The idea of using intrathecal (IT) medication to treat chronic pain began to grow after mu-opioid receptors were found in the dorsal horn of the spinal cord [1]. Since the receptors were located in the dorsal horn, the concept of delivering medications to their appropriate targets, with a catheter placed directly over these receptors, seemed to make sense. Later, in 1991, the Food and Drug Administration (FDA) approved Medtronic’s intrathecal drug delivery system (IDDS) . This led to an increased use of intrathecal analgesics for the relief of cancer and non-cancer-related pain [2]. This method of treatment was used when conservative medical, interventional, and surgical therapies had failed. Intrathecal delivery was also considered when there were intolerable side effects to oral opioids, such as sedation, constipation, and urinary retention [3].

As the need for IT therapy grew, a number of issues need to be addressed for this to be successful as a long-term solution for chronic pain patients. ITT bypasses the blood–brain barrier, which results in higher cerebrospinal fluid (CSF) concentrations of medications. This allows achievement of equipotent doses of equivalent oral medications to be delivered, so that drugs, such as opioids , can be reduced or even stopped [4]. Variables include which drug or combination of drugs to use, the concentration of medicines, catheter placement, and infusion strategies, such as continuous, bolus, or patient-activated bolus. This called for more research to be done on the dynamic forces present in the IT space. Work began to elucidate the complexities in delivering therapy by this means and a new understanding of how best to apply this therapy grew [5, 6]. Based on new data, guideline statements were created to improve patient safety by reducing interprovider variability in catheter placement, medications used, and patient selection [7, 8].

Patients with chronic pain can have separate or mixed pain states and both nociceptive and neuropathic pain qualities. Neuropathic pain is typically described as burning, gnawing, and lancinating, whereas nociceptive pain is commonly described as aching, mechanical, and sharp. Conservative therapies commonly include ultrasound or fluoroscopically guided injections, oral adjuvant medications, such as gabapentin or tricyclic antidepressants, systemic medication trials with IV lidocaine or Ketamine, topical analgesic therapies, and careful use of opioid medications. Chronic opioid therapy has not been found to be beneficial for long-term treatment of neuropathic pain and can actually worsen pain, as in patients with HIV-induced peripheral neuropathy [9]. Failure of patients to respond to conservative therapy obviates the need for advanced therapies, such as spinal cord stimulation (SCS) and ITT. For many chronic pain syndromes, SCS methods of treatment are used before ITT due to data suggesting that SCS is the safer option to start with [10]. When limitations of SCS therapy do not allow sufficient treatment to be obtained, as when paresthesias are unable to entirely cover painful areas, ITT should be the next consideration [11].

IT drug delivery for malignant and nonmalignant pain has become a well-established and effective treatment option for resistant or refractory pain that has failed conservative therapy [12]. Commonly, the safety concerns have placed ITT at the end of the treatment algorithm [10]. Thus, ITT has been viewed as a salvage therapy, due to the risks associated with IT opioids; however, there are nonopioid agents, which have led to its use earlier in the pain treatment algorithm [13]. Despite designation as a last ditch therapy, success has been demonstrated by randomized controlled trials with nonopioid agents [14–16] and opioids for malignant and nonmalignant pain [12].

Patient populations likely to benefit from ITT include those with failed back surgery syndrome, vertebral compression fracture, nonoperative spondylolisthesis and radiculopathy, as well as those patients unlikely to benefit from surgery [11]. This therapeutic option can also benefit patients with visceral, pelvic, and abdominal pain, as well as end-of-life care for cancer patients [17]. In order to be an appropriate ITT candidate, the patient must meet both a disease indication as well as patient selection criteria for optimal outcomes. Patient selection criteria include optimized preoperative management of comorbidities, autonomy and capacity to understand the therapy, ability to be present for medication refills and scheduled visits, no present symptoms of psychosis, and stabilization of any depression, anxiety, or personality disorders [11].

Currently, only two agents are FDA approved for intrathecal use in pain: morphine and ziconotide [18]. Ziconotide is a hydrophilic molecule that acts as a selective N-type voltage-gated calcium channel blocker. This results in limiting the release of nociceptive molecules, such as glutamate, calcitonin gene-related peptide, and substance P [19]. There are also other agents, which are commonly used off-label, including bupivacaine, clonidine, and fentanyl [20]. There have been studies examining the use of other medications in the IT space, such as sufentanil, methadone, adenosine, hydromorphone, meperidine, gabapentin, baclofen, ketorolac, midazolam, neostigmine, octreotide, ropivacaine, dexmedetomidine, and lidocaine [7]. Critical factors needed for a better understanding of which IT therapy is better to use include the following: catheter location, volume of injectate, kinetic energy of injectate, drug dose, drug concentration, and the physiochemical properties of the drug, including density and hydrophobicity [11].

Selecting which IT medication to use encompasses many factors. These include the disease state (region of pain, type of pain), pharmacokinetics of the IT space, medication physicochemical properties, and device variables [11]. Physicochemical properties of the drug and its mechanism of action are critical in treating patients with neuropathic pain. The agent’s density and hydrophobicity influence the length of therapeutic time when the medications are in the cerebrospinal fluid. The more hydrophobic a medication is, the less it is thought to spread, and the more it is thought to penetrate the lipid dense tissues of the spinal cord [7].

This means that the positioning of the catheter can be critical, especially with use of lipophilic medications [21].

As with opiates, intrathecal agents typically work by binding to particular receptors in the superficial layers of the dorsal horn. Prior to reaching their targets, intrathecal medications may be taken up by both fat tissue as well as blood vessels. The lipophilic agents are more likely to be taken up by the systemic circulation than hydrophilic agents, as the lipophilic agents readily diffuse past fatty cell membranes and into the circulation. Hydrophilic opioids, such as morphine and hydromorphone, can be preferred in certain cases, because they stay in the CSF longer, which allows them to diffuse more slowly into the layers of the dorsal horn not adjacent to the catheter tip.

Much effort in trying to understand the pharmacokinetic characteristics of intrathecally administered medications has revealed that lipid solubility plays a very important role in analgesic responsiveness [21, 22]. For example, unlike other agents used intrathecally, local anesthetics act earlier on sodium channels at the rootlets of nerve fibers in the IT space, rather than targeting spinal cord receptors [5]. Bupivacaine is the predominant local anesthetic used in chronic intrathecal infusion systems and is highly lipophilic.

A randomized double blind cross-over study looking at the addition of bupivacaine to deliver 4, 6, or 8 mg/day, through an intrathecal pump already delivering chronic morphine or hydromorphone, found no added benefit for bupivacaine [23]. On the other hand, a double blind study of 20 cancer pain patients, who failed conservative medical management, found that the combination of intrathecal morphine and bupivacaine blunted the escalation of intrathecal morphine dosing significantly [24]. The high lipid solubility of bupivacaine means that the catheter tip location is likely critical for its effectiveness in regional pain conditions.

Again, while preservative-free morphine and ziconotide are the only FDA-approved medications for intrathecal administration, the treatment of chronic pain often employs combination therapy in clinical practice. These other agents are used off-label or in combination with each other. The lack of FDA approval for these other medications hinders prospective studies and limits ability to adequately investigate their effectiveness when used alone or in combination. Neuraxial administration of a combination of local anesthetics and opioids is synergistic for pain relief in rats [25]; however, such an assertion cannot be easily made in human studies and may involve a number of other variables [26]. Research could demonstrate that combination therapy is superior to monotherapy, given the complexity of pain signaling mechanisms; however, no human studies have shown that potential [4].

The agent that has grown in popularity and is more routinely employed in ITT is the nonopioid medication ziconotide. It is the only nonopioid intrathecal option for IT treatment of chronic refractory pain [27]. There are three randomized placebo-controlled trials that suggest efficacy and another open-label multicenter study that demonstrates safety [14–16, 28]. The use of ziconotide has been shown to be helpful in both neuropathic and nociceptive pain in properly selected patients [14]. The side effects include dizziness, nausea, confusion, ataxia, myalgia, memory impairment, and induced psychiatric disorders. The psychiatric disorders are less frequent but can include auditory and visual hallucinations. This is why it is contraindicated in people with a history of psychosis and schizophrenia.

Ziconotide has been clearly defined in both animal and human studies to have linear kinetics, with a half-life of 4.5 h [6, 29]. Trials for this therapy are usually single-shot boluses; however, chronic ziconotide therapy is routinely begun as a simple continuous rate, with low starting doses and a slow titration schedule. There is a possibility that failure of this therapy after a positive trial may be the result of a pharmacokinetic difference between chronic continuous infusion and bolus delivery. The behavioral side effects, as represented in the dog model, were also altered with intrathecal infusion, but not with the intrathecal bolus [6]. This has been observed in human clinical trials, whereby patients using fast titration schedules consistently reported pain relief at high doses, but the usefulness of this relief was mitigated by side effects [13]. These side effects included neuropsychiatric adverse reactions, reduced level of consciousness, and elevation of serum creatine kinase. Thus, patients with a history of psychosis should not receive ziconotide. Pain physicians must have partnerships with mental health specialists to evaluate ITT candidates with a history of psychological pathology. If a patient has such a history, morphine may be a better choice, assuming the patient meets the other selection criteria [30].

Morphine , and other opiates used in ITT, underwent preclinical safety examination in animals, as measured by the Neurotoxicity Standardized Assessment. In chronically catheterized large animal models, the data showed that continuous infusions of morphine, hydromorphone, methadone, or fentanyl, for at least 28 days, caused no spinal tissue damage at the highest doses and concentrations examined [31]. Morphine monotherapy efficacy clinical data on IT morphine continued to support its use as a first-line therapy. Results from several long-term studies support the efficacy of IT morphine in treating patients with chronic pain, including both cancer and noncancer pain types [7]. One example is a retrospective study, which examined patients with chronic malignant pain on long-term IT opioid therapy including morphine, hydromorphone, or sufentanil [32]. They noted that the Visual Analog Scale (VAS) scores significantly decreased from baseline up to the time of first refill. These scores remained stable and significantly lower than baseline scores for 3 years.

In a prospective, open-label study of IT morphine infusion, 110 patients with chronic pain were implanted and followed for 1 year [33]. Pain relief was noted within 1 month and was sustained for the 12-month period. Another open-label study examined patients with intractable pain due to chronic pancreatitis. These results showed a reduction in pain scores from an average of 8.3 to an average of 0.75 at the last follow up after 29 months [34]. For patients with vertebral fractures due to osteoporosis, who did not respond to oral opiates, an open-label study of IT morphine was conducted [35]. The mean VAS pain scores decreased significantly from 8.7 cm before IT therapy to 1.9 cm after 1 year. They also saw improvements in quality of daily life, ambulation, and perception of health status. Interestingly, a retrospective study designed to identify characteristics of patients likely to benefit from IT morphine therapy found a greater than 50% decrease in pain in 73% of patients [36]. The study included patients with multiple subtypes of pain, including cancer related, nociceptive, and neuropathic. No differences in responder rates were noted, regardless of pain type, patient age, or morphine dosage.

Many providers struggle with which agents to start with and which ones to add if the previously tried medications fail. The Polyanalgesic Consensus Conference in 2012 defined tiers of therapy in treating neuropathic pain [7]. Tier one for neuropathic pain includes morphine and ziconotide as monotherapy, along with morphine and bupivacaine in combination. If this fails, the second tier includes hydromorphone as monotherapy and combination therapy with bupivacaine or clonidine. Also included in the second tier is a combination of morphine and clonidine. The final tier suggests monotherapy with clonidine or fentanyl, as well as combination therapy using ziconotide with an opioid in combination with bupivacaine or clonidine [7].

The understanding of drug distribution in the CSF has been a large focus of investigation. Textbooks have portrayed CSF in the IT space as flowing cephalad to caudad, by bulk flow, along the posterior surface of the spinal cord, and returning cephalad along the anterior surface [37, 38]. If true, this CSF motion would be expected to move drugs considerable distances. Animal studies have found that this portrayal of CSF movement is incorrect [5]. Numerous human studies using Magnetic Resonance Imaging techniques have shown that CSF oscillates back and forth along the rostro-caudal axis [39, 40]. This motion is driven by cyclic expansion and contraction of the cerebrospinal vasculature during cardiac systole and diastole. The magnitude of motion is greatest in the upper cervical regions and decreases with more caudal distances from the foramen magnum. The oscillation of CSF becomes negligible at the level of the cauda equina [5].

One detailed examination of drug distribution in the CSF using bupivacaine (lipophilic) and lioresal (hydrophilic) found most of the bupivacaine and lioresal were recovered within 1 cm of the site of administration [5]. Drug concentrations in CSF between these two drugs reached steady state using a continuous infusion before the 8th hour of administration. This suggests that a longer period of drug administration would be unlikely to significantly alter the limited distribution of either bupivacaine or lioresal. Other studies have shown that net CSF motion is limited for multiple reasons, which include the following: CSF being propelled in opposite directions during each cardiac cycle, smaller CSF pulse waves at larger distances from the cranium, and CSF motion only occurring in the rostro-caudal axis—not circumferentially [5]. This could explain why patients can have marked, permanent rostro-caudal CSF concentration gradients for many molecules. These pharmacokinetic properties of medications in the CSF have led to a paradigm shift regarding the importance of catheter position. Yet, there is little published data on region-specific catheter location recommendations. Most practitioners determine catheter placement based on the patient’s dermatomal location of pain or based on SCS paresthesia mapping [11].

There is no historical literature indicating a sound trialing method for predicting long-term success of intrathecal therapy by slow continuous infusion [7]. Trialing was previously thought to be critical, but this has come under scrutiny of late. It is felt that real insight into the success of long-term ITT cannot come from a single-shot trial or even from a brief 72- to 96-h infusion. Trialing may lead to an underestimation of the failure rate with long-term infusion. In chronic noncancer pain patients, it was found that groups of patients who had previously tolerated a drug after a trial bolus were accurately predicted to have long-term success with slow continuous infusion [41]. Yet, explants of IT pumps secondary to refractory pain do happen. In addition, the national trial-to-implant ratio is close to 40%, due to lack of at least a 50% reduction in pain or an improvement in function [42]. Contrary to ITT, positive results with an SCS trial are an excellent predictor of implant success.