Intrathecal analgesic therapy allows the drug to reach the site of action directly through the cerebrospinal fluid, resulting in significant pain relief in patients who are tolerant or intolerant of side effects to other modes of administration. However, the success of intrathecal analgesic treatment requires several factors to be considered: strict knowledge of the patient’s indications, detailed knowledge of the patient’s pain condition and reasonable patient expectations. Dr. Robert Bolash summarized the current indications, case selection, techniques and prognosis for intrathecal analgesia in a recent issue of Neurosurg Clin N Am. Intrathecal analgesia is currently one of the most important treatment options for patients with chronic pain. Although many drugs are available for the treatment of injurious pain and neuropathic pain, only morphine and ziconotide are currently permitted by the FDA for intrathecal administration of pain medications. Continuous intrathecal administration of pain medications increases local drug concentrations in the subarachnoid space, which can lead to lower pain scores and alleviate many of the side effects that can be caused by systemic administration. Intrathecal drug delivery results in lower costs for patient life measures and overall healthcare utilization compared to traditional drug delivery, suggesting that this route of intrathecal drug delivery will have an important place in the increasingly cost-conscious world of healthcare. Indications for Use Although intrathecal drug delivery has been widely used to treat intractable pain from a variety of malignancies, there is growing evidence supporting their use, in addition to the continued popularity of epidural opioid delivery for non-cancerous chronic pain. By delivering opioids to the posterior horn of the spinal cord pain can be relieved at low concentrations relative to systemic administration. In addition, side effects are often mitigated by the administration of drugs via analgesic pump implantation devices, which also allows for some resolution of opioid dosing problems and drug dependence issues. Newer intrathecal drug delivery devices also allow for the adjustment of analgesic effects by the patient’s own needs. Although opioids have been administered in many ways, recent studies have found that the non-opioid analgesic ziconotide needs to be administered directly through the cerebrospinal fluid and intrathecally to have its only efficacy. As the use of ziconotide has increased, the number of patients using intrathecal delivery devices has also increased over time. Although not discussed in this article, intrathecal administration is also widely used to treat spasticity in children and adults. Intrathecal analgesic treatment is often the last option for patients who have failed or cannot tolerate conservative treatments such as opioids, non-opioids, and non-pharmacologic interventions. Therefore, diagnostic criteria for pain should be established to classify pain as injurious or neuropathic, and its severity, in order to guide the choice of drugs for intrathecal administration. In addition, the treatment of chronic pain requires circadian administration of drugs. The cause of pain often cannot be corrected by other means, and the risk of treatment by surgery is usually considered much greater than intrathecal administration of analgesic therapy. Patients with progressive intolerable side effects due to oral opioids can benefit from direct injection of the drug into the cerebrospinal fluid, including intolerable sedation, constipation, and other adverse effects despite pain relief from oral opioids. When these drugs are administered intrathecally, many patients not only experience pain relief, but also avoid cognitive and gastrointestinal adverse effects. Case selection The judicious selection of patients for intrathecal analgesia may be the key to successful continuous intrathecal drug delivery. Patient selection requires a collaborative discussion among interventionalists, counseling professionals, patients, and their caregivers to decide. There are several steps to determine if a patient should receive intrathecal drug delivery. Treatment of all patients also requires evaluation and optimization of complications due to pain. Indications for the need to receive intrathecal analgesic treatment: 1. The diagnosis of pain has been established and can be classified as neuralgia, injurious pain or mixed pain according to its symptoms; 2. Chronic or progressive pain due to cancerous or non-cancerous causes; 3. The pain can last almost all day and cannot be relieved; 4. The patient has failed with conservative pharmacological treatment; 5. The patient has developed tolerance or cannot tolerate oral painkillers First, the physician identifies the patient in need of intrathecal analgesia, diagnoses the pain, and ensures that other conservative treatments are no longer effective. Second, the patient is shown the intrathecal drug delivery device and his or her expectations, comprehensive understanding, and support system are assessed. Because intrathecal administration can only achieve pain control but not eradication, physicians and patients should have realistic expectations about the outcome of treatment. It is also important to assess and treat patients for psychiatric complications, which may hinder the success of treatment. Assessing mental status is particularly important when treating with ziconotide because ziconotide itself can exacerbate mental illness, impair cognition and produce suicidal ideation. Although no prospective studies have shown that ziconotide use can make patients with pre-existing psychopathology more susceptible to the development of new psychiatric symptoms, many psychiatrists still consider psychosis a contraindication to ziconotide use. Multidisciplinary teams should focus on how they can optimize the success of patients treated with intrathecal drug delivery and not just as a last resort for treatment. Patient dissatisfaction with treatment outcomes continues to be a reason for premature adjustment or early device removal, with only 51% of patients being satisfied with treatment outcomes after 12 months of treatment. These dissatisfied patients were mainly due to the high cost of treatment. In the authors’ unit, 11% of all patients successfully underwent permanent intrathecal drug delivery device implantation due to dissatisfaction with long-term treatment. Surgical Techniques Perhaps some of the unique implantations in the management of pain interventions are an opportunity for patients and physicians to ensure successful and satisfactory patient care. Similar to the short-term temporary spinal cord stimulation trial, the implantable intrathecal drug delivery system is performed through a simple trial in which the drug can be temporarily administered through this sheath tube. During this trial, the degree of pain relief is quantified and the occurrence of adverse effects is recorded, and the final prognosis of the patient is evaluated. Intrathecal drug delivery devices often contain a drug reservoir, pump, and catheter. Trial Trial A definitive diagnosis of pain is important for the decision to proceed with intrathecal analgesic pump implantation and is critical to the success of a patient in an intrathecal pain relief trial. This trial provides us with several roles, including the ability to provide an evaluation of pain score change and functional status recovery. It also allows evaluation of opioid-related side effects and the degree of reduction in oral pain medication dependence, and the observation of patient mental status during the trial provides data for psychiatric evaluation, as well as quantifying dose at response consistency and providing a basis for observing patient expectations. There are no expected data to demonstrate the superiority of a single trial method over other methods, and the operator can complete the trial by continuous or intermittent epidural or intrathecal administration. Although the recommended procedure is outlined, the actual test depends on the operator’s preference and the equipment available, and the duration of the test is determined by the patient’s response to the drug. The epidural test can avoid subdural puncture and potential post-puncture headache episodes, but it requires a 10-fold increase in the dose of opioids. In addition, the epidural test can exclude the influence of cerebrospinal fluid dynamics on the test drug. While the positive epidural test group yielded supportive information, the negative epidural test group could not exclude the possibility of successful intrathecal drug administration. Intrathecal testing can be accomplished by single, multiple, or continuous drug administration via intrathecal catheter implantation. The catheter implantation allows for continuous drug entry into the sheath, mimicking the technique of drug pump pharmacokinetics and avoiding drug fluctuations due to repeated dosing. The end point of intrathecal drug delivery trials is defined as greater than or equal to 50% pain relief in the study or clinic. Many investigators also tend to consider the return of function and diminished dependence on oral opioid analgesics as the cut-off point for a successful trial. A trial is considered a failure if pain relief is not achieved, the side effects of the trial drug are significantly worse than the benefits achieved, patient satisfaction with treatment is low or psychiatric symptoms are significantly worse during treatment. Drug Selection Although the only drugs currently permitted by the FDA that can be administered intrathecally for pain relief are morphine and ziconotide, many single or combination drugs, including hydromorphone, fentanyl, sufentanil, bupivacaine, baclofen, and colistin drugs, are also in use. Non-permitted drugs are also recommended in consensus guidelines, even to be used as first-line drugs for neuropathic and injurious pain. An FDA clinical phase 3 trial is underway to verify the safety and efficacy of intrathecal hydromorphone administration. Baclofen is also permitted by the FDA to be administered intrathecally, but only in the late treatment of spasticity and severe neuropathic pain. Intrathecal administration trials are usually with a single drug, such as morphine or ziconotide. The committee has proposed two methods for selecting drugs for long-term intrathecal administration of therapy. Drug selection and recommended decisions vary depending on the different causes of pain. Single-drug therapy is recommended at the beginning of treatment, and drugs with synergistic effects are used in combination only in the later stages of treatment. Drug recommendations for intrathecal analgesia for neuropathic pain Devices Intrathecal drug delivery systems require an infusion pump device implanted into the sheath, including a reservoir, mechanical pump, and catheter. A variety of non-programmable and programmable pumps and various catheter systems are available on the market. Non-programmable fixed-frequency pumps deliver medication continuously into the sheath, and although these devices are less expensive, the concentration of medication in the reservoir must be changed if the dose needs to be adjusted. Programmable pumps can deliver different doses of medication into the sheath by adjusting the frequency of drug delivery. There are two types of programmable pumps available: SynchroMed II (Medtronic, Minneapolis, MN) and Prometra (Mount Olive, NJ). Physicians can pre-set different doses, and patients can administer a single dose according to their needs via the SynchroMed II system’s wireless sensor. There are also a variety of sizes of storage devices that patients can choose from based on their habits and desired refill intervals. Implantation procedure The drug reservoir is usually placed in the dural sac in the subcutaneous channel of the abdominal wall. Prior to implantation, the midpoint of the rib cage and iliac crest is marked as the site for placement of the drug reservoir, which is chosen to meet the patient’s wishes and to ensure that the patient does not experience discomfort. The patient is placed in a lateral position during the procedure, with the drug reservoir placed laterally upwards. After the procedure begins, the puncture needle is oriented toward the dural sac, advanced along the median plane until the dura is pierced, and cerebrospinal fluid is visible after the needle core is plucked out, and the catheter is implanted through the needle hole into the subarachnoid space. The puncture needle is immobilized, and an incision is made at the caudal end of the needle to separate the skin and deep subcutaneous tissue up to the supraspinous ligament. A non-absorbable thread is fixed to the supraspinous ligament and the catheter is secured to the supraspinous ligament after the puncture needle is withdrawn. After everything is in place, it is confirmed that the cerebrospinal fluid can flow out of the catheter. An incision is made in the preoperatively marked anterior abdominal wall area to create a drug reservoir placement pocket. The subcutaneous tissue is bluntly separated along the incision to a depth of 1 inch, where the reservoir is placed and secured in the deep tissue to prevent rotation or flipping. Finally, the intrathecal catheter and pump are connected through a subcutaneous channel. The extra catheter site is placed deeper in the pump to prevent pulling during patient movement. The incision is closed with continuous sutures and the parameters are set after activation of the device to start drug delivery. Results There are numerous reports in the literature regarding the effectiveness of intrathecal drug delivery for the treatment of neuropathic and injurious pain due to cancerous and noncancerous causes. Although intrathecal analgesia has been accepted by most patients with end-of-life pain, the use of intrathecal analgesia for non-cancerous pain can improve quality of life as more and more evidence supports this. Ziconotide is also widely accepted because its therapeutic dose level, once established, no longer requires continuous dose increases. Cancer pain A subset of patients in a terminal state have been extensively treated with intrathecal administration of pain relief with success. In a multicenter trial, 119 patients with cancer pain or intolerance of opioid side effects received intrathecal devices through which patients received the amount of medication they needed. Results showed that after 1 month of intrathecal administration, 90% of patients had pain scores that were reduced by more than or equal to 50%; at the end of the 4-month study, pain scores were consistently decreasing. Intrathecal analgesia combined with pharmacologic management is beneficial in patients with intractable cancer pain. Although clinical success with intrathecal analgesia was defined in this study as a reduction in pain scores greater than or equal to 20%, patients with intrathecal analgesia achieved more success than those in the conventional medication management group. In addition, fatigue testing and alertness were improved in the intrathecal analgesia group, which ultimately led to an improvement in the patients’ quality of life. Ziconotide has also been shown to be effective in the management of pain in oncology and AIDS-related terminal patients. In a randomized controlled trial, patients were treated with ziconotide and placebo in a crossover of the arm. Results showed a 53.1% reduction in mean pain scores in the treated arm, with 52.9% of patients reporting moderate to complete pain relief during the treatment period. Non-cancer pain A cohort study including 57 patients confirmed the success of intrathecal opioids in the treatment of non-cancer pain. Patients’ visual analog pain scores decreased between the start of implantation and the first refill, and remained low over the 3 years of observation. After 1 year of follow-up, the dose of oral opioids was reduced from 183.9 mg per day to 43.5 mg per day in intrathecally administered patients. In a study including 24 patients with intractable pain due to vertebral compression fractures that were not treated with oral and percutaneous opioids, the mean pain score decreased from 8.7 to 1.9 in a cohort managed with intrathecal morphine administration, and after the first intrathecal morphine treatment, quality of life and perceived health status also improved. Although the cohort study showed an increase in intrathecal morphine use at 1 year, all patients had significantly lower doses of oral pain medication. Ziconotide has been shown to be similarly effective in the treatment of non-cancer pain. In a randomized, double-blind controlled trial of 169 patients with non-cancerous pain who received ziconotide as a continuous infusion over a six-day hospital stay, pain scores in the treatment arm improved by 31.2%, compared with only 6% in the placebo group. Intrathecal analgesic management not only resulted in lower pain scores, but more importantly, improved functional and mental status. In a prospective study of 30 patients with chronic non-cancerous pain, 24 months after implantation of intrathecal analgesic pumps, the rating, affective and sensory components of the McGill Pain Questionnaire improved, 92% of patients returned to work, and 82% of retired patients were largely self-care at home without care. Several investigators have published, in large cohort studies, factors that influence increasing doses of opioids when managing patients with chronic noncancer pain. There was no consistency between age and prediction of rapid increases in drug dose, with the older the age, the slower the development of tolerance. Preoperative factors, including gender, comorbidities, duration and dose of oral therapy and diagnosis, predicted which group of patients would require rapid dose increases for intrathecal administration. Subgroup analysis found a strong association between patients with neuropathic pain and rapid dose increases. In another cohort study, it was found that the combination of patients in the bupivacaine group resulted in a reduced increase in drug dose compared to the opioid alone group. In conclusion The success of intrathecal analgesia depends on a number of factors, including a thorough understanding of the pain situation, careful patient selection, meaningful experimental use, and an understanding that patient expectations need to be consistent with the realism of the outcome. As intrathecal drug delivery systems become more frequent and less costly, and as there is increasing evidence that intrathecal drug delivery improves prognosis, it will continue to be an important part of the treatment of chronic pain syndromes.