Implantable Drug Pump Research Articles

Transition from Compounded to Monotherapy Intrathecal Pain Medication Reduces Drug Costs: Retrospective Analysis of Patient Billing Data

Chronic pain accounts for several hundred billion dollars in total treatment costs, and lost productivity annually. Selecting cost-effective pain treatments can reduce the financial burden on both individuals and society. Targeted drug delivery (TDD), whereby medications used to treat pain are delivered directly to the intrathecal space, remains an important treatment modality for chronic pain refractory to oral medication management. These medications can be administered alone (monotherapy), or in conjunction with other medications to give a synergistic affect (compounded therapy). While compounded therapy is often prescribed for pain refractory to both oral management and intrathecal monotherapy, compounded administration has not been approved by the United States Food and Drug Administration (FDA), and is thought to be more expensive. In this study, we hypothesized that TDD delivering monotherapy vs compounded therapy would differ significantly in cost. In 2015, a pharmacy-led initiative resulted in an institution-wide policy requiring that all TDD patients, being treated with compounded therapy, be transitioned to FDA-approved intrathecal monotherapy. The intent of this new policy was to eliminate use of non-FDA approved, "off-label" medications. During this transition, our practice used the opportunity to retrospectively analyze and compare the costs of monotherapy vs compounded therapy. Billing, drug dosing, and pain data were collected from 01/2015 to 01/2019, and reviewed retrospectively for patients originally on compounded intrathecal medication therapy, and compared before and after transition to monotherapy. A multidisciplinary hospital-based spine center within an academic tertiary care facility. Electronic medical records from the institutional TDD program were retrospectively reviewed to identify all patients on compounded drug therapy before the transition period (2015-2016). Patients were excluded from the study if they chose to switch their care to another practice rather than transitioning from compounded therapy to monotherapy. Cost per medications refill, cost per year, and reported pain scale before and after the transition were computed, and differences were compared using unpaired t tests. Refill costs of individual drugs were also compared. Of 46 patients originally on compounded therapy, 26 patients met inclusion criteria. The most common pre-transition drugs administered as compounded therapy were bupivacaine (n = 17), morphine (n = 15), and clonidine (n = 14), while hydromorphone (n = 10), baclofen (n = 5), and fentanyl (n = 1) were less common. There was a 51.3% decrease in cost per refill (P = 0.135) and a 50.0% decrease in cost per year (P = 0.283) after transition. Morphine and clonidine were both significantly more expensive than hydromorphone and bupivacaine (P < 0.05). After removing cases in which hydromorphone was the baseline opiate, there was a 64.8% decrease in cost per refill (P = 0.041) and a 66.8% decrease in cost per year (P = 0.190). There was no significant difference in the average reported pain scale across the transition (P = 0.323), suggesting stable pain management efficacy. This retrospective study is limited by its small cohort size and lack of a control group. Based on single-institutional billing data, transition from compounded therapy to monotherapy TDD resulted in cost savings, dependent on the specific combination of drugs initially used for therapy. A larger multi-institutional study is indicated.

Industry Update Covering November 2018

November 2018, the period covered by this article, showed strong activity in mergers/acquisitions and collaborations, including the announcement of a deal for the global manufacture of a micellar nanoparticulate formulation of paclitaxel. The month also brought positive clinical trial news in therapeutic areas such as pancreatic cancer using CAR-T therapies and asthma. In regulatory news, the US FDA issued a warning highlighting concerns about the serious complications that can occur when using unapproved painkillers with implantable drug pumps and approval was announced for an oral film formulation to treat Lennox-Gastaut syndrome. November also saw patents being issued on novel therapeutic delivery methods for ocular delivery and the use of proprietary vitamin A-micellar delivery vehicle. Information sources used in compiling this update included company press releases and other news websites.

Intrathecal Clonidine via Lumbar Puncture Decreases Blood Pressure in Patients With Poorly Controlled Hypertension.

Oral clonidine is used to treat hypertension but often produces sedation and severe dry mouth; intrathecal clonidine is used to treat chronic pain but may produce hypotension. This clinical feasibility study was conducted to determine if intrathecal clonidine decreases blood pressure in patients with poorly controlled hypertension. This prospective, single-arm, open-label study was conducted in ten subjects who were taking at least three antihypertensive medications including a diuretic and had an in-office systolic blood pressure between 140 and 190 mm Hg. On the day of treatment, blood pressure was measured before and after a single lumbar intrathecal dose (150 mcg) of clonidine using an automatic oscillometric device every 10-15 min for four hours. Student's paired t-test was used for statistical comparisons. Maximal reductions in systolic and diastolic blood pressures averaging 63 ± 20/29 ± 13 mm Hg were observed approximately two hours after clonidine administration. Decreases in systolic pressure were strongly correlated with baseline systolic pressure. Clonidine produced a significant decrease in heart rate of 11 ± 7 beats/min. No subject required intravenous fluids or vasopressor rescue therapy, or reported spinal headache. This is the first clinical study in subjects with hypertension that demonstrates significant and profound acute reductions in blood pressure after a single dose of intrathecal clonidine. Future placebo-controlled, dose-escalating studies are warranted to assess the long-term effects of intrathecal clonidine infusion via an implantable drug pump in patients with treatment-resistant hypertension at risk of stroke or myocardial infarction.

Management of symptomatic intrathecal catheter-associated inflammatory masses

ObjectiveIntrathecal catheter-associated inflammatory masses (CIMs) are a serious complication of implanted drug pumps. The goal of this study was to review our experience with CIMs, including the pathology of all resected CIMs, and identify objective data which may guide management. MethodsWe performed a retrospective review of 13 patients who developed symptomatic CIMs during continuous intrathecal opioid therapy for chronic pain. Eight patients presented with pain plus neurologic deficit and 5 patients presented with pain alone. ResultsCIM resection via laminectomy and intradural exploration was ultimately performed in 8 patients, 3 of whom were initially treated with a non-resective surgical approach (catheter repositioning or pump removal) that failed.All 3 patients who experienced a failure with non-resective surgery had CIMs located in the thoracic spine with a maximum diameter≥13mm and 2 of these patients had neurologic deficits on presentation. ConclusionsOur experience, with the largest reported single-surgeon series of patients harboring CIMs, favors early resection, especially in patients with neurologic deficit. Resection may also be a prudent first-line strategy for patients with larger thoracic masses (≥13mm) regardless of neurologic status. Neurologic deficits engendered by CIM usually improve after resection and the majority of patients in our series would have still elected to have an intrathecal pump for pain control knowing a CIM would have developed.

Repetitive single subarachnoid injections for trial administration of the intrathecal morphine pump in patients with intractable non-cancer pain -A case report-

Since the early 1980s, the implantable intrathecal drug pump (ITDP) has been used increasingly to manage chronic pain. Prior to making a decision to implant an ITDP, trial administration of the intrathecal (IT) drug should be performed to estimate the effective dose for a starting set of implantable ITDPs. There is no standard method of trial IT drug administration, though. Therefore, this paper reports 20 cases of IT morphine trial with single and repetitive injections until the appropriate dose was attained with respect to analgesia and its side effects. The trial procedure was performed with daily sequential IT injections using morphine and 0.3% mepivacaine. Twelve out of the total of 20 patients had positive responses. Thus, it is inferred that daily sequential IT morphine injections combined with a placebo injection as a trial ITDP would be useful in evaluating the effectiveness and adverse effects of IT morphine infusion with clinically insignificant side effects.

Measurement of Impact Loads Applied to an Implanted Drug Pump Connector in a Porcine Cadaver Specimen

Anecdotal and documented reports from both patients and doctors have described unanticipated breaks in connections between implanted catheters and drug pumps. In extreme cases, such disconnections in patient-required therapies could result in either withdrawal symptoms or possible deaths. Patients typically attribute such device failures to falls or impacts associated with vigorous physical activity; subsequent failure analyses most often have indicated pump connector uncouplings. We fabricated a facsimile of the Medtronic®SynchroMed® II pump that included both an accelerometer and a force sensor. The force sensor measured forces imparted on the pump connector via the attached catheter and surrounding tissues. The test pump was implanted in the lower left abdominal areas of porcine cadavers in various orientations. Wire-reinforced catheters were tunneled for 20–25cm under the abdominal epidermis, anteriorly toward the head, and the non-connector pump ends were secured by sutures. Following each simulated implant, the cadaver specimens were loaded into a harness and hoisted to a height where either their buttocks or backs were 80–86cm above the floor, simulating a worst-case scenario in which a patient might have fallen down a flight of stairs or off a step stool. The cadavers were then quick released from the hoist attachment, while forces (X, Y, and Z) and accelerations (X, Y, and Z) versus time were simultaneously recorded. Six porcine cadaver specimens were utilized for a total of 72 trials. Subsequent Monte Carlo analyses allowed us to model the variation in stress imparted onto the pump connectors and the estimated variation of the pump connector strength, as a means of predicting required connector retention impact specification for future designs. The recorded forces applied onto the connectors, including data from all three connector axes (X, Y, and Z), were typically within the range of 4.5–9N. However, in several trials, applied forces ranged as high as 30–49N. Monte Carlo modeling provided a maximum resultant load specification of 100.4N for a 0.033msec duration. Based on this value, due to predicted impact events, subsequent failures of future designs would be estimated at 7ppm. Based on our data, a new design requirement has been generated to ensure that implantable drug pump connector assemblies will, in high probability, perform their intended functions.

Electronic medical devices: a primer for pathologists.

Electronic medical devices (EMDs) with downloadable memories, such as implantable cardiac pacemakers, defibrillators, drug pumps, insulin pumps, and glucose monitors, are now an integral part of routine medical practice in the United States, and functional organ replacements, such as the artificial heart, pancreas, and retina, will most likely become commonplace in the near future. Often, EMDs end up in the hands of the pathologist as a surgical specimen or at autopsy. No established guidelines for systematic examination and reporting or comprehensive reviews of EMDs currently exist for the pathologist. To provide pathologists with a general overview of EMDs, including a brief history; epidemiology; essential technical aspects, indications, contraindications, and complications of selected devices; potential applications in pathology; relevant government regulations; and suggested examination and reporting guidelines. Articles indexed on PubMed of the National Library of Medicine, various medical and history of medicine textbooks, US Food and Drug Administration publications and product information, and specifications provided by device manufacturers. Studies were selected on the basis of relevance to the study objectives. Descriptive data were selected by the author. Suggested examination and reporting guidelines for EMDs received as surgical specimens and retrieved at autopsy. Electronic medical devices received as surgical specimens and retrieved at autopsy are increasing in number and level of sophistication. They should be systematically examined and reported, should have electronic memories downloaded when indicated, will help pathologists answer more questions with greater certainty, and should become an integral part of the formal knowledge base, research focus, training, and practice of pathology.

Treatment of Failed Back Surgery Syndrome Patients with Low Back and Leg Pain: A Pilot Study of a New Dual Lead Spinal Cord Stimulation System

Objective. Treatment of pain associated with failed back surgery syndrome was evaluated in a pilot clinical study of a new dual lead spinal cord stimulation (SCS) system. Methods. The following data was retrospectively sought from 20 non-randomized patients at 2 centers treated by the new SCS system, instead of an implantable drug pump: 1) prior back surgeries, 2) pain and paresthesia mapping, 3) VAS ratings, 4) medication use, 5) sleep patterns, 6) physical abilities, 7) hardware problems, and 8) willingness to repeat the procedure. Two-year follow-up was sought from all patients. Results. The new dual lead SCS system provided good low back and leg paresthesia coverage. Patients reported having less pain and using fewer analgesics and narcotics during follow-up, compared to their preimplant experience. These improvements were statistically significant. Patients also improved their sleep and physical abilities during follow-up. While external hardware problems occurred, 65% of dual lead SCS patients were willing to repeat the SCS implant procedure. Conclusions. Dual lead stimulation proved beneficial for patients with low back and leg pain associated with failed back surgery syndrome.

Catheter systems for intrathecal drug delivery

A prospective study of intrathecal catheter reliability was performed at Rush-Presbyterian-St. Luke's Medical Center. All 102 patients who had baclofen administered chronically for spasticity via an implanted drug pump were included. Sixty percent of the patients had no catheter complications; the remaining patients had one to five complications over their course of treatment. Survival analysis demonstrated a steady rate of malfunction up to 80 months, with the mean time to first failure recorded at 20 months. Kinks, holes, breaks, dislodgments, and disconnections were the most common complications. On the basis of their research the authors conclude that the thin-walled silastic catheter does not perform well and that larger, thick-walled catheters should be used.

The Distribution of Medication along the Spinal Canal after Chronic Intrathecal Administration

Chronic intrathecal drug infusion for the treatment of neurological diseases, such as spasticity and chronic pain, has become an accepted method of therapy in recent years. Concurrent pharmacokinetic studies have shown that the cisternal cerebrospinal fluid (CSF) drug level is considerably lower than the lumbar CSF level during continuous infusion into the lumbar subarachnoid space. One factor that makes analysis of this decline in drug level difficult to quantify is that it is only feasible to sample CSF at the two extremes of the spinal subarachnoid space. Using a radionuclide technique, we have examined the distribution along the spinal canal of a hydrophilic compound, indium-111 diethylenetriamine pentaacetic acid, that was delivered over 72 hours into the lumbar subarachnoid space in five patients with implanted drug pumps. Over a 20-cm distance of the thoracic cord, radionuclide counts decreased gradually so that the indium-111 diethylenetriamine pentaacetic acid concentration surrounding the cord at the T2 vertebral level was 43% of that at the T12 level in four patients. Therefore, it appears that even with a hydrophilic compound, which minimizes spinal cord capillary losses, there is still a considerable reduction of CSF drug concentration along the spinal canal. The clinical implication of this gradual decline in drug level is that for intrathecal infusion of relatively hydrophilic compounds there may not be any advantage in placing the catheter tip at more rostral locations, such as at the midthoracic or cervical cord.

Intrathecal baclofen infusion: an innovative approach for controlling spinal spasticity.

Severe and disabling spasticity frequently occurs in people with multiple sclerosis and spinal cord injury. Approximately 30% of these people are treated with oral antispasmodic medications that do not provide adequate relief from spasticity (Hattab, 1980). Clinical trials with spinal stimulation and ablative neurosurgical procedures have not been as uniformly successful for controlling spasticity as has intrathecal baclofen injection (Kasdon, 1986). Delivered by an implantable programmable drug pump, intrathecal baclofen injection has proven to be successful in treating individuals with intractable spasticity. Significant reduction in muscle tone and frequency of spasms have contributed to improved function with activities of daily living, bladder management, overall comfort, and quality of sleep (Penn et al., 1989; Parke, Penn, Savoy, & Corcos, 1989). This article introduces an innovative therapy for controlling spasticity and discusses the nurse's role in patient selection and management.

Comparison of cortical bone and serum concentrations of clindamycin achievable by direct local infusion and intravenous administration

Tibial cortical bone and serum concentrations of clindamycin were compared using two drug delivery methods in dogs. An implantable drug pump, used to continuously infuse clindamycin directly into the cortical bone, was compared with clindamycin administered i.v. Dosage for the direct continuous infusion was 4 mg/kg/day, and 44 mg/kg/day for the i.v. bolus regimen. Serum concentrations of clindamycin were significantly higher during i.v. bolus administration when compared with those achieved during pump infusion (p less than 0.05). However, tibial cortical bone concentrations were significantly higher during pump infusion than were those achieved by i.v. bolus. When examining serum and bone clindamycin concentrations over 21 days of direct local infusion, there was no significant difference in concentrations between sampling days within each tissue (p greater than 0.05). Furthermore, there were significantly greater concentrations of clindamycin in the cortical bone than in the serum at each sampling period (p less than 0.05). Results indicate that delivery of clindamycin to canine bone by implantable drug pump achieve significantly higher bone concentrations than i.v. bolus administration of the drug at higher dosages. Direct infusion also can sustain high concentrations in cortical bone without increasing systemic concentrations of clindamycin.

Lndium-111 DTP A Flow Study to Evaluate Surgically Implanted Drug Pump Delivery System

The authors describe a radionuclide technique for evaluating intrathecal and intraventricular infusions by surgically implanted drug pump delivery systems. Sixteen patients underwent flow studies, performed by injecting 500 mu Ci of indium-111 DTPA into the pumps. Early and delayed images were obtained. These studies enabled distinction among functioning pumps, nonfunctioning pumps, and obstructed or occluded catheters. We conclude that indium-111 DTPA flow studies provide an excellent way to assess these drug pump delivery systems.

Application of portable and implantable drug pumps to achieve an effective pharmacotherapy

Application of portable and implantable drug pumps to achieve an effective pharmacotherapy

Circadian patterning of continuous floxuridine infusion reduces toxicity and allows higher dose intensity in patients with widespread cancer.

Continuous long-term 5-fluoro-2'-deoxyuridine (floxuridine; FUDR) infusion frequently causes severe and dose-limiting gastrointestinal toxicity when administered at a constant rate at commonly prescribed dose levels. In preclinical studies, a circadian infusion pattern peaking late in the daily activity phase was better tolerated and had superior antitumor activity than a constant infusion against a transplanted tumor. Based upon these data and upon other chronobiological cytokinetic and pharmacologic considerations, we compared a circadian patterned variable rate infusion with a maximal flow rate in the late afternoon/early evening and minimum flow rate during the early morning hours to a constant rate infusion in 54 patients with widespread cancer. All FUDR infusions were administered using an implanted drug pump. In a pilot crossover study and a second randomized trial, patients with metastatic malignancies treated with equal dose intensities experienced less frequent and less severe diarrhea, nausea, and vomiting following variable rate infusion. In a third study, the dose intensity of variable rate infusion was escalated stepwise to determine the maximum-tolerated dose. Patients receiving time-modified FUDR infusion tolerated an average of 1.45-fold more drug per unit time while evincing minimal toxicity. FUDR infusion was found to have activity against progressive metastatic renal cell cancer (RCC). Increased dose intensity achieved by optimal circadian shaping may improve the therapeutic index of infusional FUDR and may help control malignancies that are refractory to conventional chemotherapy.

Use of implantable pumps for central nervous system drug infusions to treat neurological disease.

Increasing knowledge of the neurochemical aspects of central nervous system function raises the possibility of treating neurological disease by the appropriate manipulation of neurotransmitters, neuromodulators, and neurohormones. Clinical application of this knowledge has been inhibited, however, by long-standing problems with drug delivery to the central nervous system (CNS). The availability of implantable drug infusion pumps and stereotactic catheter placement techniques may overcome many of these problems. The problems of drug delivery to the brain and the present and potential uses of implantable drug pumps for neurological disease are discussed. In addition, the relationship between CNS drug infusion and neural tissue transplantation is briefly reviewed.

New intrathecal drugs in Alzheimer's disease and psychometric testing.

Bethanechol chloride, a muscarinic agonist, was administered intrathecally to a sample of AD patients in double-blind crossover and open escalating-dose trials. There was a modest amelioration of disturbed behavior at a moderately high dose level, but no improvement in memory or cognition was seen at any dose. At the highest dose, cognition deteriorated. These findings, in conjunction with the results of the multicenter trial described by Harbaugh, suggest that the clinical efficacy of bethanechol in AD is limited. The disappointing results of trials with varied cholinomimetic therapies suggest that more than one biochemical abnormality is responsible for the AD dementia. The neuropeptide, somatostatin, is also reduced in AD, and the level of reduction is correlated with the degree of dementia. Manipulation of this transmitter, alone or in conjunction with acetylcholine, would appear to be a next logical step in the development of an effective neurotransmitter replacement therapy for AD. Implanted drug pumps will be needed for such clinical trials. The naturally occurring somatostatin-14 is not suitable because of its short half life. Sandostatin, an analog, is chemically stable and not metabolized by brain tissue. It does not cross the blood-brain barrier so that intrathecal administration is necessary. Pharmacological research in AD is complicated by a variety of psychometric problems including the criterion-related and construct validity of the outcome measures. Patients differ in their tolerance of various therapeutic agents and in the extent of the neurochemical pathology. It is critically important, therefore, to evaluate individual, as well as group, responses to treatment. The telephone log method may provide a useful way of generating enough observations for single subject analyses without overburdening the patient with repeated testing.

Development of an automatic implanted drug infusion system for the management of cardiac arrhythmias

Conventional management of cardiac arrythmias relies on oral drug therapy which minimizes recurrence of the arrhythmia, but risks unpleasant side effects and even long-term toxicity. The authors propose acute management instead, from an implanted drug pump which automatically senses the onset of arrhythmia, delivers a pharmacokinetically-based infusion to terminate the episode, and discontinues drug delivery until the next occurrence. A bedside system consisting of a personal computer and conventional intravenous pump has been developed and tested in five dogs and 24 patients during a catheter electrophysiologic study. After detection of the arrhythmia plasma levels of the antiarrhythmia drug rose immediately to the therapeutic range and were subsequently well-controlled for 30 to 60 minutes. In all five dogs and in seven of the eight patients in whom atrial fibrillation was induced during the study, conversion to normal rhythm occurred within fifteen minutes. >

Instability of vancomycin in Infusaid drug pump model 100.

The implantable Infusaid drug pump model 100 (Shiley Infusaid, Norwood, Mass.) is undergoing trials as a drug delivery system in the treatment of osteomyelitis. This study evaluated the stability of vancomycin (1 mg/ml) incubated at 37 degrees C for 4 weeks in the pump. Both bioassay and high-pressure liquid chromatography data demonstrated a loss of at least 38% of activity over 4 weeks and colloidal precipitation of vancomycin in the pump at the end of the experiment. This study suggests that vancomycin is not stable enough for use in the Infusaid drug pump model 100.

Antibiotics delivered by an implantable drug pump: A new application for treating osteomyelitis

Osteomyelitis is usually treated with wide surgical debridement and prolonged intravenous antibiotics. The advent of the implantable drug pump has led us to evaluate this therapeutic modality for the treatment of osteomyelitis. We have previously shown that amikacin retains microbiologic activity in an implantable drug pump over a six-week period when incubated at 37°C. We have also demonstrated in rabbits that high local levels and low systemic levels of antibiotic can be achieved using an implantable drug pump as a delivery system and that this method can be used to sterilize infected wounds. This method was applied in the treatment of osteomyelitis in 14 patients whose duration of symptoms ranged from one month to 22 years. In 13 patients, active drainage had been present for more than six months, and all patients had undergone one or more attempts at eradication of their infection. Prior therapy included surgical debridement alone (one patient), one or more attempts at debridement and extended intravenous antibiotic therapy (13 patients), debridement and local flap procedures (four patients), and extended oral antibiotic therapy (two patients). The bones involved were the tibia (six patients), femur (four patients), and elbow, shoulder, hip, and radius (one patient each). Intra-operative cultures indicated that the infecting organism was Staphylococcus aureus alone (seven patients), S. aureus in combination with gram-negative bacteria (five patients), or gram-negative organisms alone (two patients). Debridement and pump implantation were performed in one stage. On an outpatient basis, the pumps were filled with amikacin in a concentration determined by each patient's serum level. Duration of therapy was based upon cessation of drainage and erythrocyte sedimentation rate. During therapy, serum amikacin levels ranged from less than 2.5 μg/ml to 8.2 μg/ml. The amikacin concentration in the wound drainage was always greater than the upper limits of what could be measured (greater than 55 μg/ml to greater than 5,000 μg/ml). There were no cases of ototoxicity and one case of minimal renal toxicity (posttreatment creatinine clearance of 66 ml per minute; normal equal to 70 ml per minute). Length of therapy ranged from 32 to 140 days (mean equal to 63 days). Length of hospitalization ranged from five to 52 days (mean equal to 24 days). Drainage in all patients stopped during therapy, but resumed in three patients after pump removal—in two patients, for brief periods of time, and in one patient, it continues. Twelve patients have posttreatment erythrocyte sedimentation rates less than or equal to 20 mm per hour. This is a potentially important method of treating patients with osteomyelitis. It offers the advantages of extremely high local and low systemic levels of antibiotic, a low incidence of side effects, a decreased length of hospitalization, and a high rate of suppression of infection.