barriers to success with the therapy. The psychological evaluation is particularly important when considering the use of ziconotide because worsening mood disorders, cognitive impairment, and suicidal ideation have been observed with its use. Although not demonstrated prospectively, preexisting psychopathology is thought to predispose patients to new adverse psychiatric events after initiation of ziconotide therapy, and many physicians consider psychosis a contraindication to the use of ziconotide.
The multidisciplinary team should focus on how best to optimize patient success with intrathecal therapy rather than accepting intrathecal analgesia as a strategy of last resort. Patient dissatisfaction with intrathecal therapy remains a significant reason for premature revision or removal of intrathecal drug delivery systems, with only 51% of patients reporting satisfaction with the therapy 12 months after implant. These dissatisfied patients represent a significant cost to the health care system. At the authors’ institution, 11% of all patients who have undergone a successful trial undergo a surgical explant of the permanent drug delivery system due to dissatisfaction with the long-term therapy.
Techniques
Perhaps somewhat unique to implantable therapies in interventional pain management is the opportunity for patient and physician to ascertain some measure of patient success and satisfaction with the therapy prior to implanting prosthetic hardware. Similar to a short-term temporary trial of spinal cord stimulation, the decision to proceed with implant of an intrathecal drug delivery system is often proceeded by a brief trial wherein medication is administered through a temporary intrathecal catheter. Throughout this trial period, pain relief is quantified, side effects are noted, and patient outcomes are assessed. Contingent on a favorable trial, an intrathecal drug delivery system consisting of a medication reservoir, pump, and intrathecal catheter is surgically implanted.
Trialing
The decision to implant an intrathecal pump for many pain diagnoses is often contingent on patients’ success with a trial of intrathecal analgesic therapy. The trial serves multiple purposes, including the ability to assess a change in pain score or improvement in function. Conversely, a trial can assess a decrease in opiate-related adverse effects or a decrease in reliance on oral analgesics. Also, the trial may provide additional data for the psychological assessment by providing insight into the patients mental status, enabling quantification of the consistency of response to the trial medication, and observing a snapshot of patient expectations.
There are no prospective data demonstrating that a single trialing method is superior to another, and practitioners can accomplish an intrathecal trial via either continuous or intermittent epidural or intrathecal administration. Despite a consensus committee recommendation outlining a trialing technique algorithm ( Fig. 1 ), the choice is often individualized based on practitioner preference, infrastructure for patient care throughout the trial period, and an estimate of the duration needed to assess response to the medication.
An epidural trial avoids the need for dural puncture and the potential for a resultant postdural puncture headache but requires that a 10-fold increase in opiate dose is administered. Additionally, an epidural trial excludes any contribution that the fluid dynamics of the CSF may have on the trial medication. Whereas a positive epidural opiate trial yields favorable information, a negative epidural trial does not exclude the possibility of potential success with intrathecal administration.
An intrathecal trial can be accomplished via a single bolus, multiple bolus, or continuous infusion technique via a catheter inserted into the intrathecal space. The infusion permits administration of the intrathecal medication continuously, a technique that most similarly mimics the pharmacokinetics of delivery with an implanted pump, and avoids fluctuating drug levels seen with repeated intermittent bolus.
The endpoint of an intrathecal trial is often defined in both research protocols and clinical practice as a greater than or equal to 50% decrease in pain. Many investigators also prefer to see improved functionality and decreased reliance on oral opiate analgesic as clear endpoints of a successful trial. A trial may be deemed a failure if measurable pain relief is not achievable, adverse effects of the trial medication outweigh the observed benefits, patient satisfaction is low, or psychological barriers become apparent throughout the trial period.
Selecting Pharmacotherapy
Although morphine and ziconotide are currently the only FDA-approved pain medications for intrathecal use, a variety of monotherapies or combination agents, including hydromorphone, fentanyl, sufentanil, bupivacaine, clonidine, and baclofen, are in use. Nonapproved agents are recommended throughout established consensus statement algorithms, even as first-line therapies for the treatment of both neuropathic and nociceptive pain. In light of its off-label use, a study to validate the safety and efficacy of intrathecal hydromorphone is currently in a phase 3 FDA clinical trial. Baclofen also carries an FDA approval for intrathecal use but is primarily used for spasticity and appears only late in the treatment algorithm for neuropathic pain.
Intrathecal trials are often performed with a single agent, such as morphine or ziconotide. A consensus committee has proposed 2 algorithms for the selection of agents for long-term intrathecal therapy. The choice of agents and stepwise decision recommendations differ based on the cause of the pain as either neuropathic ( Table 1 ) or nociceptive ( Table 2 ). Monotherapy is typically recommended at the initial stages of the algorithm, whereas combination agents with synergistic mechanisms of actions are used in the later steps.
Related posts:
Introduction to Neuropathic Pain Syndromes
Intracranial Ablative Procedures for the Treatment of Chronic Pain
Microvascular Decompression for Trigeminal Neuralgia
Neurolysis, Neurectomy, and Nerve Repair/Reconstruction for Chronic Pain
Nerve Blocks for Chronic Pain
Transcranial Magnetic Stimulation for Chronic Pain
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