Intrathecal Drug Delivery (ITDD) systems for cancer pain

Introduction

Intrathecal drug delivery (ITDD or IDD) is a method which provides analgesia by a direct continuous infusion of medication into the cerebrospinal fluid (CSF). The rationale is based on the concept that direct delivery into the CSF within the intrathecal space avoids crossing the blood-brain barrier and allows delivery of smaller doses than oral, intravenous, transdermal or epidural drug administration¹. The spinal cord is a key anatomical site for pain processing and more specifically the dorsal horn of the spinal cord within the intrathecal space. There are various receptor targets within the spinal column that can be utilized in relieving pain. These receptors include opioid (mu, kappa, and delta), GABA, alpha-2, dopaminergic, NMDA as well as sodium and calcium channels². The advantage of delivering the medication directly into the CSF in smaller dosages to target the specific receptors is that it may reduce the systemic side effects and the direct delivery to the site of action allows a more rapid and effective response. As a popular alternative for patients experiencing cancer or chronic pain, intrathecal analgesia has become a therapeutic option for patients who have exhausted all other treatment avenues as well as patients experiencing side effects from their current treatment options. The system uses a small pump that is surgically placed under the skin of the abdomen and delivers medication through a tunneled catheter directly into the intrathecal space³. The pump is refilled periodically through a subcutaneous access port in an office setting utilizing a sterile technique. The pump can be programmed to be a fixed-rate, constant flow device or a variable rate pump with the option of boluses via patient controlled analgesia programming using a wireless radiofrequency transmitter given to the patient¹. In contrast to more conservative oral or intravenous delivery methods, ITDD is becoming increasingly popular for its efficacy in managing cancer and chronic pain. This review will specifically target ITDD uses for patients with cancer-related pain although its use has also been very popular in patients with chronic non-cancer pain.

Cancer pain: epidemiology

The incidence of deaths due to cancer has been estimated to be 6.6 million people globally each year⁴. Pain is often considered as the most feared symptom amongst individuals living with cancer and it can occur at any point during the course of the illness. Pain is often also the first sign of malignancy⁴. Pain is also often associated with the treatment of cancer and it can present itself as both acute and chronic pain. Furthermore, advancement of the disease process can lead to pain or make the existing pain worse. It is difficult to estimate the prevalence of cancer pain because of a lack of standardization in definitions of pain and in the measures used to assess it⁵. The other factor that makes it challenging in estimating the prevalence is the heterogeneity of nociceptive and neuropathic pain conditions⁶. About 50% of patients will report pain as a symptom at the time of cancer diagnosis and early in the course of disease⁶. Its prevalence increases to 75% or more at advanced stages. A strategy should be devised to evaluate the prevalence of pain in patients with cancer by separating the pain related to the disease process, to its treatment, or to unrelated causes.

Prevalence of pain related to cancer

According to a systematic review of the past 40 years by van den Beuken et al. published in the Annals of Oncology in 2007⁴, the range of reported prevalence of pain is highest for the following tumors:

Treatment options

The various treatment options for cancer pain generally depend on the location, character, duration, its origin, and the success or failure of previous and ongoing treatments. Treatment options for cancer-related pain include oral non-steroidal anti-inflammatory drugs, oral opioid analgesics, neuropathic pain medications, parenteral opioids, peripheral nerve blocks, neurolysis such as celiac plexus blocks, local anesthetic injections, spinal cord stimulation, continuous epidural analgesia, and intrathecal pumps. In most cases, multiple forms of treatment are used for the most effective treatment combination. Opiates such as morphine, dilaudid, fentanyl, and sufentanil are most commonly administered via the intrathecal drug delivery system for cancer-related and non-malignant pain⁷. There is increasing evidence that intrathecal opioids are superior to oral delivery in malignant pain, especially when narcotic dosage is limited by its side effects¹. It is believed that this advantage results from delivering extremely small doses on target receptors in the spinal column⁸ (see Table 1).

There are other agents also available to treat neuropathic pain, spasticity related pain, sympathetic pain, and visceral pain (see Table 2 for examples). In addition, ITDD systems can also be used to deliver chemotherapy agents such as floxuridine and methorexate for the treatment of primary or metastatic cancer. Table 2 below lists the most commonly targeted receptors and the medications used for each receptor.

One of the most important clinical decisions a provider has to make is what agent to use in the intrathecal pump and in some cases, multiple forms of treatment are used for the most effective treatment combination. In this review, we looked at the recommendations of The Polyanalgesic Consensus Conference (PACC) 2012 which lists the algorithms for intrathecal therapies in both neuropathic and nociceptive pain (Table 3 and Table 4). The algorithm lists the medications that are arranged in a hierarchy on the basis of evidence of efficacy and safety. The approaches are listed from Line 1 (first line approach) to Line 5 (a more advanced approach if previous approaches are unsuccessful).

Intrathecal drug delivery systems

One option, intrathecal analgesia, has become a therapeutic option for patients who have exhausted all other treatment avenues as well as patients experiencing side effects from their current treatment options³. In intrathecal drug delivery or ITDD, medication is delivered directly into the CSF in the intrathecal space (Figure 1); therefore, a substantially smaller dose of medication is required compared to the oral or intravenous route. With lesser dosage of the medication and a more direct route to the pain processing center in the spinal cord, the patient generally experiences superior analgesia with fewer side effects such as nausea, pruritis, erythema, flushing, constipation, etc. However, intrathecal delivery of medication also poses significant risks such as respiratory depression, infection, bleeding, epidural/spinal hematomas, spinal cord injury during initial catheter placement, wound dehiscence, pocket seromas, pump malfunction, and costs.

Figure 1. © 2010 Image of the spine illustrating placement of the catheter into the intrathecal space which is connected to an implanted pump containing the drug reservoir.

Reprinted with the kind permission of Medtronic, Inc.

There have been various publications and consensus guidelines in regards to a screening trial before proceeding with pump implantation^2,3,7. Previously, trialing was considered to be the standard of care and critical in evaluation of a patient’s response and potential side effects from a certain agent. However, more recently, the PACC 2012 expert panel has called it debatable specifically in cancer-pain patients⁷. The issues of opioid-induced hyperalgesia (OIH) or disease progression is difficult to assess from a single-shot trial or even with a brief 72–96 hour infusion. A trial may also lead to underestimation of the failure rate and potential side effects. Still, the rationale for performing trials is based on the intuitive basis that it best mimics the system that would eventually be implanted⁷. Generally speaking, there is currently no solid base to either refute or adopt preimplantation trials but it is generally recommended although not required². The British Pain Society expert panel suggested that trials should always be performed before the implantation of an intrathecal drug delivery system⁷.

There is a spectrum of intrathecal system options that range from a percutaneous catheter/external pump to a totally implanted system. Choice is dependent on a number of factors including, but not limited to, life expectancy, cost and availability of professional expertise and patient’s wishes and comfort level.

ITDD devices

There are two systems available for implantable intrathecal devices–those that are programmable and those that are fixed-rate. In addition, some systems come with a bolus option that gives patients more control in managing their treatment. The needs of the patient as well as the suitability of the system for use with selected drugs need to be considered when deciding between the options.

Programmable devices

Programmable devices such as Medtronic’s SynchroMed system deliver a specific amount of medication intermittently (Figure 2 and Figure 3). These systems are preferred by providers because they allow drug dosages to be changed without invasive intervention as the disease progresses and/or the patient builds tolerance to the medication. In cases of suspected or actual medication overdose or implant malfunction, the pump can be interrogated and deactivated without having to empty the drug reservoir. However, since it is battery driven, the life of this pump is usually 5–8 years and a surgical revision is required to implant a new pump. In addition, regular attendance for refilling is required because the drug reservoir tends to be smaller in volume than those found in fixed-rate devices.

Figure 2. © 2009 Image of the SynchroMed II Pump with specifications.

Pump is programmable to deliver a specific amount of medication at different times and can be increased or decreased depending on the individual’s needs. Reprinted with the permission of Medtronic, Inc.

Figure 3. © 2010 X-ray of the SynchroMed II Pump.

The pump has 20 and 40 cc reservoirs to extend the time between refills. Drug is refilled via the reservoir fill port. Reprinted with the permission of Medtronic, Inc.

Placement

The placement of ITDD consists of two parts: 1) placement of the catheter in the intrathecal space surrounding the spinal cord and 2) placement of the pump/reservoir in the abdomen/flank region. The pump is implanted in the lower abdomen and is attached to the intrathecal catheter which is tunneled under the skin from the patient’s back towards the abdomen. The procedure requires two surgical incisions: 1) Lower back where the catheter is inserted into the intrathecal space and is secured to the fascia. 2) The lower abdominal wall to create a pocket for the pump. The procedure generally takes 3 to 4 hours from start to finish¹².

Dosing and titration

As mentioned previously, ITDD delivers medicine directly into the cerebrospinal fluid, bypassing the route that oral medication takes through the body. Generally 1/100^th–300^th of the amount of medication is used with the pump delivery as compared with the amount when taken orally. A survey conducted among a small group of physicians highly-experienced in ITDD revealed that morphine was the more frequently used and prescribed choice of medication, both alone and in combination with other drugs¹³. The concentrations and daily dosages administered of medications varied from patient to patient. Providers often adjusted the dosages of drugs or drug combinations by a fixed percentage, between 10% and 20%, whether increasing or decreasing the dosage. An average of five to eight adjustments in dosage was completed before a different drug or drug combination was introduced in cases of inadequate analgesia¹³.

Efficacy

Studies have suggested that ITDD is effective in providing pain relief to 60–80% of patients experiencing chronic malignant pain⁷. Long-term intrathecal application of opioid medications in cases of carcinoma pain is substantially more effective than its systemic application. Intrathecally applied opioids exert a strong analgesic effect via spinal receptors, without significantly influencing motor, sensory, and sympathetic reflexes. It has been shown to improve patients’ overall mood and reduce the incidence of systemic side effects. As a result, patients have reported an improvement in quality of life and the ability to participate more fully in daily activities.

Complications

As with any surgical procedure, serious complications may arise post-implant that require immediate attention and perhaps the removal of the device.

Cost effectiveness

With estimates of pain care treatment costs exceeding $1 billion annually in the United States, cost and efficacy are important factors in clinical decision making. Although the initial cost of intrathecal drug delivery is substantially more, maintenance costs over time are significantly lower than conventional routes of administration. Cost analyses by the group concluded that intrathecal delivery is the most cost-effective route of opioid administration for patients who require long-term management of cancer (≥ 3–6 months) or nonmalignant pain (≥ 11–22 months)¹⁶.

An analysis by Kumar et al. showed that intrathecal therapy is a cost-effective method of treating chronic nonmalignant pain caused by failed back syndrome and that the break-even point occurs at 28 months, after which conventional pain therapy is the more expensive treatment option¹⁷. A separate analysis by Scott Guillemette from Ingenix Consulting on patients suffering from failed back surgery syndrome concluded with similar results. Despite the higher upfront costs, patients utilizing intrathecal drug delivery returned to ‘normal living’ more quickly than those with conventional therapy and the break-even point between the two points occurred between months 19 and 20¹⁸.

Conclusion

The treatment of pain poses an ongoing challenge to the healthcare field and better prevention, assessment and treatment of pain is needed. Intrathecal drug delivery can become a critical component of this transformation in treatment when more conservative forms of pain management have failed to provide adequate pain relief. In comparison to more conservative delivery methods such as drugs administered orally or intravenously, ITDD is more effective because the medication is directly introduced into the subarachnoid space⁸. The spinal cord is a key anatomical site for pain processing and more specifically the dorsal horn of the spinal cord within the intrathecal space^5,8. The advantage of delivering the medication directly into the CSF in smaller dosages is that it may reduce the systemic side effects and the direct delivery to the site of action allows a more rapid and effective response. As a popular alternative for patients experiencing cancer or chronic pain, intrathecal analgesia has become a therapeutic option for patients who have exhausted all other treatment avenues as well as patients experiencing side effects from their current treatment options. However, there are limitations such as adequate patient selection, ability to tolerate the procedure, and costs. There are also potential complications related to the device, drug, and procedure that may require hospitalization and immediate removal/revision of the device. Despite numerous studies involving existing and novel drugs, only limited data is available to address the issue of medication safety, efficacy, stability and compatibility with the intrathecal drug delivery system. As this option becomes more popular with patients and physicians, future research should focus on cross-site studies that would provide a more accurate outlook on this type of delivery.