Ziconotide is a synthetic version of a 25 amino acid polybasic peptide found in the venom of a marine snail (Conus magus) that selectively blocks the presynaptic N-type Ca²⁺ channels. Blockade of these Ca²⁺ channels inhibits pain signal transmission by inhibiting the release of calcitonin gene-related peptide, glutamate, and substance P [39]. Ziconotide is one of the two medications approved by the FDA for the treatment of chronic pain in the IT space, and a number of clinical trials have shown that ziconotide is safe and efficacious in the treatment of intractable pain [40–43].

Significant adverse effects are associated with the administration of IT ziconotide at a sizable rate (11.6–30.6 % compared to a placebo rate of 2–10 %) and include psychiatric disturbances (depression, anxiety, hallucinations), pain, dizziness, diplopia, nystagmus, gait abnormalities, headache, cognitive (memory) impairment, speech disorder, urinary retention, nausea, somnolence, and nervousness [44–47].

The 2012 PACC considers ziconotide to be a treatment for patients with nociceptive and neuropathic pain. Ziconotide may be used alone as a first-line agent or in combination with an opioid as second-line treatment in the PACC algorithm. The use of ziconotide in combination with an opioid (hydromorphone or fentanyl), bupivacaine, or both opioid and bupivacaine was associated with delayed adverse effects leading to discontinuation of ziconotide in nearly two-thirds of the patients [48]. It should be noted that ziconotide has limited stability in combination with intrathecal morphine [49]. One must be cognizant that there is a higher prevalence of adverse effects associated with increased dosage, patient age, and titration rate [41]. Initial doses should not exceed 0.5–2.4 mcg/day and the maximum daily dose recommended is 19.2 mcg/day. Titration should be done carefully to limit the potential adverse effects.

Local anesthetics are commonly used in the treatment of both acute and chronic pain, and are utilized for both regional and neuraxial anesthesia. The mechanism of action for local anesthetics is to block the voltage-gated Na⁺ channels in the neuronal cell membrane, thereby blocking action potential propagation [50]. Local anesthetics preferentially act on the fila radicularia given the large surface-to-volume ratio of the rootlets compared to the spinal cord [51].

Bupivacaine, an amide anesthetic with high lipid solubility, is the most commonly used local anesthetic utilized for continuous spinal infusion to relieve acute and chronic pain. Although many local anesthetics have been used for the treatment of pain in the IT space, bupivacaine is the only local anesthetic included in the PACC algorithms for IT therapies in neuropathic and nociceptive pain. According to the 2012 PACC algorithms, bupivacaine is considered to be first-line treatment in combination with morphine for neuropathic pain and second-line treatment for nociceptive pain in combination with opioids (fentanyl, hydromorphone, and morphine) [32]. Again, it should be noted that these recommendations are likely based on consensus rather than evidence, as local anesthetics block neuronal transmission of pain signals regardless of nociceptive or neuropathic nature. Combination therapy is often utilized because local anesthetics and opioids have been found to act synergistically when administered intrathecally for pain in acute pain (postoperative and labor) and animal models of chronic pain [52–58]. Combination therapy has the added benefit that it can also decrease the rate of dose escalation [37, 58]. Conversely, a double-blinded randomized control trial found that bupivacaine, up to 8 mg/day, did not offer better pain relief when added to opioids when compared to opioids alone [59]. However, other studies have shown a beneficial effect on pain with average bupivacaine daily doses around 10 mg [37, 60].

The long-term safety of bupivacaine infusion in the IT space has been shown in animal models [61, 62]. Although local anesthetics are considered to be safe, there is a potential for adverse effects such as neurotoxicity [63–65], weakness, numbness, urinary retention, and hypotension. The limiting factor is generally due to sensory and motor loss. Doses of IT bupivacaine as high as 125 mg/day have been reported [66]; however, guidelines recommend an initial dose of 1–4 mg/day and a maximum of 10 mg/day [32]. Nonetheless, many studies report average daily bupivacaine dosage around 10 mg [37, 60], suggesting that a substantial proportion of patients receive greater than 10 mg/day—especially if one factors in amounts received through patient-activated boluses.

Clonidine is a selective alpha-2 adrenergic agonist that is occasionally used in the spinal space for the treatment of pain. Clonidine acts by inhibiting nociceptive impulses at the dorsal horn of the spinal cord by activating pre- and post-junctional alpha-2 adrenoceptors. In addition to this mechanism, increasing evidence has shown that activated spinal cord glial cells contribute to enhanced pain states due to the release of proinflammatory cytokines. In the IT space, clonidine has been shown to markedly inhibit the neuroimmune activation associated with neuropathic pain states which is characterized by glial activation, production of cytokines, and activation of NF-κB and p38 [67].

The addition of clonidine may be considered for a patient who has neuropathic pain [32, 68–70] or to potentiate the effect of opioids, as alpha-2 agonists and opioids have a synergistic relationship [71–73]. According to the PACC 2012, clonidine may be used for neuropathic or nociceptive pain states. When treating neuropathic pain, it is a second-line agent when used with morphine or hydromorphone, a third-line agent as monotherapy or when used with fentanyl, and a fourth-line agent in combination with an opioid and/or bupivacaine. For nociceptive pain, it is a third-line agent when used in combination with an opioid and fourth line in combination with an opioid and bupivacaine. The starting dose recommended by the PACC is 40–100 mcg/day with a maximum recommended dose of 600 mcg/day [32]. It should be noted that clonidine has been shown to provide analgesia in a dose-dependent manner when used in the spinal space [67, 68, 74].

Adverse effects may include bradycardia, confusion, dizziness, dry mouth, hypotension, nausea, orthostasis, and sedation. Cardiovascular adverse effects paradoxically occur more frequently at lower doses. In addition, depression, insomnia, and night terrors have been reported with the use of intraspinal clonidine [75]. With abrupt discontinuation, rebound hypertension occurs [76], making titration down of clonidine, when used in combination with other drugs, a challenge.

A trial is generally performed before a patient undergoes permanent implantation of an IDDS. The reasoning behind trialing is that it can provide clinical information on whether or not the therapy will prove to be efficacious for the patient. Although the trial only proves efficacy in the short term, the long-term efficacy can be inferred. There are many techniques that can be utilized when performing a trial. Trialing techniques include single shot or bolus dosing (epidural or IT), continuous infusions (epidural or IT), or using a combination of these methods. In addition, trialing can be performed on an inpatient or outpatient basis [77]. The most common technique utilized for trialing in the USA is the continuous IT catheter (45 %) [78]. The continuous IT catheter is considered to be the “gold standard” since it closely replicates the permanent IDDS. However, there is limited data to support that this technique is superior. One should also consider the potential disadvantages when placing a continuous catheter: risk of infection, increased cost, and the potential for spinal cord injury [79]. Additionally, most externalized pumps used in trialing deliver rates around 20 times the daily infusion rate used in IDDS; such high infusion rates result in wider and deeper spinal spread [24] and may explain occasional reports of significantly better analgesia during trial that are not replicated after implant. Each practitioner should adhere to a trialing protocol that is safe and appropriate to obtain the information needed to determine if a trial is successful or not. In general, a trial is considered successful if the patient has >50 % pain relief and at that point would undergo permanent implantation.

FBSS and VCFs are the most common indications reported in the literature for IDDS use for spine-related pain [8, 11–13, 68, 80, 81]. FBSS refers to patients with persistent or new pain after spinal surgery for back or leg pain. In patients who have FBSS with a predominance of axial pain, an IDDS can be a good option if other more conservative measures fail or are not tolerated. Many studies have shown significant improvement in pain scores in FBSS patients following implant of an IDDS [8, 12–14]. VCFs can also cause a significant amount of axial pain amenable to treatment with an IDDS if refractory to conservative measures. In one study, 24 patients with severe osteoporosis and VCFs who were refractory to conservative measures underwent placement of an IDDS [9]. The results from this study by Shaladi et al. revealed significant improvement in VAS scores (8.7 pretrial to 1.9 at 12 months), improved quality of life/function, and eliminated use of oral opioids [9]. Although there is literature to support the use of IDDSs in patients with spine-related pain especially in patients with FBSS, there is a need for more supportive evidence with prospective randomized control trials.

The complications associated with IDDS implantation can be grouped into several categories which include drug, device, procedural, or programming related.

Drug complications are common and are most commonly associated with the use of IT opioids; these drug complications can include peripheral edema, hormonal changes, respiratory depression, and granuloma formation. IT ziconotide is associated with CNS side effects that may make the drug intolerable (see “Intrathecal Medications” for further discussion of drug complications). A retrospective review revealed that the most common cause of IDDS complication was secondary to IT medications, although the effects were transient (77 %) [82].

Complications due to the device can be attributed to the pump and/or the catheter. However, catheter-related complications do account for the majority of known device complications. Potential causes of device failure include changes in performance or failure of the catheter (micro-fracture, pinhole leak, kink, disconnection, breakage, shearing, migration, partial occlusion, tip fibrosis, inflammatory mass), unexpected battery depletion, component or motor failure (corrosion), and catheter access port failure [83]. One prospective study revealed that most catheter-related complications are determined by surgical technique [84]. The type of catheter used may also play a role in developing a potential complication [84]. Placement of the IT catheter in a paramedian approach can prevent shearing by spinous processes and decrease the likelihood of a catheter complication [82]. Device failure secondary to the pump is less common and has been reported to be between 1 and 12.5 % [82, 85]. Type of IT drug may play a role in device failure. Device failure has been reported to occur at a significantly higher rate when using non-approved IT drugs (7.0 %) versus approved IT drugs (2.4 %). Non-approved drugs can cause corrosion inside the pump due to corrosive agents (chloride ions, sulfate ions) in the drugs. Drug qualities such as hydrophobicity, degree of positive ionization, impurities, preservatives, pH adjustments, and concentration adjustments can increase the rate of corrosion. Catheter and device failure can result in abrupt cessation of IT medications and depending on the drug can be serious and potentially life threatening.

Procedural related complications include post-dural puncture headaches, CSF leak, pocket pain, spinal cord injury, hematomas (epidural or pocket), and wound dehiscence. Needle entry should be at or below the L2/3 interspace, if possible, to decrease the likelihood of spinal cord injury. Placement of a purse string suture around the catheter is recommended to reduce the chance of a CSF leak. Securing the reservoir to the fascia rather than the muscle will decrease the rate of persistent pocket pain. Adequate hemostasis and adherence to anticoagulation guidelines can help decrease the risk of hematoma. Should a patient develop a post-dural puncture headache, they can be managed conservatively with analgesics, hydration, caffeine, and laying in the supine position. If refractory, a post-dural puncture headache following IDDS placement may be treated with an epidural blood patch, and care must be taken to avoid damage to the IT catheter. Although there are many possible procedural complications, most can be avoided by utilizing proper surgical technique [34].

An IDDS-related infection is a potentially serious complication that may require discontinuation of therapy. The rate of infection reported in the literature is usually reported as less than 5 % [34]. A preoperative prevention technique for surgical site infection may include intranasal mupirocin in patients who are carriers of Staphylococcus aureus [86]. Some practitioners may have patients shower preoperatively with chlorhexidine gluconate which may reduce skin flora; however, it has not been found to reduce surgical site infections [87]. A superficial skin infection may be treated with close monitoring, consultation with an infectious disease specialist, and appropriate oral antibiotics. If a patient develops a deep infection the device should be removed, intraoperative cultures should be obtained, and appropriate antibiotics should be initiated. When an epidural or bony infection is suspected, advanced imaging with and without contrast should be ordered. There have been reports of successful device salvage, although this is not common practice and the risks and benefits must be weighed [88, 89].

IDDSs have proven to be beneficial in the treatment of chronic spine pain. When utilizing this treatment it is important to have in-depth knowledge of the neuraxial space, CSF flow dynamics, indications, IT medications, device matters, and potential complications. This advanced technology is not first-line therapy due to the fact it is invasive and costly, but when it is applied to a well-selected candidate it can be life changing. The current use of IDDSs focuses on chronic pain and spasticity although novel applications are being studied. Additionally, novel devices have entered the marked and some are in pre-market stages. The future of intrathecal drug delivery for pain will depend on successful delivery of positive outcomes with limited complications as well as on the performance of competing neurostimulation devices.