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AHCPR Health Technology Reviews. Rockville (MD): Agency for Health Care Policy and Research (US); 1992-1995. 

                        - This publication is provided for historical reference only and the information may be out of date.

**This publication is provided for historical reference only and the information may be out of date.**

## AHCPR Health Technology Reviews.

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Agency for Health Care Policy and Research (US)

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#  7External and Implantable Infusion Pumps

Ann A Graham, CRNA, MPH and Thomas V Holohan, MD.

Published: January 1994.

##                 Introduction

The Office of Health Technology Assessment (OHTA) has previously published five                technology assessments on infusion pumps: three on external infusion pumps (two on                insulin and one on heparin), and two on implantable infusion pumps (chemotherapy of                liver cancer and chronic heparin therapy).(1-5).

In this technology review, OHTA, which is part of the Agency for Health Care Policy                and Research, Public Health Service, has combined several requests from the Health                Care Financing Administration (HCFA) for technology assessments on drug-device                delivery systems. Specifically, HCFA requested that OHTA evaluate the safety and                effectiveness of: chemotherapeutic agents, used with an external infusion pump (EIP)                or implantable infusion pump (IIP), access system, and temporary or permanent                indwelling catheter; morphine for intractable malignant and nonmalignant pain, used                with an EIP or IIP, access system, and temporary or permanent indwelling catheter;                and intrathecal baclofen for chronic, intractable spasticity. Additionally, the                appropriate settings and clinical situations for use of both EIP and IIP were to be                identified.

This report is divided into two sections: classification and description of EIPs and                IIPs; and review of the literature and discussion of the effectiveness of                implantable infusion devices when used to administer chemotherapy for metastatic                liver disease, morphine for chronic pain, or baclofen for chronic spasticity. It                will not address the use of external or internal pumps to deliver heparin, insulin,                or antibiotics, or for unlabeled (unapproved) drug uses. For preparation of this                report, an extensive literature review was undertaken, encompassing all journals and                textbooks available through on-line search capabilities (PaperChase). The following                medical subject headings (i.e., MeSH terms) were used: cytotoxic agents, drug                therapy, pain/nonmalignant, pain/chronic, antispasmodic drug therapy, infusion                pumps/implantable.

The search was limited to human studies published in English from 1984-1992. It was                expanded to include pertinent references cited in reviewed articles and texts, and                was contracted to exclude case reports, uncontrolled studies, animal studies, and                studies of unapproved drugs and devices. During the literature search, it became                clear that "infusion pumps" is a subject heading used interchangeably to describe                several different kinds of medical devices, including implantable or transcutaneous                catheters connected to EIPs, access ports or reservoirs, and IIPs.

##                 Background

Infusion pumps are an important means of drug delivery in a wide range of clinical                conditions, such as cancer therapy and chronic pain therapy. The functional                requirements of infusion pumps include reliability, precision, safety, simplicity in                handling and maintenance, light weight, biologic compatibility (for implantables),                easy access, long-acting power source or batteries, and chemical compatibility with                the drug to be infused. All of the benefits of these pumps necessarily require that                the delivery system use a drug that is effective for the clinical condition in                question.

The flow range and reservoir capacities of EIPs vary among manufacturers and extend                from simple, manually-set, gravity-flow drip rate controllers and volumetric                infusion pumps to sophisticated, programmable infusion delivery systems.(6). Miniaturization and microprocessor                control have made IIPs comparable to EIPs in terms of performance characteristics.                The IIPs have been developed primarily to promote patient independence from the                hospital setting during chronic infusion therapy, particularly for pain control and                chemotherapy Other devices, such as implantable drug pellets and capsules (for                hormone delivery) and rate-specified pharmaceuticals (i.e., pilocarpine or                intrauterine progesterone) are considered to be implantable drug delivery devices                but are beyond the scope of this report.

Components for both EIPs and IIPs include the infusion pump and reservoir,                bacteriostatic filters, fluid administration sets, and delivery catheters. No device                standards exist for external or internal diameter size, and many EIP components are                interchangeable among manufacturers. The IIPs are usually sold as a complete                infusion system with all necessary components. Table 1                summarizes currently available EIPs and IIPs.

#### Table

Table 1. External and implantable infusion pumps. 

##                 External infusion pumps 

There are over 600 different models of EIPs, most of which have been approved for                marketing by the Food and Drug Administration (FDA) through a prenotification                application (510(k)).(7). These devices                are labeled for general use and, if marketed before 1991, may not have undergone                human clinical trials for safety and effectiveness. None of the infusion pumps are                specifically labeled for home or nonhospital use, although this use is common.(8). Rather, the FDA classifies infusion                pumps into functional categories: implantable, ambulatory, and patient-controlled                analgesia pumps.

The majority of EIPs are used to administer antibiotics, particularly in the                nonhospital setting. Other uses include administration of chemotherapy, analgesics                and opioids, total parenteral nutrition formulas, insulin, lipids, vasopressors,                blood products, and other drugs or biologics for which a controlled rate of delivery                is desirable or necessary. The EIP requires a disposable administration set and an                optional micropore filter, to be used with a variety of delivery catheters. The                functional range of EIP infusion rates extends from high volume delivery (400 mL/h)                for hydration therapy to very low flow rates (0.04 mL/h) that can be used for                chemotherapeutic agents.

Recently, ECRI evaluated several noninsulin EIPs.(9). A variety of models allow continuous, intermittent, or bolus                administration by means of a programmer controlled by a physician or pharmacist.                Other, nonprogrammable pumps offer continuous, fixed-rate flows. System alarms are                generally present to warn both patient and provider of occlusion, battery                malfunction, empty reservoir, and air in the line. The proposed use (chemotherapy,                rehydration, analgesia) will influence the choice of model or device, because of the                specific performance requirements in those applications (flow rate, bolus dosing,                external reservoirs).

External infusion pumps are available in four distinct designs: peristaltic,                cassette, syringe, and elastomeric(7).                    (Table                    1.). Linear peristaltic pumps are the most common ones                used today. The fluid administration set is placed in a pump channel, where                finger-like eccentric disks occlude the tubing successively, in a rippling,                wave-like motion. The tubing is held against a stationary back plate and alternately                compressed and released by the moving fingers, forcing fluid to flow. Rotary                peristaltic pumps use a short length of tubing (usually silicone rubber) held taut                around rollers that have been mounted on a rotor. As the rotor is turned at precise                speeds by a motor drive, the rollers occlude the tubing and force the fluid into the                patient at a prescribed rate.

Cassette pumps include either of two designs: motor-driven plungers or                piston-actuated diaphragms. The motor-driven plunger has a syringe-like action in                which the plunger moves in and out of a cylinder. The inward motion pumps the fluid                out of the cassette toward the patient, while the outward motion draws fresh fluid                from the solution container to refill the cassette. In the other type of cassette                pump, a diaphragm is mounted near a moving piston that displaces a small volume of                fluid toward the patient with each inward stroke and allows the diaphragm to refill                with each outward stroke. Syringe infusion pumps expel fluid from a syringe by                advancing either the plunger or the barrel of the syringe at a predetermined rate.                In most of these syringe pumps, a motor drives a lead screw or gear mechanism. The                speed of the motor controls the rate of delivery of solution. Elastometric infusion                pumps have a pressurized balloon reservoir connected with kink-resistant tubing to a                small distal flow restrictor that provides a single, fixed-flow rate. The approved                labeling for these devices, in general, allows 15 tolerance in accuracy for flow                rates, although flow-rates are usually within 5, even at low rates.(9).

In its evaluation of some currently marketed EIPs, ECRI tested the performance and                safety of EIPs by measuring a range of flow rates and reservoir volumes for                different applications.(9). It also tested                flow accuracy under a variety of operating conditions that can be found in                ambulatory use: high viscosity fluids, infusate temperature variations, low battery,                extended use (beyond 72 hours), high back pressures and negative pressures,                electromagnetic interference and electrostatic discharge, and ease of use (human                factors). Further, it listed the performance characteristics of pumps tested, so                that suitability for the four major infusion indications (chemotherapy, pain                control, antibiotics, total parenteral nutrition) could be evaluated by a provider.                It concluded that there were no major performance failures in those pumps evaluated                for flow rates, reservoir capacity and programming features.

The drug delivery catheters used with infusion pumps are inserted percutaneously into                a peripheral vein or subcutaneous space, tunneled over a guide wire into a central                vein from a distal insertion site, or surgically implanted into an artery, or other                compartment. When EIPs are used over an extended period of time, peripheral delivery                catheters should be replaced every 48-72 hours to reduce the incidence of entry-site                infection and phlebitis. More permanent catheters, such as the Hickman, and access                ports are usually cannulated into central vessels and have an extended period of                usefulness (weeks or months). External infusion pumps produce measurable,                predictable, and controllable flow rates and have eliminated reliance on less                accurate timing methods such as manual flow adjustment. They have made infusions                possible against greater than venous pressures by active mechanical pumping. Some of                the advantages of using EIPs are ease in establishing a controlled delivery rate,                portability, reusability, and cost. They have battery backup power sources and can                be mounted on carrier poles, or worn with a shoulder strap or backpack that permit a                range of activities by the user.

Adverse effects associated with use of EIPs reflect complications similar to other                infusion devices and delivery catheters. They include overinfusion, underinfusion,                infection, phlebitis, emboli, and fluid extravasation. In a recent FDA report,                malfunctions (battery, software, alarms, displays), and user error were found to be                associated with adverse effects.(10). Many                of the early designs were not user-friendly, were subject to performance degradation                in the very locations for which they had been designed, and end users lacked proper                training.

##                 Implantable Infusion Pumps 

Implantable infusion pumps are distinguished from devices such as an implanted access                port or pulsatile pump by the way the bulk flow of drug is generated, either by                fluorocarbon propellant or direct electromechanical action powered by a                    battery.(11).

The unsuitability and inconvenience of existing routes of drug administration for                provision of site-specific drug therapy, as well as the need for chronic intravenous                and subcutaneous infusions, led to the development of implantable drug delivery                systems. Programmable and nonprogrammable IIPs are capable of delivering therapeutic                plasma levels of active drug to a target organ or compartment for prolonged periods                of time. Programmable IIPs have variable delivery rates that are set and adjusted                through radiofrequency control. Nonprogrammable pumps deliver predetermined,                constant rates of infusate and are limited in their ability to provide bolus or                modulated patterns of delivery.

Two IIPs are currently approved by FDA for marketing: a nonprogrammable                vapor-pressure powered (flourocarbon propellant) pump, and a programmable                peristaltic pump.(12). Other designs have                been reported in the literature but are not approved for marketing at this time. The                pumps are implanted in a subcutaneous pocket and connect to a dedicated catheter                that has been placed in the appropriate compartment. Constant or variable-rate                infusions are possible over long periods of time (several weeks to years) with                minimal human intervention (refilling or reprogramming), while the capability for                external control of rate and volume of primary and supplemental drug delivery is                    retained.(11). The pumps are labeled                for specific drugs and routes of administration, e.g., intravenous fluorouracil                (5-FU), intra-arterial floxuridine, epidural morphine sulfate, intrathecal morphine                sulfate, and intrathecal baclofen.

Implantation of infusion pumps was first attempted in the early 1960s, particularly                for insulin delivery. Today, the objectives of implantable drug-delivery systems                include: provision of long-term access to various compartments of the nervous and                vascular systems (epidural, subarachnoid, hepatic artery) to enable site-specific                drug therapy; reduction in infections at the injection site that are associated with                external access devices; and provision of drug delivery through a device or system                that promotes patient mobility and independence (Table 2.).                    (13).

#### Table

Table 2. Classification of implantable drug delivery system.(13). 

###                      Access ports

Although technically not infusion pumps, a description of implanted access ports                    and pulsatile pumps are included here because they have been used clinically to                    administer long-term drug therapy, have been reported in the literature as                    implantable infusion devices, and have been successfully used for long-term                    infusions of chemotherapeutic drugs, antibiotics, and opioids. Clinical studies                    that compare the effectiveness of access ports and IIPs are reviewed below.

Access ports are subcutaneously implanted, rigid reservoirs with injection ports.                    The reservoirs are connected internally to catheters terminating in a                    compartment (i.e., subarachnoid space or hepatic artery).(11). They are manufactured from relatively biocompatible                    materials such as titanium, stainless steel, polysulfone, or reinforced                    silicone, in a variety of sizes and volume capacities. To refill the access port                    with drug, a self-sealing, rubber septum over the reservoir is punctured                    transcutaneously with a Huumlberlike noncoring needle. The septum determines the                    useful lifetime to the access port, which is designed to accept multiple refills                    (some, up to a few thousand). The rate of drug delivery is controlled by passive                    diffusion, since drug concentration in the reservoir is greater than in the                    target compartment. There is no battery or other power source. Because the                    reservoir volume is small it needs to be filled manually at frequent intervals                    (hours or days). Subcutaneous reservoirs have been used as a permanent delivery                    system, as well as temporary reservoirs for patients undergoing evaluation for                    permanent epidural or intrathecal drug delivery systems.

Virtually any marketed drug can be delivered through a subcutaneous reservoir,                    even though a particular drug may not have undergone pharmacokinetic evaluation                    by this route of administration. The FDA has allowed all access ports for                    non-intraspinal delivery to be marketed under the prenotification (510(k))                    provisions of the Food, Drug, and Cosmetic Act of 1938, as amended. Intraspinal                    drug delivery by access port requires premarket drug-device approval. Concerns                    about drug-device biocompatibility are not as important with the ports as with                    IIPs because of the limited time that the drug remains in the reservoir.

###                     Pulsative pumps

Pulsatile pumps are nonprogrammable, mechanical, hand-operated systems that are                    totally implanted subcutaneously. They incorporate a series of one-way valves                    that are manually compressed by the patient for bolus administration of a single                    drug. The dosage is adjusted by either varying the number of compressions or the                    concentration of active component of the drug. The pump is made of polysulfone                    and has a reservoir capacity of 12-15 mL. It can be used for patient-controlled                    bolus doses of opioids for intractable pain, (14). as well as insulin.

###                     Vapor-pressure powered                    pumps

First approved by the FDA in 1982, the vapor-pressure powered implantable pump is                    labeled for the following indications: in patients who require continuous                    hepatic artery infusions (CHAI) of floxuridine with bacteriostatic water of                    physiologic saline for treatment of unresectable tumors of the liver or colon                    (either primary or metastatic); and in patients who require anticoagulation with                    continuous intravenous (e.g., superior vena cava) infusion of herapin, who                    suffer from recurrent thrombophlebitis or pulmonary emboli when on oral                        anticoagulants.(15). This pump is                    unique in that it is powered by the vapor pressure of an inexhaustible                    flurocarbon charging fluid, freon, in a vapor-liquid mixture at normal body                    temperature and atmospheric pressure. The implantable components of the system                    include the pump itself, reservoir, and accessories that may include a micropore                    filter and various size catheters.

This nonprogrammable pump consists of a hollow titanium disc separated into two                    chambers by a metal bellows diaphragm, which serves as a flexible impermeable                    membrane. The dual-phase charging fluid is permanently sealed on one side of the                    diaphragm. The other side of the diaphragm serves as a refillable drug                    reservoir. The diaphragm exerts a constant pressure on the drug chamber (450 mm                    Hg) causing expulsion of drug from the reservoir through a 22 micro-outlet                    filter and flow-restricting capillary tube assembly to the patient.(10). Refilling of the drug chamber by                    percutaneously injecting the drug through a self-sealing septum causes the drug                    reservoir to expand, while simultaneously causing the fluorocarbon to condense                    into a liquid state, recharging the pump for the next flow cycle.

Several relative contraindications preclude its use in certain patients: those                    with severe psychiatric, emotional, or neurologic disturbances; persons whose                    body size is not large enough to accommodate the bulk and weight of the pump;                    and those who undergo frequent or long-term changes in altitude or engage in                    rough or vigorous occupations or activities, such as contact sports.(15). Each drug label dictates the                    contraindications and precautions associated with use of approved drugs in                    IIP.

Complications reported with the use of this vapor-pressure pump are attributable                    to the drug itself, the pump, and the accessories. They include, but are not                    limited to, pump pocket complications such as wound infections, skin necroses,                    seroma, abscesses; complications of hepatic artery infusion such as hepatic                    artery thrombosis,(16). duodenal                        atony,(17). chemical hepatitis,                    biliary sclerosis,(18,19). and biliary tract inflammatory                    responses; and systemic complications related to specific drugs, such as                    diarrhea, constipation, nausea, vomiting, somnolence, urinary retention, and                    various cutaneous reactions. Accessory equipment problems include catheter                    kinking, occlusions, and dislodgements.

###                      Peristaltic pumps

The FDA approved a programmable, peristaltic infusion pump in early 1988 for                    chronic intravascular (intra-arterial) infusion of floxuridine with heparinized                    bacteriostatic water or physiologic saline for palliative management of                    unresectable tumors of the liver or colon.(15). This pump was also approved at the same time for systematic                    intravenous infusion of doxorubicin with bacteriostatic water or physiologic                    saline for palliative management of various solid tumors, lymphomas, and                    leukemias.

In 1991, the pump was approved for epidural administration of preservative-free                    morphine sulfate solution for the treatment of chronic intractable pain of                    malignant or nonmalignant origin, and for intrathecal (subarachnoid)                    administration of preservative-free morphine sulfate sterile solution for the                    treatment of chronic intractable pain of malignant or nonmalignant origin. In                    1992, intrathecal baclofen was approved for use with this pump for management of                    severe spasticity of spinal cord origin for patients unresponsive to oral                    baclofen or who experienced intolerable central nervous system (CNS) side                    effects at clinically effective doses. 

The implantable components of the system are the pump, which includes a                    radiofrequency receiver and battery, vascular catheters, optional access port,                    connectors, and a variety of catheter accessories. The lithium and thionyl                    chloride battery power the pump and each model dispenses drug in accordance with                    information transmitted from a hand-held external programmer. The pump consists                    of: an 18 mL collapsible, seale, titanium drug reservoir that can be filled                    percutaneously through a self-sealing septum; an optional 22 micro-bioretentive                    filter; and a rotor, driven by a stepp motor through a gear train, attached to                    several rollers that compress a flexible U-shaped tube and force the drug                    through a delivery catheter. The step motor, controlled by the hand-held                    programmer, controls the flow rate of the drug. The programmer, placed over the                    implanted device to provide a magnetic field, transmits radiofrequency signals                    that record patient identification, date, current prescription, drug name,                    concentration, dose rate, infusion mode (five choices), reservoir volume, alarm                    settings and status. All models are programmed with an audible alarm system that                    warns the user of low battery power, low reservoir volume, and pump memory                    error. The battery has an expected life of several years. Accuracy is reported                    to be within +/-10-15 of the programmed flow rate under a variety of conditions.                        (14,20).

The pump is contraindicated in the presence of infection, when it cannot be                    implanted less than 2.5 cm from the skin surface, when the patient has another                    implanted programmable medical device, or in those whose body size is not                    sufficient to support the bulk and weight of the pump. Each drug label dictates                    the contraindications and precautions associated with the use of this                    drug-device delivery system. 

##                 Clinical Effectiveness

###                     Intrahepatic chemotherapy for metastatic colorectal                    carcinoma 

The age-adjusted incidence, mortality, and 5-year survival rates for colorectal                    carcinoma in the US are 50.0/100,000, 19.6/100,000, and 58.4.(21).

The liver is the most frequent site for metastatic spread of this disease.                    Hepatic metastases are present in 18 of patients at the time of their primary                    tumor diagnosis and in 60 of patients who develop advanced disease.(22). Putative curative surgical                    resection (removal of all detectable gross tumor with negative margins) of                    metastases occurs in approximately 4-24 of patients. (23). For unresectable lesions, standard systemic 5-FU                    therapy produces response rates of 15-20. The survival time for untreated                    metastatic disease ranges from a few months to 2 years, and depends on disease                    extension at presentation.

Continuous hepatic artery infusion (CHAI) of chemotherapeutic agents was first                    used clinically by Watkins in 1962.(24). Its use is based on the observation that hepatic metastases result                    primarily from vascular rather than lymphatic spread and that such metastases                    derive most of their blood supply from the hepatic artery.(25). Fluorouracil and floxuridine were both used                    initially but Ensminger et al(26).                    later demonstrated that hepatic extraction ratios (heptic arterial drug level                    minus hepatic venous drug level divided by hepatic arterial drug level) of                    floxuridine ranged from 94-99, while those of fluorouracil were lower (19-51).                    These authors also showed that floxuridine provided up to a 500-fold higher                    intrahepatic drug concentration than systemic agents.

Regional (hepatic) chemotherapy, by means of an external infusion pump and an                    externalized catheter fluoroscopically placed into the hepatic artery through                    the femoral vein or brachial artery, has been in clinical use for over 30 years.                    Complete and partial tumor response rates have ranged from 30-80, although these                    responses were based on biochemical, as well as radiographic evidence of tumor                    Survival was limited because of intrahepatic toxicities, marginal tumor response                    to fluorouracil, and extrahepatic metastatic progression (lung, brain, bone).                    Treatment failures secondary to catheter dislodgements, leaks, and kinks, as                    well as arterial embolization, made the safety and marginal effectiveness of                    this treatment a concern.

The advent of a completely implantable system (pump or access port and catheter)                    was believed to increase the safety and efficacy of this mode of therapy by                    reducing infections, catheter dislodgements, arterial thrombosis, and hepatic                    malperfusion. Fluorouracil and floxuridine have been used in combination with                    each other and with the addition of other cytotoxic agents such as mitomycin C                    or cisplatin, as well as in combination with systemic (intravenous) infusion of                    folinic acid with varying tumor response.(27). The therapeutic margin of these cytostatic agents is narrow,                    and toxicity is dose-dependent. Floxuridine dosages between 0.2 and 0.3 mg/kg/d                    are associated with frequent interruption or cessation of therapy, while dosages                    of 0.1 mg/kg/d are less likely to cause biliary toxicity.

Today, patients who are candidates for CHAI by implantable pump require                    intra-operative placement of the pump and hepatic catheters and must undergo                    extensive pre-and postoperative laboratory and vascular studies, including                    serial carcinoembryonic antigen (CEA) levels, liver enzymes, transfemoral                    arteriograms, and computed tomography (CT) scans. Prophylactic cholecystectomy                    and segmental devascularization of the distal stomach and duodenum are now                    performed to reduce biliary toxicity and to increase total hepatic                        perfusion.(28). Patients with                    variant hepatic artery architecture may require multiple, simultaneous catheter                    or pump insertions, ligation of the variant vessels, or construction of an                    arterial vessel with an autologous vein or synthetic vascular implant. A                    fluorescein scan of the liver intra-operatively and a scintillation scan of the                    liver post-operatively are required to confirm complete perfusion of the liver                    and the lack of extrahepatic (gastroduodenal) perfusion. Arterial angiocomputed                    tomography (AACT) has also been recommended for followup evaluation of                    intrahepatic drug delivery because of poor resolution from scintigraphy.                    Chemotherapy by IIP is usually not initiated until liver enzymes have returned                    to les than three times normal.

Several controlled clinical trials have been conducted to demonstrate the                    effectiveness and safety of CHAI by IIP for hepatic metastases from colorectal                    cancer by measuring survival, time to progression of liver disease, time to                    overall (or extrahepatic) disease progression, complications and side effects                        (Table 3). The comparative efficacy of                    these drug/device interventions has been difficult to asses because of varying                    efficacy definitions, unreported patient selection criteria, and crossover                    treatment designs. For example, one study(29). used a 50 reduction in CEA levels exclusively as a definition                    of partial response to floxuridine, while others(30). used 50-90 regression of measurable disease by CT                    scan.

#### Table

Table 3. Studies of unresectable, metastatic, colorectal carcinoma                            with CHAI. 

In an early case series of 55 patients implanted with a vapor-pressure powered                    IIP, Ramming et al(29). reported that                    median survival time of all patients was 19.2 months from diagnosis of hepatic                    metastases to death, and survival time from pump implantation to death was 11.5                    months. There was no difference in survival time between those initially treated                    with CHAI of floxuridine by IIP and those who had received previous systemic                    flourouracil treatment. Also, the time from diagnosis of metastases (less than                    3, or more than 3 months) to pump implantation did not influence median survival                    (14 months, 21 months, respectively.) A significant difference in survival time                    from pump implantation to death was noted between those patients implanted                    before August 1983 (9.3 months) and those implanted afterward (15.2 months),                    although the clinical significance of this finding remains unclear.

Substantial local toxicity occurred in this group: gastric ulcers (13), gastric                    obstruction (2), duodenal ulcers (4), chemical hepatitis (13), and sclerosing                    cholangitis (2). Unfortunately, although there was no known extrahepatic disease                    at the time of implantation, distant metastases occurred in 34 patients                    undergoing IIP treatment.

Martin et al(31). reported that,                    despite a delay in intrahepatic tumor progression, disease-free progression and                    overall survival time did not differ between patients treated with bolus hepatic                    artery infusions (BHAI) of floxuridine by a programmable implanted pump and                    patients given intravenous fluorouracil. This prospective, randomized trial                    demonstrated a complete or partial tumor response of 48 in the BHAI group and 21                    in the systemic group, as well as longer time to intrahepatic disease                    progression (15.7 vs. 6 months, respectively), but no difference in any-site                    (extrahepatic) disease progression (6.0 vs. 5.0 months, respectively) or                    survival (12.6 vs. 10.5 months, respectively). These authors believed that                    despite the lack of survival advantage, BHAI may be valuable if it improves the                    patient's quality of life. However, they found no difference between the two                    groups in weight gain, Eastern Cooperative Oncology Group performance scale, or                    symptoms, although the BHAI patients did report fewer side effects and more                    subjective satisfaction. Based on these findings, they concluded that they could                    not recommend BHAI since there was no difference in survival time to                    counterbalance the greater expense and morbidity associated with its use.

Regional (intrahepatic) chemotherapy trials were unsuccessful in demonstrating an                    effect on extrahepatic metastases and, therefore, survival time. Lorenz et                        al(32). attempted to demonstrate                    that extrahepatic disease progression could be slowed and survival prolonged, by                    also administering fluorouracil systemically to those patients receiving CHAI of                    floxuridine. They randomized 46 patients with unresectable metastatic disease to                    either CHAI of floxuridine (26) or CHAI of floxuridine and systemic fluorouracil                    (CHAI/S) (20) to see whether the addition of a systemic arm would influence                    extrahepatic disease occurrence and survival. The results demonstrated no                    difference between the groups in extrahepatic disease progression (16/26 vs.                    12/20 patients, respectively), tumor volume reduction, response rate (partial                    response measured as a significant reduction in tumor mass by CT and more than a                    50 reduction in CEA), or median survival time (16 months and 19.5 months,                    respectively). Addition of the systemic treatment arm did not significantly                    alter tumor progression, occurrence of extrahepatic disease, or survival.

Complications included three pump pocket infections requiring explantation in two                    patients. Catheter dislodgement and thrombosis in three patients prematurely                    terminated CHAI. Severe toxicity occurred in both the CHAI group and the CHAI/S                    group: chemical hepatitis (50, 40, respectively); biliary sclerosis (15, 10,                    respectively); gastrointestinal toxicity (15, 45, respectively); and nausea and                    vomiting (0, 25, respectively). The authors reserved judgment on the efficacy of                    this therapy and, because of safety concerns about toxicity associated with                    these two drugs, concluded that CHAI should not be viewed as a primary treatment                    but should be reserved for further prospective studies.

In an attempt to determine differences in tumor response rates between                    intrahepatic floxuridine and intravenous fluorouracil, Kemeny et al(33). compared each drug's efficacy in 93                    patients with colorectal adenocarcinoma and measurable liver metastases in a                    prospective, randomized trial. All patients underwent laparotomy for staging,                    confirmation of no extrahepatic disease, and intrahepatic artery catheter and                    IIP placement. Forth-eight patients were treated with CHAI of floxuridine by IIP                    and 51 were initially treated with systemic fluorouracil by IIP. In those                    patients randomized to systemic treatment, an access port was also implanted at                    the time of laparotomy, so that crossover to intrahepatic floxuridine would be                    possible at the time of disease progression. The IIP was connected to a cephalic                    vein catheter to administer the fluorouracil, and the hepatic artery catheter                    was attached to an access port until needed. Twenty-four of 45 patients in the                    CHAI group has a complete or partial response (1 complete, 23 partial); whereas,                    10 of 48 patients in the systemic group, had a partial response (50 vs. 19.6,                    respectively). This study also demonstrated a significant tumor response in                    initially nonresponsive persons who crossed over form the systemic arm of the                    study to CHAI at the time of disease progression. Thirty-one patients from the                    systemic arm crossed over at that time to CHAI. The 20 patients who did not                    cross over the CHAI arm had a median survival time (from initial study entry) of                    8 months (3.4 months from disease progression). Among the 31 patients who did                    cross over, median survival time was 18 months from initial study entry (9.5                    months form disease progression and crossover). Although median survival time                    did not differ significantly between the two groups (17 vs. 12 months,                    respectively; p=0.42), median time to disease progression was significantly                    delayed in the CHAI group (9 months vs. 5 months, respectively; p = 0.016).                    Unfortunately, a determinative finding for the agent responsible for any of                    these subsequent responses was impossible because of the crossover design. No                    pumps failed, although poor catheter placement and migration occurred in three                    patients, one patient had pump pocket erosion, and seven catheter occlusions                    occurred in the systemic group.

In a protocol similar to that of Kemeny et al(33). , Hohn et al(34).                    randomized 143 patients to either floxuridine by CHAI or administered                    intravenously (superior vena cava) for treatment of metastatic intrahepatic                    colorectal cancer, to determine if any differences in tumor response occurred in                    the two groups. Disease ascertainment was not comparable between the two groups.                    The systemic group had their IIPs implanted under fluoroscopy, while the CHAI                    group had their IIPs implanted during staging laparotomy, underwent biopsy of                    suspicious lymph nodes, and had infusion pumps inserted even in the presence of                    extrahepatic disease. Initial intravenous dosages started at 0.075 mg/kg/d and                    were escalated until diarrhea developed. Initial CHAI dosages started at 0.3                    mg/kg/d, but were reduced to 0.2 mg/kg/d because of hepatobiliary toxicity (200                    of baseline alkaline phosphatase). Crossover was allowed from systemic treatment                    to CHAI at the time of disease progression. Mean time to intrahepatic disease                    progression, regardless of crossover, was 13.2 months in the CHAI group and 6.7                    months in the intravenous group. Median time to disease progression was 5.5                    months in the crossover group (28 patients). Mean survival time was similar in                    the CHAI and systemic groups (16.7 and 16.2 months, respectively). Because of                    early disease progression in the systemic group, the effect of CHAI or systemic                    floxuridine on extrahepatic disease progression was not determined.

Wagman et al(30). stratified 91                    patients with histologically confirmed colorectal carcinoma with liver                    metastases according to tumor burden and resectability (A = solitary resectable                    metastasis, B = multiple resectable metastases, C = multiple unresectable                    metastases), and then randomized each of these three groups to either CHAI or,                    depending on their tumor load, observation, surgical resection, or systemic                    treatment with 5-FU, respectively (Table 4.). The purposes                    of this study were to measure the effect of CHAI when combined with surgical                    resection of metastases, to measure the difference in morbidity when CHAI is                    used after multiple hepatic resections, and, to measure whether, in patients not                    rendered disease-free at the time of laparotomy, CHAI improved survival or                    delayed progression of disease.

#### Table

Table 4. Results for a series of patients with metastatic colorectal                            carcinoma of the liver randomized to treatment with continuous hepatic                            artery infusion of floxuridine or surgical resection(30). (more...)

CHAI = continuous hepatic artery infusion; 5-FU = 5-fluorouracil; C = complete                    response (disappearance of all metastatic disease); P = partial response; M =                    mild response; Pr = progression of intrahepatic or extrahepatic metastatic                    disease; MI = myocardial infarction; NR = not reported; Tx = treatment

As expected, patients in the group with solitary, resectable metastases showed                    the best median survival over the other two groups (A = 37.3 months, B = 22. 4                    months, C = 13.8 months). The authors demonstrated a significant difference in                    survival time between the stratified groups with A over B and C (p = 0. 03,                    0.002, respectively) as well as a significant difference between groups B and C                    (p = 0.06). However, there were no differences in survival time within group B                    (p = 0.42) or group C (p = 0.55). Disease progression in those patients with                    solitary lesions who were treated with CHAI and resection (groups A2 and B1) was                    delayed significantly vs. those treated with resection only (p = 0.03), and to a                    lesser extent, with CHAI only (p = 0.18). No difference was found in time to                    disease progression in patients with unresectable metastases (with or without                    portal nodes), despite treatment with CHAI, fluorouracil, or both.

These five prospective, randomized studies assigned patients to treatment with                    CHAI of floxuridine by IIP or alternative therapies, ranging from intravenously                    administered floxuridine or fluoruracil, surgical resection, or no treatment.                    Overall response rates to floxuridine by IIP (complete and partial) ranged from                    42-64, while median times from treatment to death ranged from 12.6 to 17 months                    in the floxuridine groups and 10.5 to 19.5 in the systemic groups (including                    crossover patients), although overall survival time did not differ between those                    treated with floxuridine by IIP and other treatments. Extrahepatic progression                    of disease was not influenced by CHAI, but intrahepatic disease was slower to                    progress in patients treated with CHAI of floxuridine.

One factor that may influence the therapeutic effectiveness of CHAI of                    floxuridine by IIP is the ability of the drug to continuously perfuse the liver                    and metastases in adequate concentrations over the course of the treatment                    period. Safi et al(35). evaluated the                    results of AACT retrospectively in 82 patients with mixed metastatic hepatic                    disease (carcinoid, squamous cell, neurosarcoma, and colorectal), including 6                    patients with extrahepatic metastases. Despite a difference in perfusion                    patterns (70 homogenous, 24 heterogenous, 6 incomplete) of the liver and                    metastases (16 total and 84 peripheral) with CHAI of floxuridine, the complete                    and partial response rates of patients with homogeneous perfusion of both                    hepatic lobes were identical (57) to the response rates in patients with                    inhomogeneous perfusion patterns (55). Patients with colorectal metastases with                    both homogeneous and inhomogeneous perfusion on their AACT (n = 69) demonstrated                    a complete response in 20, a partial response in 19, stable disease in 17, and                    progression in 18.

The median duration of response was similar among those with complete, partial                    and stable disease (15, 14, and 15 months, respectively). The 1-, 2-, and 3-year                    survival rates for patients with colorectal metastatic disease were 80, 45, and                    20, respectively. The median survival time was 20 months; 27 months for                    responders, 10 months for nonresponders (p<0.01). The pretreatment metastatic                    tumor volume (MTV) of the liver in each patient was measured and compared to                    response rates to CHAI. Before therapy, 23, 25, 21 patients, respectively, had                    <25, 25-50, and >50 MTV, and their respective response rates (complete and                    partial) were 62, 68, and 43. The authors concluded that, in the presence of                    complete metastatic perfusion, response to regional chemotherapy was not related                    to MTV or the perfusion pattern of the metastases but to the direct response of                    the tumor cells to floxuridine. They also concluded that AACT use permits                    precise assessment of CHAI at the time of pump placement and subsequently. The                    response rates in this retrospective report are comparable to those of the                    previously discussed prospective trials.

A comparison of these results with those of two studies that employed implantable                    access ports to administer floxuridine demonstrated comparable complete and                    partial responses to chemotherapy, despite retrospective evaluation and biased                    designs. Civalleri et al(36). reported                    on 39 patients with primary or metastatic hepatic carcinoma who underwent                    treatment of CHAI with either an IIP (22 patients) or an access port and EIP (17                    patients) with programming capabilities comparable with those of the IIP. The                    two drug-delivery systems were evaluated for comparability in terms of implant                    duration, number of treatment cycles administered, and complications. All                    patients were intra-operatively staged and had a CHAI catheter inserted under                    direct vision. The authors do not state how the patients were chosen for either                    device. Post-operatively, they were evaluated by physical examination every 2                    weeks and arterial perfusion scan every 3 months. Mean followup was 9.4 months                    in the implantable pump group and 7.0 months in the port group. The total number                    of treatment cycles was 130 in the pump group (mean = 5.6), and 66 (mean = 3.6)                    in the port group. After 10 months, 46 (10/22) of the patients were alive with a                    functional IIP; 58. 8 (10/17) were alive with a functional port; 3 patients were                    alive without any device and 15 patients had died of disease progression. There                    were more complications in the pump group (15 vs. 9). Treatment was stopped for                    access-related complications in 18.4 of the IIP group and 29.4 of the access                    port group.

Tuchmann et al(37). treated 36 patients                    between 1983 and 1988 using implantable access ports and EIPs, in a protocol                    that delivered floxuridine at a rate of 0.3 mg/kg/d for 14 days and saline for                    14 days. Twenty-three patients were evaluable at 6 months for duration of                    survival, clinical condition, CEA levels, and size of tumor by ultrasound or CT.                    Ten of the 23 responded (response was defined as either a 30 reduction in CEA,                    and/or a 50 reduction in tumor volume as determined by ultrasound or CT), while                    in 6 patients disease progressed, and 7 patients had stable disease. Mean                    survival time was 13.1 months (range: 2-27), while the interval between the                    initiation of chemotherapy and relapse (time to progression) was 10.6 months                    (range: 6-16). The survival results and response rates in these two studies are                    similar to those reported in the prospective clinical trials above.

The National Institutes of Health (NIH)(38). informed OHTA that while several randomized trials have                    demonstrated superior response rates (usually partial) for CHAI vs. systemic                    fluorouracil, no trial has demonstrated advantages in survival or time to                    disease progression. Little if any advantage results from shrinkage of hepatic                    metastases in otherwise asymptomatic Considerable morbidity is associated with                    the placement and long-term presence of CHAI devices, and increased hepatic                    toxicity is observed from CHAI infusion compared with intravenous therapy. In                    the absence of demonstrable benefit in terms of survival of quality of life, and                    particularly considering the cost, this practice is difficult to defend. "At the                    present time this approach is still considered a potentially promising one, but                    it still is an investigational approach that cannot be recommended outside the                    clinical trial setting."

Overall initial response rates (complete and partial) to intrahepatic                    chemotherapy in patients with unresectable, metastatic hepatic disease ranged                    from 42-64 (EIP with an access port, and IIP), while median times from treatment                    to death did not differ significantly in patients treated with CHAI or systemic                    drugs. Extrahepatic progression of disease was not influenced by CHAI, although                    intrahepatic disease was initially slower to progress in patients treated with                    CHAI. 

What data are available to compare implantable and external infusion devices, in                    terms of tumor response, progression, and survival, indicate that the                    rate-limiting factor is not the infusion delivery system, per se, but the                    cytostatic effect of the drug.

In these studies, moderate to severe complications occurred, most commonly,                    chemical hepatitis (a tripling of SGPT and bilirubin), seen in over 50 of all                    CHAI-treated patients.(18). The most                    serious and irreversible complication was biliary sclerosis (narrowing of the                    biliary ducts and secondary rise in alkaline phosphatase), which has been                    associated with higher dosages of floxuridine (0.3 mg/kg/d), and has been                    reported to occur in 5-60 of patients.(17,39,40). Other complications include partial                    or complete thrombosis of the hepatic artery, leakage of drug from the artery                    causing gastritis, duodenitis, ulcers, occlusion of the catheter, catheter                    displacement, and hemorrhage.(18,26,41). Gastrointestinal complications (nausea, vomiting, diarrhea)                    occurred in 6-90 of enrolled patients.

In the early clinical trials that utilized implantable pumps for chemotherapy,                    not all the patients underwent catheter tunneling. This was presumably                    responsible for a large percentage of early failures due to catheter kinking,                    migration, and their sequelae. Technical complications of the IIP and delivery                    catheters, such as leakage and kinking, have been ameliorated by redesign of the                    pump and catheter connections, by open surgical techniques for placement of the                    pump and catheter, and by concurrent prophylactic surgical procedures such as                    cholecystectomy and gastroduodenal devascularization. Except in the early                    experiences reported in CHAI therapy, complications requiring explantation of an                    infusion pump were infrequent. Other complications related to implantation of                    the infusion pumps were seroma and localized infection.

Methodologic issues may have obscured significant outcome findings or biased the                    study: nonuniformity in disease staging (noninvasive vs. intra-operative),                    inadequate sample size (power) to detect a difference in outcomes, and crossover                    of treatment upon disease progression to alternate treatments (from systematic                    chemotherapy to CHAI). When cytotoxicity caused dosage reduction, the                    differences in the calculated and actual dose administered were not reported in                    most studies. Finally, investigators used various definitions of complete and                    partial response to chemotherapy, which made comparisons of outcome difficult,                    if not impossible.

The costs of pre-operative angiography, prophylactic cholecystectomy, and gastric                    devascularization, and frequent laboratory and radiologic postimplantation                    studies, as well as additional expenditures associated with reoperation for                    complications or explantation of the infusion pump, must be balanced with the                    expectation of limited palliation and no benefit of increased life expectancy in                    these patients.

###                     Intraspinal morphine for chronic                    pain

Intrathecal morphine administration was first attempted in 1977 and, since                    clinical introduction of the implantable infusion pump in 1982,(42). has been used to treat pain of                    malignant origin. Morphine injected into the cerebrospinal fluid (CSF) creates a                    reservoir of drug that diffuses passively into the dorsal horn of the spinal                    cord, binds to opiate receptors, hyperpolarizes the interneurons and inhibits                    release of neurotransmitter substance P,(43). which inhibits pain transmission at the spinal cord level.                    Morphine is cleared from the CSF by diffusion along the neuraxis, by vascular                    absorption, and by rostral spread from the subarachnoid space to the supraspinal                    cisternae. (44). Its analgesic effect                    depends on the drug concentration near the receptor, on receptor response to                    drug stimulation, and on the number of opioid receptors available.(44). Morphine and other opioids are                    reversible with the use of narcotic antagonists. 

Morphine injected into the epidural space produce analgesia by two                        mechanisms.(45). Initially some of                    the drug crosses the dura mater to enter the CSF. From there, it penetrates into                    the dorsal horn of the cord, similar to an intrathecal injection. At the same                    time, extradural drug is absorbed systemically, producing a plasma profile that                    resembles an intramuscular injection. Analgesia is produced as the drug is                    distributed to both the brain and spinal cord.

Although morphine has been approved for both intrathecal and epidural                    administration to alleviate chronic malignant pain and pain of nonmalignant                    origin, the choice of one route over the other depends, in part, on the skill of                    the pain specialist in locating the epidural or subarachnoid space. Another                    consideration is the anticipated duration of catheter implantation. Fibrous                    reactions and dural thickening have occurred with prolonged exposure to epidural                        catheters,(46). and are thought to                    be influenced by the catheter material and drug preservative. One advantage of                    the epidural route is the ability to control the level of sensory blockade.

The intrathecal route allows drugs to be deposited directly into the CSF, near                    the spinal cord receptors, resulting in a more rapid onset of action and a lower                    dosage requirement than the epidural route (approximately one-tenth to one-third                    the epidural dose).(47).

No controlled studies have been published that compare the effectiveness of                    intrathecal and epidural opioid use in chronic pain. However, Nitescu et                        al(48). studied 25 patients with                    advanced cancer pain who, while receiving epidural morphine and bupivacaine,                    experienced severe pain, as well as intolerable side effects from systemic and                    adjuvant analgesics. The purpose of the study was to assess comparative efficacy                    of the epidural and intrathecal routes by measuring the total amount of                    analgesics given by all routes to bring pain relief to an acceptable level. Both                    epidural and intrathecal drug delivery was accomplished by bolus doses through                    percutaneously inserted catheters. Total analgesic effect (all systemic,                    adjuvant, oral, and intraspinal drugs delivered), responses to visual analog                    scales (VAS) for pain, and changes in daily activities and sleep patterns were                    recorded. Total analgesic drug use during epidural administration of morphine                    and bupivacaine was assessed retrospectively, and evaluated prospectively during                    the intrathecal phase of the study.

As expected, the intial intrathecal dose that effectively controlled the pain was                    significantly lower than previous epidural doses in the same patient. This                    effect lasted up to 1 week for intraspinal morphine and bupivacaine, and 6                    months for total analgesic use. Lower drug volumes and higher drug                    concentrations were needed with intrathecal delivery. Median daily effective                    doses of intrathecal morphine and bupivacaine were somewhat stable for the first                    4 weeks of administration (15-17 mg/d), although 9 of the 25 patients were no                    longer in the study by this time. By 3 months, the remaining 10 patients were                    receiving median effective doses in the range of 38-40 mg/d, and at 6 months the                    4 remaining patients were receiving median doses of approximately 100 mg/d.

In 1987, Ventafridda et al(49).                    analyzed the results of 37 papers published from 1979-1985 that reported on the                    efficacy of intraspinal morphine in pain of malignant origin. Three hundred and                    six patients had epidural infusions (21, implantable pumps; 79, external pumps                    attached to an externalized epidural catheter) and 107 had intrathecal                    (ubarachnoid) infusions, (76, implantable pumps; 24, external pumps attached to                    an externalized intrathecal catheter). They reported that the implantable pumps                    were used for a longer period of time, and that fewer side effects (drowsiness,                    sweating, itching, nausea, vomiting and urinary retention) were recorded for the                    epidural group. In their own study of 75 patients who received either                    intrathecal or epidural infusions, they concluded that patients who do not                    obtain adequate pain relief from oral morphine cannot develop adequate pain                    control by either epidural or intrathecal morphine because of other reasons for                    the pain, such as movement, deafferentation, or spinal cord compression. No                    evidence was presented to support this conclusion. They recommended EIPs for                    those patients with diffuse pain who respond to either intrathecal or epidural                    opioid treatment who are intolerant of oral and parenteral narcotics, and who                    have a short life expectancy (less than 6 months), and implantable systems for                    comparable patients whose life expectancy is greater than 6 months. Further,                    they recommended other concurrent routes of administration for opioids which                    contribute to the overall clinical management of pain.

Hassenbusch et al(50). 69 consecutive                    patients over a 6-year period in a prospective case series with administration                    of continuous, constant-rate infusions of epidural morphine by IIP to patients                    with terminal cancer. A temporary percutaneous epidural catheter was inserted                    for 2 -4 days and continuous morphine was infused. Visual and verbal analog pain                    scales, drug diaries, and complications were used to measure the effectiveness                    of pain control. Significant pain control was defined as at least a 30 reduction                    in pain analog values at epidural morphine dosages less than 40 mg/d. Forty-one                    of the 69 patients were implanted with a permanent system, and 37 of them were                    evaluable. No information was reported on the 28 patients who did not receive                    the permanent system, or on the 4 who were alive but unevaluable after 1 month                    in the permanent-system group.

Systemic use of morphine was reduced after 1 month from 77.7 +/-19.1 mg/d to 16.                    1 +/-3.6 mg/d, but rose to 27.9 +/-2.6 mg/d after 9 months. The mean epidural                    dose of morphine after 1 month was 20.7 +/-2.6 mg/d, rising to 49.3 plusmn; 9.9                    mg/d after 9 months of infusion. Responses on the pain VAS decreased from a mean                    of 8.6 +/-0.3 before epidural infusion to 3.8 +/-0.4 after one month. At 1, 3,                    and 6 months, satisfactory pain relief was obtained by 87.1, 81, and 81.2 of the                    41 patients, respectively. Ten infusion system complications were reported,                    ranging from catheter migration to superficial wound infections, along with                    three complaints of voiding disturbances. One patient was suspected of having                    drug tolerance after 24 months, but further examination showed aggressive                    extension of the underlying pelvic cancer. The mean survival time in this series                    of patients was 7 months (range not reported).

Onofrio et al(51). evaluated 53                    terminal cancer patients with unacceptable side effects (somnolence) from                    parenteral narcotics, and measured the efficacy (quantity of drug, mobility,                    pain relief) of intrathecal morphine. Although these authors did not find any                    association between analgesic effect and age, mobility, prestudy analgesic drug                    use, or prestudy duration of pain, all patients had significant pain relief at 4                    weeks. The intrathecal dose of morphine increased two to threefold within the                    16-week study period. Pain relief experienced from the preimplantation bolus                    dose of intrathecal morphine was the only parameter predictive of long-term                    efficacy. Patients also received systemic (intravenous) analgesics during the                    study period, possibly masking or confounding any effects, or lack thereof,                    attributed to the epidural route.

Penn and Paice(52). studied 43                    patients, 35 with pain of malignant origin and 8 with chronic nonmalignant pain                    (CNMP), and attempted to demonstrate that early treatment of pain with                    intrathecal morphine would be effective. Objective measurements included                    systemic drug use and activities of daily living (ADL): Twenty-eight of the 35                    cancer patients manifested improved pain management, 3 were classified as                    treatment failures, and 4 had a poor response. The eight patients with CNMP all                    had a good or excellent response. The mean followup period was 21 months.

The use of access ports also has been evaluated in the treatment of chronic pain.                    Madrid et al(53). treated 100 cancer                    pain patients who were opioid-naive with morphine via access port and a lumbar                    intrathecal catheter. No concurrent systemic drugs were administered during the                    study period. The purpose of the study was to evaluate the safety, feasibility,                    and long-term effectiveness (greater than 3 months) of morphine administered                    outside the hospital. All had good pain control but 28 complained of urinary                    retention and 13 of pruritus. Catheter occlusions developed in 8 of the patients                    and CSF fistulae occurred in 4.

Gourlay et al(54). treated 29 patients                    with terminal cancer in whom oral opioids with adjuvant drugs no longer provided                    effective pain relief. After a 2-day trial of epidural morphine, the patients                    were randomized to receive either intermittent bolus doses of epidural morphine                    via access port or continuously infused epidural morphine by IIP. Effectiveness                    measures included VAS, a categorical scale to measure pain relief, problems with                    the device, and recommendations. Dosage adjustments were made according to                    patient responses to these and other psychometric results. When a patient's                    morphine requirements exceeded the maximum delivered by the pump, the route of                    administration was changed to intrathecal (10/28 patients). The mean duration of                    implantation was 140 days (range 28-378, median 100) for the access port group                    and 169 days (range 6-537, median 100) for the infusion pump group. The VAS                    scores, and the categorical scores were equivalent in both groups. No                    significant differences were found in any of the measured parameters. Both                    groups required more drug over time, with significantly greater dosage                    escalation in the continuous infusion group. 

Crul and Delhaas(47). described their                    5-year experience in treating 140 cancer patients with intraspinal morphine via                    an implanted access port. One hundred and ten patients with a short life                    expectancy were offered an epidural catheter, and the 30 others an intrathecal                    catheter. Both tunneled catheters (20 epidural and 30 intrathecal) and                    transcutaneously inserted catheters (90 epidural) were used. While the epidural                    group was complication-free during the first 3 weeks, 23 patients (25) with                    transcutaneous catheters experienced catheter dislocation, necessitating removal                    or replacement.

The most frequent complication in the intrathecal group was CSF leaks (26.6),                    occurring early in treatment. A significant difference in the incidence of                    complications arose between the epidural and intrathecal groups within the first                    3 weeks of treatment, 8 vs. 25, respectively (p = 0.02). During the remainder of                    the treatment period (20-366 days), epidural complications rose to 55 and                    intrathecalones dropped to 5.

Among the 110 patients with epidural catheters inserted, 121 major complications                    (dislocation, obstruction, infection) were reported in the transcutaneous                    catheter group (90 patients) and 7 were reported in the 20 patients with a                    tunneled catheter. Thirty patients with tunneled intrathecal catheters had fewer                    major complications.

Auld et al(55). evaluated patients with                    CNMP to determine patient selection criteria for intrathecal narcotic delivery.                    Patients underwent a trial epidural bolus morphine injection to measure                    effectiveness (phase 1). If they experienced good to excellent pain relief, an                    access port and epidural catheter were implanted (phase 2). They were stabilized                    over 4-12 weeks, and if they continued to have good pain relief, were implanted                    with a vapor-pressure powered infusion pump (phase 3). Serum morphine levels,                    pain medication log, patient pain assessment, and serial ADL measurements were                    all used to define effectiveness. Sixty-two patients entered phase 1; 37 entered                    phase 2; and 32 entered phase 3. The 30 patients who did not complete the trial                    dropped out because of incomplete pain relief or relief of too short a Seventeen                    of the 32 patients who entered phase 3 had recurrent pain during the 24-month                    trial.

Coombs,(56). in a study reported in                    1983, attempted to compare the effectiveness of epidural morphine in five                    patients with CNMP and five patients with chronic intractable pain secondary to                    adenocarcinoma. Measures of effectiveness used were the McGill Pain                    Questionnaire, VAS, drug diaries, Zung Depression Scale, and a trial of                    cognitive drills. The CNMP patients reported more pain during baseline that the                    cancer patients, and less relief of pain at the 12-week evaluation. Tolerance                    developed in all patients. Four of the five CNMP patients showed no improvement                    in cognitive skills during the trial.

With regard to the use of infusion pumps for management of chronic pain, NIH has                    stated that there are limitations on the conclusions that can be drawn from the                    data. For example, the studies do not give information about disease status or                    progression during the trial; there is no information regarding patients who                    discontinued treatment; there are no direct comparisons of effectiveness of                    intraspinal morphine vs. other delivery systems in matched subjects; no                    discussion is present regarding patient satisfaction data nor the incidence of                    side effects. "These limitations preclude a definitive answer to the question of                    clinical effectiveness of external and implanted infusion pumps for the                    management of cancer pain. "

At the same time, there is a belief among some experts in cancer pain management                    that "a small proportion" of pain patients may obtain substantial relief from                    epidural or intrathecal administration of opioids. An example of the prevalence                    of this group of patients was cited from the study of Hogan et al(57). in which 12 of 1,205 cancer                    patients achieved pain relief with epidural morphine or morphine plus                    bupivacaine.

Nonetheless, these authors stated that data are insufficient to determine whether                    these techniques should be used in a more widespread fashion in patients with                    cancer. Randomized studies comparing chronic systemic treatment to spinal                    infusion would be necessary to determine the cost-benefit ratio from more                    widespread use of these methods. Similar arguments hold for use of these methods                    in nonmalignant conditions. 

Measures of the effectiveness of intrathecal or epidural morphine included                    subjective quantification of pain reduction with VAS, drug diaries, and                    correlations between plasma opioid level and VAS. In the studies reviewed ,                    short-term (within 4 weeks) good to excellent pain control was achieved with                    intraspinal narcotics, systemic opioids and/or other analgesics, or a                    combination of these. Total analgesic drug use (all routes) decreased initially                    in all studies, and slowly escalated over time. Only one study(54). utilized drug exclusively by the                    epidural route and demonstrated excellent pain relief in narcotic-naive                    patients. Serum and CSF morphine levels did not correlate at all with subjective                    measures of pain relief (i.e., VAS), while activities of daily living,                    concurrent systemic drug use, and changes in patient mobility reflected patient                    response.

All of the studies demonstrated increased total analgesic use over time. At 5                    months or longer, the intraspinal mean analgesic equivalent dose had increased                    to more than three times the initial effective dose. "Morphine holidays" with                    adjuvant drugs such as bupivacaine were successful in treating patients who                    experienced acute drug escalations, and these holidays enabled successful                    resumption of morphine at much lower dosages. Other authors reported a change                    from epidural to intrathecal routes to treat dosage escalations that would have                    required drug delivery rates beyond the capability of the pump. Whether these                    escalations derived from underlying disease progression (particularly in                    oncology patients), tachyphylaxis (tolerance), or device failure was not                    determined in all cases. In CNMP patients, the drop out rate was high owing to                    insufficient pain relief, dissatisfaction by the patient, or tolerance.

Foley(58). classified cancer pain into                    five types: acute, chronic, chronic nonmalignant pain in patients with cancer                    pain, cancer pain in the presence of illicit drug addiction, and pain in dying                    patients. This classification system enables health care practitioners treating                    patients to acknowledge both the acute and chronic aspects of mixed pain                    syndromes, and assists them in treating not only the underlying cause of the                    pain, but also the attendant psychological or social consequences of their pain.                    Patients with chronic, nonmalignant pain, including neurogenic or idiopathic                    pain, present different management issues,(59,60). such as tolerance,                    drug dependence (addiction, physical dependence), undertreatment of pain, and                    availability of opioids for *bona fide* medical uses.

It is recommended that treatment regimens for chronic pain be effectively                    tailored to the individual patient(61). by evaluating: (1) the natural history of the malignancy or                    underlying lesion; (2) the patient's physical and psychological condition,                    including pulmonary function tests and evaluation of general mobility; (3) the                    locations, intensity, and mechanisms of the pain and the types of responses to                    previous pain relief therapies and regimens; (4) the drugs, medical devices, and                    other resources available to the patient; (5) the knowledge and skill of the                    personnel available to apply each method most effectively; and (6) the decision                    of the patient to undertake a particular regimen, given the benefits and risks                    of that regimen, and the patients cooperation with the caregivers.(62,63). The information elicited in this evaluation can be utilized to                    effect a coordinated, multidisciplinary approach (neurosurgical, anesthesia,                    behavioral and pharmacologic therapies) for chronic pain treatment.(58).

In virtually all of these studies, little information was reported on why                    patients dropped out during the trial period. No objective data were provided                    about treatment responses or reasons for going off protocol. These factors                    remain a critical impediment to understanding the overall effectiveness of                    intraspinal morphine in eligible patients and to recommendings its widespread                    use.

The studies of the effectiveness of intraspinal morphine for chronic pain                    (whether of malignant or benign origin) highlight the progression of analgesic                    therapy in patients with chronic pain syndromes, and also point out some of the                    difficulties in measuring the effectiveness of pharmacologic interventions for                    pain relief. Individual patient response to an acute intraspinal trial                    administration of opioids was the single most predictive measure of short-term                    (4 weeks) effectiveness of morphine.

###                     Intrathecal baclofen for chronic spasticity                    

Chronic spastic syndromes, a heterogenous group of clinical entities, are                    sequelae of upper motor neuron damage such as spinal cord trauma or multiple                    sclerosis. They may manifest in painful involuntary hyperactive monosynaptic and                    polysynaptic reflexes with accompanying hypertonic increases in muscle                        tone.(64). The antigravity muscles                    (arm flexors and leg extensors), are predominantly affected by exaggerated                    tendon reflexes. At rest, the muscles are flaccid and electromyelographically                    silent. If the muscles are stretched rapidly, a "clasp-knife" phenomenon                    develops, in which initial movement of the limb is abruptly halted almost in a                    locked position. Continued passive extention or flexion slowly dissipates this                    resistance, and full range of motion is possible.

Maynard et al,(65). in an                    epidemiological study that measured incidence of spasticity after traumatic                    spinal cord injury in 100 patients, reported that spasticity developed in 67 of                    patients by the time of hospital discharge (mean days to discharge 118 +/-                    7.4).

Treatment regimens for spastic patients are often difficult because of the                    elapsed time since the onset of injury, the extent of the spinal cord lesion,                    and other accompanying disabilities such as dystonic posturing, synkinetic                    movements, flexor spasms, and the fact that some treatments often mask residual                    voluntary motor movement. (66).                    Treatment is centered around the preservation of the remaining neurologic                    function, and ablation or control of painful or debilitating flexor                    spasticity.

Since the 1950s, treatment for spasticity has included a variety of invasive                    surgical procedures, such as spinal cord stimulation with implantable, epidural                        electrodes,(67). deep brain and                    cerebellar stimulation,(68). and                    selective peripheral neurotomies,(69).                    to interrupt the spinal reflex arc or reduce afferent neuronal stimulation of                    the dorsal horn.(70). The sequelae of                    these surgical procedures and medical therapies have induced disabilities such                    as bladder dysfunction, partial paresis, sensory loss, drowsiness,                    hallucinations or loss of voluntary motor control. These treatment options are                    often combined with the use of oral antispasmodic agents such as baclofen and                    other oral agents such as morphine, fentanyl, benzodiazepines, or dantrolene to                    control the severity and pain of spasms.

The effectiveness of intrathecal baclofen for the control of spasticity was first                    shown in 1984 and relevant clinical studies are reviewed.

Penn et al(71). in an open-label,                    compassionate-use protocol investigated 66 consecutive patients (32 with spinal                    trauma, 33 with multiple sclerosis, and 1 with lateral sclerosis) with                    intractable spasticity, who had failed oral antispasmodic therapy. All patients                    who consented underwent a screening procedure, as follows. An intrathecal                    catheter was inserted percutaneously under fluoroscopy into the lumbar                    subarachnoid space. Incremental bolus doses of baclofen were administered (25 to                    100 micro-g) over a period of days to weeks to judge efficacy of intrathecal                    administration before the implantation of a permanent delivery system; to test                    individual drug tolerance; and to fix the baclofen dosage effective for 8 to 12                    hours in order to optimize the drug administration schedule. This study employed                    a randomized, placebo-controlled crossover design, allowing patients to act as                    their own controls. If there was no effect on spasticity, measured as a                    reduction in the intensity and number of spasms, or if someone did not                    experience the anticipated relief from spasticity or pain, or refused further                    treatment with intrathecal baclofen,; that person was considered ineligible for                    the chronic phase of the study, and those who failed to pass the screen were not                    evaluated in measurement of the effectiveness of baclofen. 

Once successfully through the screening period, 62 of the 66 patients had an                    implantable infusion delivery pump inserted subcutaneously, attached to the                    previously implanted intrathecal catheter. Patients were evaluated for changes                    in muscle tone, frequency of muscle spasms, reflexes, electrodynamic studies of                    lower extremity muscle groups, induced spasms, and voluntary control of the                    lower extremities. The mean treatment period was 30 months (range 3 -84); median                    length of treatment = 27 months; mode = 8 months. Sixty patients had good relief                    of spasticity. It required 18 to 24 months of escalating baclofen doses to gain                    food control over muscle spasms. The mean preimplantation Ashworth (spasticity)                    score declined from 3.8 to 1.4 postimplantation. Spasm frequency scores also                    dropped from their preimplantation levels. Three patients had recurrence of                    spasms at 2, 3, and 3.5 years of intrathecal baclofen infusion. Two patients                    withdrew (time not reported) because they wanter more extension rigidity for                    standing. Four patients died of underlying disease progression.

The 62 patients were implanted with a total of 91 infusion pumps. Nine of these                    pumps failed (including early prototype models). Catheter complications occurred                    with "unfortunate regularity" (5 punctures, 11 kinks, 3 dislodgements, 4                    disconnections, 2 breaks). Intrathecal baclofen infusion was restored in all                    patients by replacing the catheter. Five surgical complications required either                    explantation or reimplantation of a pump. Four infusion pumps stalled, requiring                    removal and reimplantation.

Several different transient side effects were reported in 31 patients, primarily                    due to baclofen overdose. All side effects resolved by reducing the dosage. One                    patient with multiple sclerosis developed grand mall seizures after several                    months of intrathecal baclofen and was treated with chronic anticonvulsant                    therapy. Varying degrees of effectiveness were found in 97 of the patients in                    this series. The two failures were one patient each with multiple sclerosis and                    lateral sclerosis. The infusion pump had a failure rate of 7, while catheter                    complications that required interruption of drug delivery occurred in over 50 of                    the 

Lazorthes et al,(72). in a protocol                    similar to that of Penn, treated 18 of 38 patients (6 with multiple sclerosis, 8                    with trauma, and 4 with cerebral vascular disease) at home with intrathecal                    baclofen by either access of port or IIP. The other 20 were not treated because                    of significant ineffectiveness of intrathecal administration, overeffectiveness                    (loss of useful extensor rigidity), difficulties in followup, and patient                    refusal. The effectiveness measures used were the Ashworth scale, motor                    performance scale, and neurophysiologic assessments. Fourteen of 16 patients                    showed improvement in the occurrence of painful muscle spasms. Functional                    improvement varied. Moderate to good and lasting improvement occurred in 12                    patients. In the remaining six patients, five of whom had multiple sclerosis,                    spasticity was reduced but there was no functional improvement. The longest                    followup in this study was 18 months (two patients). The treatment effect                    (either preservation of residual spastic function in patients with some useful                    functional motor activity, or total antispasticity in patients without any motor                    activity) required careful drug titration to reach an effective therapeutic                    dose. From the titration period to the end of followup, the mean daily effective                    dosage of baclofen (90 micro-g, range 15-250 micro-g) doubled (range 26 to 500                    micro-g). The question of long-term tolerance was not addressed by this study                    design, although the trend certainly demonstrated increasing dosages over the                    18-month period. Device complications included three catheter dislodgements, and                    one pump failure requiring explanation. The four cases of local sepsis and the                    three incidents of purulent meningitis were seen in patients implanted with an                    access port. The need for daily percutaneous refilling in immunosuppressed                    individuals convinced the authors to abandon access port insertions in favor of                    IIPs. Severe drug complications occurred in two patients from drug overdose,                    requiring resuscitation and artificial ventilation in one of them.

Loubser et at(73). evaluated patients                    with refractory spasticity for long-term rehabilitative issues and for                    tolerance. After weaning from all previous medication, 9 out of 10 eligible male                    patients had an intrathecal catheter inserted and were randomized, in 12-hour                    intervals, to receive either continuous baclofen or placebo for spasm and reflex                    control. Muscle tone, frequency of spasms, urodynamometry, reflexes, pulmonary                    function, brainstem auditory-evoked potentials, functional abilities, and                    personal independence were assessed every 12 hours. Ashworth scores declines in                    7 out of the 9 patients during the placebo period (p = 0.02), while 6 of 9                    reflex scores decreased during the same period (p = 0.001). During the period of                    baclofen administration, Ashworth and reflex scores declined significantly in                    all patients (p = 0.01). Eight of the 9 patients improved in independence and                    functional status. During the second phase of this study, a permanent infusion                    pump was implanted in seven out of the nine eligible patients (two elected not                    to proceed). Four patients experienced a decrease or withdrawal from plantar                    stimulation; two manifested higher threshold for spasm triggering; two displayed                    decreased minimum voluntary motor control; and significantly reduced Ashworth                    and reflex scores (p = 0.001). One patient had no change in any parameter                    tested, five had decreased reflex motor activity and four had a decrease stretch                    response. Two catheter complications requiring surgical intervention occurred.                    There were no IIP malfunctions. The daily dosage of baclofen gradually increased                    over the observation period in all patients. The initial mean dosage was 164                    micro-g/d (+/-134) and rose to 536 micro-g/d (+/-269) at 2 years, although by                    then only three patients remained.

Ochs et al(74). reported on a                    multicenter series of 28 patients with chronic spasticity unresponsive to oral                    baclofen (10 with trauma, 12 with multiple sclerosis, 6 with mixed                    myelopathies), who were treated with intrathecal baclofen. Muscle tone,                    reflexes, and systemic drug use were evaluated. Other subjective measures were                    patient assessment of pain relief, improvement in mobility, facilitation of                    nursing care, and changes in physical therapy. The results demonstrated that                    baclofen was difficult to titrate in those patients able to walk by using                    residual extensor tone. Muscle tone was reduced (Ashworth scale: 3.6 +/-0.35 to                    1.75 +/-0.31) and the mean number of spasms per hour decreased from 2.5 to 1.4                    after 1 month of intrathecal baclofen administration. The mean drug requirement                    necessary to maintain the initial effective response was 144 micro-g/d (range                    32-620 micro-g) which increased to 203 micro-g/d at the end of the study. Mean                    followup was 9.5 months (range 1-25). Pain secondary to muscle spasm was                    effectively controlled, but deafferentation pain remained unaffected in this                    group of patients. One pump failure and a pump pocket infection occurred, both                    requiring explantation and reimplantation of new pumps. Four catheters were                    replaced owing the displacement, blockage, or nerve-root irritation.

Parke et al(75). reported on eight                    patients (four with multiple sclerosis and four with spinal cord injury)                    followed for at least 6 months (range not reported) for functional and sleep                    status after intrathecal baclofen by IIP. These patients were part of Penn's                    larger series. All had immediate improvement in spasticity and night spasms,                    while bowel and bladder performance improved in all but one. Among the four                    patients not independently performing bladder care, one achieved some degree of                    independence at 3 months, another at 6 months, and the two remaining ones,                    although not functioning independently, achieved some improvement. Of seven                    patients needing help from others in dressing, five achieved some level of                    independence.

The baclofen studies reviewed demonstrated that patients successfully treated                    with trail bolus doses of intrathecal baclofen are able to maintain this initial                    effectiveness with increasing daily baclofen dosages. Most studies demonstrated                    the need for slow, incremental increases in dosage over the first 6 months to 1                    year of treatment. Patients who developed tolerance were either successfully                    treated with higher daily dosages or effectively treated with intrathecal                    opioids for a short period of time, followed by resumption of baclofen.

The severity of the original motor damage is not necessarily predictive of the                    functional gain in voluntary motor control, if any, that an individual may                    achieve with intrathecal baclofen administration, particularly if the dose of                    baclofen used to control the spasticity reduces extensor motor control. (76). Full benefit of intrathecal                    baclofen on functional improvements, i.e., sleep patterns, bowel and bladder                    care, feeding and dressing, may not manifest itself for several months or years                    after the initiation of therapy.(75).                    Data addressing improvement in the quality of life are few, and do not permit                    conclusive judgments regarding that parameter. Drug-device complications,                    particularly in more recent studies, were infrequent.

##                 Conclusions

Technologies permitting drug self-administration and automated drug delivery outside                the hospital have become increasingly more sophisticated, adaptable, and available,                with over 300,000 persons annually receiving home infusion therapy.(8). There are over 600 models of EIPs,                several types of access ports, and two noninsulin implantable infusion pumps                currently on the US market. Multifunction external and implantable programmable                devices are available, and complex delivery regimes that alter dosage,                concentration, and rate of administration, are possible.

###                     Continuous hepatic artery                    infusion

The literature does not support a conclusion that CHAI by implantable infusion                    pump is a lifesaving or unique therapeutic intervention (other reasonable                    alternatives exist). Implantable infusion pumps provide another drug management                    option for treatment in limited circumstances, although the cost-effectiveness                    of intrahepatic chemotherapy, intrathecal baclofen, and intraspinal opioids                    remains unanswered.(77,78,79).

The outcomes measured in that CHAI studies have demonstrated that CHAI does not                    influence survival in patients with hepatic metastases of colorectal carcinoma,                    although progression of intrahepatic disease was delayed significantly. Survival                    is inversely proportional to tumor burden at diagnosis. Patients who are                    surgically staged and undergo curative resection, or who have tumor replacement                    volumes less than 50 at the time of diagnosis and treatment, have longer                    survival times than those who are surgically unresectable (multiple metastases)                    and are treated with adjuvant cytotoxic agents. The morbidity experienced by                    patients in cytotoxic studies, and the inherent biases in the study designs,                    cautiously lead us to limited generalizable conclusions about the effectiveness                    of CHAI by IIP for the treatment of metastases of colorectal cancer.                    Chemotherapy with CHAI by IIP offers a limited benefit to patients. This benefit                    must be evaluated in light of the known potential side effects related to both                    the drug and device, the costs, and patient's life expectancy.

###                     Morphine and baclofen

A stepwise treatment plan from nonopioid oral analgesics and antispasmodics to                    opioids, adjuvant therapy and, as a last resort, neuroablative procedures,                    should be followed when severe pain or spasticity incapacitates the patient.                    Eligibility criteria for placement of an IIP should include evaluation of prior                    responses to noninvasive methods of pain management and spasm control, such as                    oral or subcutaneous opioids, anti-spasmodics, alone or combined with                    nonsteroidal anti-inflammatory drugs or anticonvulsants (depending on the                    disease progression and the patient's symptoms). Life expectancy, physical and                    behavioral abnormalities that may interfere with the patient's ability to assess                    pain, the patient's support systems and the cost of the delivery system(79,80). need to be reconciled. Actual or imminent spinal compression,                    obstruction, or anomaly, as well as all potentially reversible causes of pain or                    spasticity should be ruled out.(18). A                    preliminary trial of intraspinal opioid(82). or intrathecal baclofen(71). with a temporary epidural or intrathecal catheter should be                    undertaken before implantation of an access port of infusion pump so that pain                    relief or reduction in spasticity, side effects, ADL, and patient acceptance can                    be evaluated. Implantation of a permanent IIP should be attempted only when less                    invasive steps have been unsuccessful in alleviating pain or spasticity and the                    patient experiences acceptable relief during the trial phase. And finally,                    because of the expense of implantation of infusion pumps and the attendant                    costs, the patient's anticipated life expectancy should be several months from                    the time of implantation of the infusion delivery 

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                        - 
AHCPR Pub. No. 94-0013

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Bookshelf ID: NBK63978

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                    - Cite this Page Graham AA, Holohan TV. External and Implantable Infusion Pumps. 1994 Jan. In: AHCPR Health Technology Reviews. Rockville (MD): Agency for Health Care Policy and Research (US); 1992-1995.  7.

### In this Page

                    -                 Introduction
                    -                 Background
                    -                 External infusion pumps 
                    -                 Implantable Infusion Pumps 
                    -                 Clinical Effectiveness
                    -                 Conclusions
                    - References

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