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Intrathecal Infusion Pumps

DISCUSSION OF INTRATHECAL INFUSION PUMPS AND INSTILLED MEDICATIONS:

Since the late 1980s, intrathecal (IT) analgesic therapy has increasingly become an accepted alternative to standard medical management for the treatment of persistent pain for selected patients with malignant as well as non-malignant pain. Causes of non-malignant pain that may represent an indication for intrathecal drug-delivery systems include: failed back syndrome, neuropathic pain, axial spinal pain, Complex Regional Pain Syndrome, diffuse pain, brachial plexitis, central pain, failed spinal cord stimulation (SCS) therapy, arachnoiditis, post-stroke pain, spinal cord injury pain and peripheral neuropathy.

Because drug doses are much lower when applied directly to the IT space compared with oral or parenteral application, side effects and drug toxicities are theoretically supposed to be less. With the development of implantable IT drug delivery devices, there was hope and expectation that patients may benefit from continuous IT administration of analgesics with lesser possibilities of infection. Newer implanted IT drug delivery systems and drug development held the promise to clinicians to further improve analgesia and limit adverse effects through combination therapy and more precise delivery control. A wide variety of available agents and devices to tailor treatment regimens to individual patients are being tested.

In general, the use of opiates in any form for Chronic Persistent Pain (CPP) of a non-malignant etiology is not recommended in the absence of any objective functional improvement. Additionally, individuals on chronic opiates should not only sign a pain management contract, but should be totally and completely psychologically evaluated.

While there are many studies of opiates for treatment of chronic non-malignant pain, there is a dearth of quality evidence regarding long-term efficacy and adverse effects of intrathecal continuous drug delivery. Most available evidence from studies for these types for non-malignant pain shows that evidence to support treatment with opiates is weak.

The Occupational Medicine Practice Guidelines, 2nd Edition, in a systematic review of intrathecal medication for pain patients concluded that the results confirmed lack of efficacy; further studies were needed before any positive recommendation could be made for use of opioid chronic pain management with indwelling pain pumps. A systematic review of intrathecal pain delivery systems on chronic non-malignant pain failed to find any support for use of the devices. Review of the several studies showed mixed results; some had pain reduction; complications were rife; and overall size, medication volume and battery issues remain problematic.

Review of the literature indicates there is not yet sufficient evidence to conclusively show within a reasonable degree of medical certainty that the introduction of pain management pumps is efficacious.

Intrathecal opiate drug delivery systems are invasive and costly. The potential side effects are granulomas, migration of the catheter, infections and in general the side effects associated with opiates. The benefits to be achieved from intrathecal drug delivery appear limited at best, short in duration and fraught with side effects. Furthermore, psychological evaluation should be complete and thorough for any individual with chronic pain, as a number of individuals have proven not to be able to handle and cope with chronic opiate treatment of any sort, as well as group of people who can deal with continuous care of an implanted machine. Moreover, the patient should have some positive ameliorative response to opiates.

MEDICATIONS:
Three Polyanalgesic Consensus Conferences of expert panelists have convened since 2000 for the purpose of formulating an algorithm for drug selection in IT polyanalgesia. These guidelines were published in 2000 and subsequently revised in 2003, 2007 and again in 2009 based on “best evidence” and expert opinion, including guidelines for utilizing an IT drug selection algorithm based on the results of surveys given to clinicians in the field.

Medications used in implantable drug delivery systems include opioids, local anesthetics, adrenergic-agonists, N-methyl-D-aspartate receptor agonists, and other agents. Consensus guidelines have been developed by an expert panel to guide clinicians when there is a variation in practice and lack of firm evidence in support of either of these interventions.

The first line of treatment includes morphine and hydromorphone. Recent studies continue to support the fact that intrathecal morphine provides good analgesia in patients with chronic refractory pain (Winkelmuller and Kumar). Another retrospective study examined the effects of hydromorphone after treatment with morphine found that nausea and drowsiness decreased. Lower extremity edema was noted as a side effect. Pain scores remained comparable with morphine and hydromorphone (Anderson, et. al).

The second line of treatment may actually be chosen as first line in cases where an individual has neuropathic symptoms. Either hydromorphone or morphine is used with bupivacaine or clonidine. There is little data to confirm the safety of these mixed agents. Some of the expert panelists have expressed concern regarding the hypotensive symptoms associated with clonidine.

Third line agents show some clinical promise but both evidence and clinical experience is extremely limited. Third line drug combinations are chosen only after failure of first and second line drug combination treatments, either due to intolerable side effects or inadequate analgesia. Third line drug combinations include adding both bupivacaine and clonidine to either morphine or hydromorphone. Some case reports have suggested that bupivacaine may be more effective in cancer patients with intractable mechanical and visceral pain with small boluses in addition to basal rate (Buchser et al.). Other third line drug combination can be considered such as adding bupivacaine and clonidine to an alternative opioid, before progressing to fourth line agents.

Fourth line agents are not supported by clinical research evidence and experience, even by the most experienced pain practitioners. Fourth line agents include lipophilic opioid agents such as fentanyl and gamma-aminobutyric acid (GABA) agonists such as baclofen and midazolam. The reasoning behind using lipophilic opioids is that there would be less drug diffusion to the rostral brain centers.

Baclofen is a safe and effective drug in the intrathecal space used extensively in the United States in the management of spasticity.

A number of medications have been proven to be safe. Fentanyl, a potent anilinopiperidine analog was evaluated in several retrospective studies and demonstrated good analgesia and no severe adverse effect (Willis et al., Kamran et al. and Waara-Wolleat et al.). Methadone has also been studied in the intrathecal space. Three studies, two of which were prospective, demonstrated pain reduction and improvement in Quality of Life scores, from 38 to 80% (Mironer et al. and Shir et al.).

Ziconotide is a non-opioid, with several studies examining its efficacy in the intrathecal space. Most recently, a randomized, double-blind; placebo-controlled study of ziconotide in the intrathecal space was completed with 220 patients (Rauck et al.). In this study, a very slow titration was used to decrease side effect profile. Patients had significant pain relief when compared to placebo. It was found that a slower titration of ziconotide, a non-opioid analgesic, to a low maximum dose resulted in significant improvement in pain and was better tolerated than in two previous controlled trials (Staats et al) that used a faster titration to a higher mean dose.

PUMP ROUTINE MAINTENANCE, COMPLICATIONS AND MANAGEMENT:
The most common intrathecal drug infusion pump, the Medtronic SynchroMed II, is programmed externally by use of a telemetry wand and a programming computer. The pump can be programmed to deliver a bolus of drug, to increase or decrease the rate of infusion, or to be stopped entirely. The rate of delivery can be varied within each 24-hour cycle. The pump is reprogrammed at the time of each refill to reflect the volume within the pump reservoir. The period of time between refills depends on the drug being used and its rate of delivery. After pump implantation, the dose typically needs to be increased over time.

In the case of intrathecal baclofen, patients have been treated for up to 66 months with no cases of late tolerance reported in one series. The typical sequence is that a patient will require a gradual increase in dose, especially over the first three months, and then level off after one year, although studies have shown routinely a tolerance to the drug.

The battery life of Medtronic infusion pumps range from 3 to 7 years (the newest Medtronic SynchroMed II programmable pump battery life is 6 to 7 years). The discrepancy is due to varied infusion rates. Replacement of the battery necessitates replacement of the entire pump.

Complications from the implantation of an intrathecal pump can be categorized into surgical, mechanical, pharmacological, and medical (endocrine, edema, infections). Intrathecal pump catheter complications are the most common cause of failure in drug delivery, together accounting for over 20% of the complications.

Turner et al. described complications derived from 10 published reports. Non-pharmacological biological complications included wound infection 12% in three (3) studies, meningitis 2% in three (3) studies, and pump malposition in 17% in two (2) studies. CSF leaks during catheter placement leading to postural headache were not commonly reported but occurred.

There were a number of intrathecal granulomas at the tip of the intrathecal catheter some of which were large enough to cause spinal cord compression and neurologic dysfunction such as urinary incontinence and paraparesis or paraplegia. Intrathecal granuloma formation is a serious complication that carries the potential to produce spinal cord compression and paralysis distal to the mass. Over 100 cases have been reported, the first of which was in 1991. The phenomenon appears to be a function of concentration (>25mg/mL), daily dose (>10mg/d), and duration of therapy. Some were noted within one (1) month of the initiation of therapy.

A list of references is available upon request.