Pharmacology of Intrathecal Therapy

Introduction

The history of intrathecal (IT) implantable drug delivery system (IDDS) therapy for chronic cancer and noncancer pain is rooted in experimentation with local anesthetics administered into the cerebrospinal fluid (CSF). For a thorough historical review see Chapter 60 .

Since the first implantable pumps were approved by the United States Food and Drug Administration (FDA), experience with more than 300,000 implanted pumps has established IDDS as a safe and effective route of administration for medications used to treat intractable spasticity and cancer and noncancer pain ( ). IDDSs were used when conservative medical management and interventional and surgical therapies failed. IT delivery was also considered when there were intolerable side-effects to oral opioids, such as sedation, constipation, and urinary retention ( ).

As the need for IDDS therapy grew and new innovations arrived, a number of issues became apparent. These included which drug or combination of drugs would be most effective for treatment of neuropathic, nociceptive, or mixed-pain disease. Other issues included the concentration of medicines to use, catheter placement, and infusion strategies such as continuous, bolus, or patient-activated bolus. This called for more research on the dynamic forces present in the IT space. Research began to elucidate the solutions to these complexities ( ). Based on new data, guideline statements were created to improve patient safety by reducing variability in catheter placement, determining which medications should be used for specific pain types, and selecting patients who would benefit most from IT therapy ( ).

A subsequent comprehensive review resulted in consensus guidelines for the selection of patients with noncancer pain for IDDS, and concluded that IT therapies were effective, cost neutral, and appropriate ( ). While device-related complications such as catheter kinking or transection can occur, the main therapy-related safety issues are respiratory depression, inflammatory mass formation, dosing errors, and pump refilling errors where the medication is mistakenly delivered into the tissue surrounding the pump rather than into the pump itself ( ). The formation of the Polyanalgesic Consensus Conference (PACC) addressed these safety concerns by analyzing all available high-quality research as well as provider experience to identify best practices, ensure safety, and optimize therapy ( ).

A serious risk with IT therapy is the formation of a sterile, expanding inflammatory mass known as a granuloma at the tip of the spinal catheter. Development of a granuloma is one of the most serious risks of IT therapy because of the potential for temporary or permanent neurological injury. The first report of granuloma formation associated with IT therapy was published in 1991, a decade after implantable pumps were introduced ( ). A retrospective longitudinal study that included 56 patients on long-term IT therapy with morphine or diamorphine found granuloma development reported in 4 patients ( ). In one study granuloma formulation was found to have a significant positive correlation with opioid dose and yearly increase in opioid dose, but not with flow rate or opioid concentration ( ).

Indications

Patients with chronic pain can have nociceptive, neuropathic, or mixed-pain states. Neuropathic pain is typically described as burning, gnawing, and lancinating, whereas nociceptive pain is commonly described as aching, mechanical, and sharp. Conservative therapies include ultrasound or fluoroscopically guided injections, oral medications such as gabapentin or tricyclic antidepressants, systemic medication trials with intravenous lidocaine or ketamine, and careful use of opioids. Chronic opioid therapy has not been found beneficial for long-term treatment of neuropathic pain, and in one study was found actually to worsen pain of HIV peripheral neuropathy ( ).

Failure of patients to respond to these conservative treatments provokes consideration of advanced therapies such as spinal cord stimulation (SCS) and IT therapy. For many chronic pain syndromes, SCS is used before IT therapy as there is compelling data suggesting SCS is the safer option to begin treatment ( ). Patient populations likely to benefit from IT therapy include those with failed back surgery syndrome, vertebral compression fractures, nonoperative spondylolisthesis, and radiculopathy ( ). These advanced therapies can also treat visceral, pelvic, and abdominal pain in both cancer and noncancer patients ( ). To be an IT therapy candidate, the patient must meet both the disease indications and patient selection criteria to optimize outcomes. Patient selection criteria include preoperative stabilization of medical comorbidities, capacity to understand the therapy, ability to be present for medication refills and scheduled visits, and stabilization of any psychiatric diagnoses such as depression, anxiety, or personality disorders ( ).

Pharmacokinetics and Pharmacodynamics

After delivery into the CSF, active molecules must diffuse across the pia mater and white matter of the spinal cord to reach target receptors in the gray matter or nerve rootlets ( ). The pia mater, being only a single layer of cells without intercellular junctions, is very permeable to IT medications. For medications to enter the parenchyma of the spinal cord, fluid pathways paralleling the intraparenchymal vasculature can be used ( ). The spinal cord white matter consists of myelinated axons, making it hydrophobic, whereas the gray matter consists of cell bodies, making it hydrophilic ( ). Continuous IT infusion results in stable CSF drug concentrations, establishing a gradient that drives drug diffusion into neural tissue ( ).

A number of physicochemical factors intrinsic to the chosen IT medication determine the level of drug uptake. Of these, lipid solubility and molecular weight are the most important. Hydrophilic medications, such as morphine and hydromorphone, have a pharmacokinetic advantage in the CSF over hydrophobic agents, such as fentanyl and bupivacaine. In the CSF, hydrophilic molecules have longer half-lives because hydrophobic agents enter the vasculature and are readily cleared out of the subarachnoid space. Hydrophilic medications have smaller volumes of distribution, resulting in deeper cord penetration and more rostral spread ( ). Hydrophobic medications have the advantage of limited spread. This is useful when precise, targeted delivery is desired ( ).