Implanted drug delivery systems for the control of chronic pain

C H A P T E R

63

Implanted Drug Delivery Systems for the Control of Chronic Pain Allan Nanney, MD  b  Kenji Muro, MD  b  Robert M. Levy, MD, PhD

While oral, parenteral, and transdermal opioids may be extremely effective analgesic agents; systemic administration may provide inadequate pain relief and cause significant side effects, and long-term use in sufficient doses may result in tolerance and an increased potential for addiction (Table 63-1). The past decade has seen increased recognition of the endocrine, cardiovascular, sexual, and psychological side effects of chronic opioid use. Thus, the control of chronic pain with systemic opioids is often accompanied by a marked reduction in the quality of life. The discovery of opiate receptors in the substantia gelatinosa of the spinal cord first led to the recognition of opioids having a spinal, as well as supraspinal, analgesic action. Fields and Basbaum1 in the United States and Besson in France subsequently described and elucidated a descending system of pain inhibition. This pathway begins with projections from the frontal cortex and hypothalamus to the periaqueductal gray (PAG) of the midbrain. PAG fibers then project to the dorsal pons and the posteroventral medulla, where projections then travel via the dorsolateral funiculus to terminate in the substantia gelatinosa of the spinal cord dorsal horn. These efferent projections inhibit the second order ascending nociceptive neurons and thus inhibit pain transmission. At the spinal level of antinociceptive processing, opiates presynaptically diminish primary afferent terminal excitability and inhibit substance P release. Postsynaptically, opiates act to suppress excitatory amino acid–evoked excitatory postsynaptic potentials (EPSPs) in dorsal horn neurons. Recognition of this spinal antinociceptive mechanism led to the first trials of direct intraspinal administration of opioids, with morphine administered epidurally2 and intrathecally3 for the treatment of cancer pain.4 Since the discovery of opiate receptors in the substantia gelatinosa and the elucidation of their associated spinal antinociceptive systems, intraspinal opioid administration has been used in over 120,000 patients.5 Intraspinal pharmacotherapy for pain attempts to largely restrict drug effects to regions associated with the source of noxious input. Systemic side effects are minimized, and a much higher local analgesic concentration is achieved at its site of action, even at comparatively lower doses. Morphine and hydromorphone are particularly well suited for this application, because of their hydrophilicity and resulting slow absorption from the cerebrospinal fluid. As a result, analgesia from intrathecal morphine or hydromorphone not uncommonly lasts up to 24 hours.2 The discovery of multiple receptor systems involved in nociceptive transmission and modulation has allowed the testing and application of other receptor selective drugs (Table 63-2) as well as nonreceptor specific agents such as local anesthetics. In fact, the use of multiple agents is now © Copyright 2011 Elsevier Inc., Ltd., BV. All rights reserved.

the rule, rather than the exception, to intrathecal drug delivery for the treatment of intractable pain.

PATIENT SELECTION To achieve optimal results, proper patient selection is crucial. The clinician must carefully consider several factors to indicate or contraindicate the use of chronic intraspinal analgesic therapy (Table 63-3).

FAILURE OF MAXIMAL MEDICAL THERAPY If a noninvasive treatment program provides satisfactory pain relief without intolerable side effects, then intraspinal drug administration is not necessary. Therefore, patients should have failed a multidisciplinary pain treatment program prior to the consideration of intrathecal drug therapy. Patients should have failed to obtain sufficient relief or developed unacceptable side effects with standard routes of pharmacotherapy including antiinflammatory agents, antidepressants, nonnarcotic analgesics, and systemic narcotics. Physical and psychological therapies should be considered when appropriate. On the other hand, it is important to recognize early the failure of medical therapy in these patients. Hence, patients on increasing oral, transdermal, or intravenous doses of opioids who have already been treated with other nonnarcotic agents should be referred for trial of intraspinal drug administration to limit their suffering and their exposure to extremely high narcotic doses.

FAVORABLE PSYCHOSOCIAL EVALUATION While most investigators highlight the importance of a favorable psychosocial evaluation in the screening for potential implant candidates, the specific variables, their quantification, and their treatment are not widely agreed upon. As part of this analysis, most advocate evaluating both the patient and his or her support system. Clearly, acute psychotic illnesses and severe, untreated depression or anxiety need diagnosis and treatment prior to surgical consideration. Other psychological issues are less clearly accepted as reasons to delay or contraindicate surgery. Furthermore, deficiencies in social support systems may leave the patient without someone to aid him or her in the event of a pain-related emergency or in the maintenance of the drug administration system.

ABSENCE OF SYSTEMIC INFECTION The consequences of infection involving the drug administration system range from the need to remove the entire system and thus eliminate, at least for some time, this option 451

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TABLE 63–1  Side Effects from Systemic Administration

TABLE 63–3  Indications and Contraindications for Chronic

of Oral, Parenteral, and Transdermal Narcotics

Intraspinal Analgesic Administration

Central Nervous System Effects of Opiates

Indications

Analgesia Mydriasis Euphoria or dysphoria Nausea and vomiting Sedation Confusion Cough reflex depression Respiratory depression

Chronic pain with known pathophysiology Sensitivity of the pain to the agent to be infused Failure of maximal medical therapy Favorable psychosocial evaluation Favorable response to trial of intraspinal analgesic agents

Peripheral Effects of Opiates Decreased gastrointestinal tract motility Constipation Urinary retention Histamine release Pruritus Increased biliary duct pressure

TABLE 63–2  Some Intraspinally Administered Drugs

in the Treatment of Intractable Pain Opiates Morphine Hydromorphone Fentanyl Sufentanil Dynorphin Beta-endorphin D-ala-D-leu-enkephalin Methadone Meperidine Alpha-Adrenoceptor Agonists Clonidine Tizanidine GABA B Agonists Baclofen Naturally Occurring Peptides and their Analogues Somatostatin Octreotide Vapreotide Calcitonin Local Anesthetics Bupivacaine Ropivacaine Tetracaine NMDA Agonists Ketamine Other Agents Ziconotide (SNX I I I) Midazolam Neostigmine Aspirin Droperidol Gabapentin GABA 5 gamma-aminobutyric acid; NMDA, N-methyl-d-aspartate.

Contraindications Intercurrent systemic infection Uncorrectable bleeding diathesis Allergy to agent to be infused Failure of a trail of intraspinal analgesic agents

for pain control, to the potentially life threatening complication of meningitis. Therefore, any local infection at the surgical site or any systemic infection contraindicates the implantation of drug administration devices. Furthermore, the use of perioperative prophylactic antibiotics is almost universally recommended and postoperative prophylactic antibiotics are often used.

ABSENCE OF COAGULOPATHIC STATES Coagulopathic states, as a complication of malignancy or as a result of the intentional use of anticoagulant or antiplatelet agents for the prevention of stroke, myocardial infarction, deep venous thrombosis, and pulmonary embolism, present serious potential risks in the patient undergoing implantation of drug delivery systems. Not only can the surgery be made more challenging by intraoperative hemorrhage, but it also can be complicated by the development of subcutaneous, epidural, or intradural hematomas. All efforts should be made to reverse the coagulopathic state prior to both the intrathecal drug trial and implantation of the drug delivery system and to continue this reversal into the postoperative period. Significant uncorrectable coagulopathy contraindicates the implantation of drug infusion systems.

ABSENCE OF DRUG ALLERGY Allergy to the analgesic agent to be infused obviously and absolutely contraindicates its use. With the availability of multiple intrathecal analgesic agents, however, this has become a less frequent reason to abandon intrathecal drug delivery. Nonallergic reactions to the infused agent, such as urinary retention or pruritus, most often occur only acutely after initial intrathecal exposure to the drug and often resolve with time or respond to specific treatment. These reactions therefore do not represent absolute contraindications to chronic intrathecal drug infusion.

ABSENCE OF OBSTRUCTION OF CSF FLOW Obstruction of cerebrospinal fluid flow historically has been identified as a relative contraindication to intraspinal drug delivery, depending on the size, location, and cause of the obstruction. In our experience, this has not been a significant problem, and patients may derive excellent



CHAPTER 63  Implanted Drug Delivery Systems for the Control of Chronic Pain

drug benefits despite such an obstruction. More important than the presence of an obstruction to CSF flow is the patient’s favorable response to the intraspinal drug trial administered at the level where permanent catheter implantation is intended. It has been suggested, however, that limitations to the regular flow of cerebrospinal fluid may predispose patients to the development of intrathecal granuloma; as such we should be acutely aware of this potential risk in such patients.

LIFE EXPECTANCY GREATER THAN THREE MONTHS While the expected length of life is not a contraindication to the use of intraspinal drug administration, it does potentially influence the method of drug administration, particularly in light of the potential costs of this therapy. Percutaneous epidural catheter attached to external pumps, internalized passive catheters with reservoirs requiring percutaneous bolus drug administration, patient activated mechanical systems, constant rate infusion pumps, and programmable infusion pumps are all viable options. The choice among these approaches, based upon ambulatory status and life expectancy, is discussed below.

FAVORABLE RESPONSE TO AN INTRASPINAL DRUG TRIAL Not all patients suffering from chronic pain syndromes will benefit from chronic intraspinal drug administration. Pain relief in response to acute intraspinal analgesic agents is generally regarded as an indicator of long-term efficacy.6 The inability to achieve sufficient pain relief after such a trial is a contraindication to implantation. Careful preoperative candidate screening for indwelling drug administration systems can help exclude those who will not benefit from this technology and predict efficacy in others. Unfortunately, bias on the part of both the treating physician and the patient can inappropriately skew the results of subjective or improperly controlled trials. This may lead to drug administration system implantation in patients who will not benefit from chronic intrathecal drug administration. Several approaches to the trial of intrathecal narcotics have been described, including single versus multiple injections, administration via lumbar puncture versus indwelling catheter, epidural versus intrathecal routes, and

bolus versus continuous infusion of the drug. Testing with a single intraspinal dose of an active agent raises the possibility that the strong desire of the physician and other health care personnel to help and the patient’s desperation to find some relief from their intractable pain, may lead to a significant placebo response. We have gone so far as to develop a quantitative, crossover, double-blind trial for the pre-implantation screening of candidates for chronic drug infusion therapy.7 Despite the importance of preoperative trialing of intrathecal drug administration, there is no documented proof of the superiority of one trialing method over another in predicting long-term outcome.

ROUTE OF ADMINISTRATION While no study has directly compared the relative efficacy of epidural versus intrathecal administration to control intractable pain, observations made by comparing the results of previous studies employing both routes are outlined below (Table 63-4). The equianalgesic epidural dose is roughly 10 times that of an intrathecal dose.8 As 80% to 90% of an epidural injection is systemically absorbed, this larger dose requirement may lead to greater systemic side effects, including constipation and urinary retention. These higher doses further increase the probability of developing tolerance. Also, the higher dose requirement with epidural infusion to reach equivalent subarachnoid concentration necessitates refilling pump reservoirs on a more frequent basis. In addition, epidural catheter placement has known complication of dural scarring, resulting in catheter failure caused by occlusion, kinking, or displacement. Although it avoids these complications, intrathecal drug administration carries the disadvantages of potential CSF leak and postural spinal headaches, respiratory depression caused by supraspinal drug redistribution, and meningeal infection or neural injury. Thus, the major advantage of epidural administration is the theoretically lower risk of serious complication, although they are remarkably uncommon. In addition, epidural catheters can be placed at virtually any level, making it potentially more useful for the treatment of upper body pain. Anderson and colleagues, however, have reported excellent results treating pain of the trunk, neck, and even the head with lumbar intrathecal morphine administration.9 The advantages of the intrathecal route, including the lower drug dosage requirements leading to increased intervals between pump refills, the lower risk of catheter failure, and

TABLE 63–4  Intrathecal Versus Epidural Administration

Intrathecal

Epidural

453

Advantages

Disadvantages

Lower dosage requirement (10 times more potent than epidural dose) Less systemic effect No dural fibrosis at tip of catheter Possible to sample spinal fluid for culture diagnosis and drug levels Reduced risk of respiratory depression Reduced risk of spinal headache Reduced risk of neural injury

Increased risk of neural injury Increased risk of spinal headaches Increased risk of supraspinal distribution Greater dose requirement Higher systemic effect Dural fibrosis possible Question of increased tolerance Limited reservoir volume

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the infrequent occurrence of potential complications, suggest this is the preferred route for intraspinal drug delivery. As a result, over the past several decades, chronic intrathecal drug administration has become the overwhelming route of choice in clinical practice.

DRUG DELIVERY SYSTEMS Despite the popularity of implantable programmable drug pumps, there are a number of different methods to accomplish intraspinal drug delivery. These systems include a percutaneous epidural catheters attached to external pumps, internalized passive catheters and reservoirs requiring percutaneous drug administration, patient activated mechanical systems, constant rate infusion pumps, and programmable infusion pumps. In light of the significant expense of implanted programmable drug pumps and the surgery required for their implantation, the choice of drug administration system should be made with careful consideration of the individual benefits of programmability, bolus versus continuous drug infusion, the patient’s general medical and ambulatory status and his or her estimated life expectancy. Several investigators have explored the question of continuous versus bolus infusion. Continuous spinal infusion results in lower peak CSF morphine concentrations and corresponding lower plasma levels than bolus administration, while providing stable steady state levels at the spinal site of action. It has been suggested that continuous infusion may result in a reduced rate of opioid receptor tachyphylaxis10 and decrease the risk of producing delayed respiratory depression.11 Clinical studies, however, have not clearly confirmed the superiority of continuous over bolus intraspinal drug infusion. Recently, in fact, there is a suggestion that intermittent bolus intrathecal administration may decrease the risk of intrathecal granuloma formation and may increase the long term efficacy of intrathecal delivery. Careful consideration should be given to the patient’s ambulatory status, general health, and estimated length of life. For patients with a life expectancy of days to weeks, especially those who are bed-bound, a percutaneously implanted tunneled epidural catheter attached to an external drug pump is a viable, inexpensive option. While the risk of infection increases over time, these catheters can be maintained for several weeks to months without complication. Over time, however, the total cost of the external drug pump along with the required nursing and pharmacy services makes this option quite costly. Careful tunneling of the catheter and rigorous hygiene of the catheter and its dressing will help maximize infusion system durability and minimize the risk of infection. For patients with a similarly limited life expectancy who are ambulatory, an implanted reservoir system attached to an intraspinal catheter is an attractive option. There are subcutaneous reservoirs manufactured specifically for this application; they are rated to withstand hundreds of punctures, while other familiar reservoirs, such as the Ommaya reservoir, are rated only for several dozen punctures. These reservoir systems require daily percutaneous access and are associated with discomfort and increased risk of infection. They do, however, allow the patient unencumbered activity during the day and can be accessed for either

bolus administration or for continuous infusion by attachment to an external pump. Mechanical patient-controlled indwelling drug administration systems are a third option for intraspinal drug therapy. Unfortunately, these devices are not available in the United States. Two major types of implanted drug pumps are currently marketed. One such device consists of a drug-filled bellows compressed by pressurized gas with its outflow regulated by a high resistance valve. The infused solution is then delivered at a fixed rate; dose changes are made by changing the solution concentration. Thus, there is some increased cost and patient discomfort when dose changes are indicated. Furthermore, changes in temperature and atmospheric pressure subject these devices to small variations in drug delivery rates. Similar pumps with some degree of programmability are currently pending FDA approval. Somewhat more expensive is the programmable, peristaltic drug pump. This pump can be programmed transcutaneously and sophisticated drug dose regimens can be instituted. Dose changes can be made with noninvasive reprogramming. Because these pumps are battery operated, they require surgical replacement when the batteries expire; under average conditions, the current generation of pumps should last seven years. Both implanted pump types require at an interval dependent upon the size of the drug reservoir, the concentration of the drug to be infused and the rate of drug delivery. The maximum interval between refills of the pump is six months, as drug stability within the pump has been confirmed for up to six months (with rare exception). Several studies have explored the costs of these drug administration systems over time. In general, it appears that for patients whose life expectancy and intraspinal drug use will exceed three months, it is cost effective to choose a fully implanted drug pump, whereas for patients with shorter life expectancy, a percutaneous catheter or implanted reservoir may be more reasonable.10,12 Kumar and colleagues13 recently published their work demonstrating the cost effectiveness of intrathecal drug therapy for the management of failed back syndrome. Of the 67 patients in this study, 23 underwent implantation of a programmable drug delivery pump whereas 44 patients continued with conventional pain therapy. During the five-year follow-up period, the actual cost of care related to failed back syndrome were tabulated. Although the intrathecal drug therapy group incurred a high initial cost because of equipment needs, at 28 months follow-up, the cumulative cost of conventional medical therapy exceeded intrathecal drug therapy. In light of current health care reform and the demands for greater cost containment in medicine, these issues should be considered in every patient who is deemed a candidate for intraspinal analgesic therapy.

INTRATHECAL AGENTS FOR PAIN PHARMACOTHERAPY Opioids have been long considered the primary agents for intrathecal pharmacotherapy of pain. Their mechanism of action has been detailed above. The field of intrathecal pharmacotherapy for pain has moved generally away from monotherapy with opioids to the adjuvant use of opioids and nonopioid agents.



CHAPTER 63  Implanted Drug Delivery Systems for the Control of Chronic Pain

OPIOIDS Morphine Morphine is approved by the United States Food and Drug Administration for intrathecal therapy for chronic pain. Its usefulness lies in the ability to achieve excellent pain control over a long duration at a fraction of the dose required for systemic opioids while avoiding many of the commonly seen side effects of systemic administration. The relative equianalgesic potency between routes of administration has been estimated to be 300 for oral administration, 100 for IV administration to 1 for intrathecal (IT) administration. Doses at the initiation of therapy are almost always below one milligram per day. Several publications on the efficacy of intraspinally administered morphine are reported; most are case reports and retrospective studies, with few prospective studies (Table 63-5).14–18 Early data suggest an efficacy of roughly 80% in the setting of cancer pain. Smith and coworkers18 published an important randomized controlled trial comparing IT opioids plus medical management versus maximal medical therapy alone in cancer related pain. The group receiving intrathecal drug therapy experienced statistically significantly better overall pain control and an improved side effect profile especially with respect to complaints of fatigue and sedation. There was also a trend toward improved survival time in the intrathecally treated group. At the present time, the data concerning intraspinal morphine for pain secondary to cancer appears to be compelling and consistent, with a success rate of approximately 80% to 90% in the first three months and 65% at one year. Success is seen not only with improved pain control, but also with better reported functional status and ability to interact meaningfully with family and friends. Data concerning its use in the setting of nonmalignant pain is less clear. Deer and coworkers15 showed that patients’ self-perceived disability levels improved significantly 6 and 12 months after the initiation of IT opioid therapy for the treatment of low back pain. Auld and coworkers reported two studies of intraspinal narcotics for the treatment of non-malignant pain; in the first report, 21 of 32 patients demonstrated adequate relief,19 whereas in the second study, 14 of 20 patients obtained satisfactory pain relief with intraspinal morphine.20 Other small studies show similar findings. A prospective, randomized, doubleblind study evaluated pain relief and opioid related side effects following intrathecal morphine administration in 144 opioid-naive patients versus 25 control patients with

455

nonmalignant chronic back pain. All patients receiving intrathecal opioids reported pain relief compared to only 25% of the control group (p,0.0005). Although intraspinal morphine likely provides pain relief in carefully selected patients with intractable pain of nonmalignant origin, further work needs to be done before this should be considered standard therapy.

Hydromorphone Hydromorphone is a potent opioid with increasing intraspinal “off label” use to treat cancer and nonmalignant pain. Unlike morphine, it is not FDA approved for this application, but hydromorphone has been elevated to a first line therapeutic status along with morphine by expert consensus panels.21 Hydromorphone is approximately five times more potent, has fewer active metabolites and a smaller supraspinal distribution than morphine; this could account for reports of fewer side effects when compared to morphine. The most common indication for using hydromorphone appears to be inadequate pain control or intolerable side effects with morphine. Currently, there are no prospective controlled trials evaluating the efficacy and toxicity of hydromorphone. Anecdotally, and also in several retrospective studies evaluating the efficacy of hydromorphone to treat nonmalignant pain (n 5 24),22 a high success rate was seen in those who were opioid naïve, as well as in those who had failed IT morphine.

Fentanyl and Sufentanil Fentanyl and sufentanil are two potent opioids that diffuse rapidly across the blood-brain barrier because of their strong lipophilicity. Fentanyl produces a functionally equivalent effect on pain compared to morphine while binding to fewer, highly potent mu agonist, receptors. Sufentanil may be more useful for segmental rather than diffuse analgesia and may elicit less drug tolerance than morphine. There are prospective studies supporting the efficacy of IT fentanyl. One randomized trial (n 5 60) showed improved pain control in patients undergoing posterior lumbar spine decompression.23 Furthermore, both sufentanil and fentanyl have theoretically better side-effect profiles than morphine, including a decreased risk of formation of inflammatory granuloma.

Methadone and Meperidine Methadone is a racemic mixture of D- and L-opioid isomers and meperidine is a synthetic opioid. Little clinical data regarding their intrathecal efficacy exists in the literature and their intrathecal use is exceedingly rare.

TABLE 63–5  A Comparison of Prospective Studies on Intraspinally Administered Morphine

Authors

Number of Patients

Route

Efficacy 11 patients with .25% reduction in nonmalignant pain after 24 months 57.5% reduction in pain, best results in deafferentation and mixed pain 60 of 71 *84.5%) with cancer pain achieved clinical success (p 5 0.05) Overall success in 83%, 90%, 85%, and 91% at months 1, 2, 3, and 4 for cancer pain Oswestry Low Back Pain Disability Scale improved by 47% for patients with low back pain; .31% for patients with leg pain

Anderson et al., 1999 Kumar et al., 2001 Smith et al., 2002 Rauck et al., 2003

22 16 143 119

Intrathecal Intrathecal Intrathecal Intrathecal

Deer et al., 2004

136

Intrathecal

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OPIOID SIDE EFFECTS, WITHDRAWAL, AND TOLERANCE The most widely recognized side effects of intraspinal narcotics include fatigue, somnolence, nausea, vomiting, urinary retention, pruritus, decreased sexual libido and decreased testosterone levels in men,24 noncardiac pedal edema, and, rarely, delayed respiratory depression. Respiratory depression is most often seen in opioid-naive patients and results from supraspinal redistribution of the drug. This side effect is both dose dependent and naloxone reversible. A more recently recognized complication, catheter tip granulomas (more properly, catheter tip inflammatory masses), will be discussed in more detail below. These side effects appear to be more prevalent with intrathecal morphine use as compared to other opioids. Fentanyl and hydromorphone have apparently better side effect profiles. The acute cessation of intrathecal opioid administration presents unique potential risk. Spinal morphine withdrawal syndrome results in hyperalgesia after cessation of morphine and is caused by the release of excitatory neurotransmitters and neuromodulators from primary afferents after long-term exposure to morphine, a type of “rebound” effect. Clinical experience has demonstrated the development of increasing narcotic requirement to maintain a similar degree of pain control in a significant fraction of patients over time. While this may reflect the development of tolerance at the receptor level, it may also result from a change in the status of the patient’s disease. For example, in the setting of pain secondary to a malignancy, tumor progression may involve new areas of pain, invade more pain sensitive structures, or change the nature of the pain from predominantly nociceptive to neuropathic. Furthermore, changes in the patient’s psychosocial status may result in the decreased ability to cope, resulting in perceived increase in the degree of pain. Complaints of decreasing drug efficacy over time may also reflect malfunction of the pump and catheter system or the development of a catheter tip inflammatory mass. Several strategies have been advanced to manage such apparent tolerance. First, one must carefully evaluate for the presence of pump system malfunction or the presence of a catheter tip inflammatory mass. If this is not the case, then simply increasing the drug dose may restore excellent pain control. When this fails, or when the drug dose is escalated to levels that are felt to be potentially problematic, some authors suggest temporarily using systemic analgesics while the pump is turned off for a period of several days to a few weeks, a so-called drug holiday. If the decreased efficacy of intraspinal narcotics is caused by receptor tolerance, this “drug holiday” often results in receptor down regulation and a return of efficacy when intraspinal opioids are reinstituted. Another strategy involves the use of narcotics active at other opioid receptor subclasses. Like mu receptor agonists, delta receptor agonists appear to work through a G-protein system to hyperpolarize the neuronal membrane through an increase in potassium conductance and thus inhibit neuronal activity. Kappa receptor agonists appear to function differently than mu or delta receptor agonists. These agents appear to activate a different G-protein

mechanism, which blocks calcium entry through a voltagedependent calcium channel. Investigators have had some success with delta receptor agonists or those with mixed receptor subclass activity. A final strategy is the concomitant administration of another intrathecal pharmacologic agent such as a local anesthetic. The combination of opioids and local anesthetics, alpha-adrenergic agents or ziconotide has been used successfully in patients failing intrathecal opioid monotherapy; algorithms for the use of these agents have been developed and recommended by expert panels (Figure 63-1).21

INTRATHECAL LOCAL ANESTHETICS Bupivacaine is an amide class local anesthetic the role of which, in the intrathecal management of chronic pain, specifically neuropathic pain, has increased profoundly. Hassenbusch and coworkers25 reported good results lasting over one year in four of seven patients with nonmalignant pain using epidural infusion of morphine sulfate combined with bupivacaine. Du Pen and colleagues26 examined the efficacy of epidural morphine and bupivacaine in a series of 68 patients who obtained no relief from epidural opioids alone. Sixty-one patients (90%) were considered treatment successes with chronic morphine and bupivacaine infusion. The data on the effectiveness of intrathecal bupivacaine is mixed. In a 2002 retrospective study of 109 patients, Deer and coworkers15 showed that opioids plus bupivacaine resulted in significantly better pain control, less oral opioid use, fewer clinic visits, and better patient satisfaction than intrathecal opioids alone. In two prospective studies,14,27 patients who failed intrathecal therapy with morphine or hydromorphone benefited from the addition of bupivacaine. In one randomized double-blind trial of 24 patients with chronic nonmalignant pain, the addition of bupivacaine to morphine or hydromorphone improved the patients’ quality of life, but did not seem to have a significant effect on pain scores.28 On the contrary, a multicenter, double-blind randomized controlled trial found that the addition of bupivacaine did not provide better pain relief than opioids alone. Bupivacaine was measured against another local anesthetic, ropivacaine, in a randomized controlled trial. An increase of 23% daily ropivacaine was required to produce equivalent pain control, and the cost of ropivacaine was three times higher. At high doses of local anesthetics, particularly lidocaine, permanent injury can result because local anesthetics injure dorsal and ventral roots by increasing glutamate concentration in the cerebrospinal fluid and produce chromolytic deterioration of motor neurons in the lumbar spinal cord with resultant vacuolation of the dorsal funiculus. In clinically applicable intrathecal doses, however, such side effects are not seen with bupivacaine. Clinically apparent side effects of bupivacaine, seen rarely and at high doses, include transient paresthesias, motor blockade, and gait impairment.

Adrenergic Agonists Alpha-adrenergic agonists are frequently used second line adjuvant agents in intraspinal pain pharmacotherapy. Alphaadrenergic receptors exist in the substantia gelatinosa of the



CHAPTER 63  Implanted Drug Delivery Systems for the Control of Chronic Pain

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2007 POLYANALGESIC ALGORITHM FOR INTRATHECAL THERAPIES

Line #1:

(a) morphine

(b) hydromorphone

(c) ziconotide

Line #2:

(d) fentanyl

(e) morphine/hydromorphone  ziconotide

(f) morphine/hydromorphone  bupivacaine/clonidine

Line #3:

(g) clonidine

(h) morphine/hydromorphone/fentanyl bupivacaine /clonidine  ziconotide

Line #4:

(i) sufentanil

(j) sufentanil  bupivacaine clonidine  ziconotide

Line #5:

Line #6:

(k) ropivacaine, bupernophine, midazolam meperidine, ketorolac Experimental Drugs gabapentin, octreotide, conpeptide, Neostigmine, Adenosine, XEN2174, AM336, XEN, ZGX 160

FIGURE 63-1  Recommended algorithm for intrathecal polyanalgesic therapies, 2007. Line 1: Morphine (a) and ziconotide (c) are approved by the Food and Drug Administration of the United States for intrathecal analgesic use and are recommended for first line therapy for nociceptive, mixed, and neuropathic pain. Hydromorphone (b) is recommended based on clinical widespread usage and apparent safety. Line 2: Because of its apparent granuloma sparing effect and because of its wide apparent use and identified safety, fentanyl (d) has been upgraded to a line 2 agent by the consensus conference when the use of the more hydrophilic agents of line 1 (a, b) result in intractable supraspinal side effects. Combinations of opioid plus ziconotide (e) or opioid plus bupivacaine or clonidine (f) are recommended for mixed and neuropathic pain and may be used interchangeably. When admixing opioids with ziconotide, attention must be made to the guidelines for admixing ziconotide with other agents. Line 3: Clonidine (g) alone or opioids such as morphine/hydromorphone/fentanyl with bupivacaine and/or clonidine mixed with ziconotide (h) may be used when agents in line 2 fail to provide analgesia or side effects occur when these agents are used. Line 4: Because of its proven safety in animals and humans and because of its apparent granuloma-sparing effects, Sufenta alone (i) or mixed with bupivacaine and/or clonidine plus ziconotide (j) is recommended in this line. The addition of clonidine, bupivacaine, and/or ziconotide is to be used in patients with mixed or neuropathic pain. *In patients with end of life, the panelists felt that midazolam and octreotide should be tried when all other agents in lines 1-4 have failed. Line 5: These agents (k), although not experimental, have little information available in the literature, and use is recommended with caution and obvious informed consent regarding the paucity of information regarding the safety and efficacy of their use. Line 6: Experimental agents (l) must only be used experimentally and with appropriate Independent Review Board approved protocols. From: Deer T, Krames ES, Haasebusch SJ, et al: Polyanalgesic consensus conference 2007: Recommendations for the management of pain by intrathecal (intraspinal) drug delivery: Report of an interdisciplinary expert panel. Neuromodulation 10: 300–28, 2007.

spinal cord, situated on both pre- and postsynaptic terminals of small primary afferents. They appear to mediate antinociception by indirectly decreasing the release of substance P. These agents have the particular advantage over opiates of little or no effect on respiratory centers, largely eliminating the possibility of respiratory depression. Another potential advantage of adrenergic agents is their specific efficacy in the management of neuropathic pain states as documented in both experimental29 and clinical20,30,31 settings. Within this category, clonidine is FDA approved for intraspinal use, and tizanidine has been tested in clinical trials. Eisenach and coworkers32 used epidural clonidine to treat nine patients with intractable cancer pain tolerant to intraspinal opioids. Patients received between 100 and 1000 micrograms per day; clonidine produced analgesia lasting more than 6 hours but also decreased blood pressure by more than 30%. Hypotension was treatable with intravenous ephedrine. Clonidine also decreased heart rate

by 10% to 30% and produced transient sedation at higher doses. There were no opioid-like side effects of respiratory depression, pruritus, or nausea. Several other studies have reported similar results. In a prospective, randomized trial of adding epidural clonidine to intrathecal morphine in 85 patients with cancer pain,33 analgesia was achieved more commonly in the clonidine group (45% vs 21%), especially among patients with a component of neuropathic pain. A recent prospective cohort study31 of ten patients with neuropathic pain treated with the combination of intrathecal morphine and clonidine resulted in a 70% to100% reduction in pain. Furthermore, four of eight patients with concomitant non-neuropathic pain also benefited from the addition of clonidine. In a phase I/II study,30 59% of the cohort were considered longterm successes with a mean follow up of 16.7 months. In contrast to clonidine, the alpha-2-adrenergic agonist tizanidine does not appear to induce hypotension. This

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agent has been demonstrated to be an effective analgesic agent when administered intrathecally in experimental29 paradigms. Tizanidine appears to be particularly useful in the treatment of opioid insensitive neuropathic pain syndromes.

ZICONOTIDE Ziconotide, originally known as SNX-111 and now marketed as Prialt, is a novel 25 amino acid peptide isolated from marine snail venom. It is a highly selective N-type voltage-sensitive calcium channel antagonist; these channels are found at the presynaptic nerve terminals in the spinal dorsal horn. The putative mechanism of ziconotide induced pain relief is the blockade of neurotransmitter release at the primary afferent nerve terminal. The FDA and the European Union have approved the use of ziconotide as a nonopioid intrathecal analgesic option for patients with neuropathic pain refractory to conventional treatments. In fact, ziconotide has become the single most intensely studied agent for intrathecal pain therapy and has been recommended by an expert panel as a first line intrathecal agent for the treatment of refractory neuropathic pain. Common causes of neuropathic pain include complex regional pain syndrome (CRPS), HIV-associated neuropathy, postherpetic neuralgia, diabetic peripheral neuropathy, and central neuropathic pain syndromes related to multiple sclerosis, poststroke pain, and spinal cord injury. Multiple animal studies have shown that ziconotide suppresses tactile and mechanical allodynia in a dose dependent manner. Its effect on hyperalgesia is less clear. More important, pivotal randomized, double-blind placebo controlled trials have been performed to establish the efficacy and safety of ziconotide in patients with chronic malignant, chronic nonmalignant, and severe neuropathic pain. In one trial, 111 patients with refractory cancer-related pain underwent intrathecal infusion of ziconotide or placebo for five to six days.34 In another trial,35 220 patients were tested using a lower dose and slower titration regimen than the previous studies; these changes were initiated because of the relatively high incidence of cognitive and behavioral side effects during the initial trials. Statistically significant improvement in pain relief was noted with ziconotide as compared to placebo in all trials (malignant pain: 53% ziconotide v. 18% placebo; nonmalignant pain: 31% ziconotide v. 6% placebo; slow titration study: 14.7% ziconotide v. 7.2% placebo). In these studies, the mean reduction in neuropathic pain was 15.7%, 31.6%, and 29.1%, respectively. Multiple case reports, case series, and randomized controlled trials have demonstrated a relatively high risk of side effects with ziconotide use, which occur in 15% to 99% of ziconotide treated subjects. This is probably related to the fact that ziconotide has a relatively narrow therapeutic window, with a small difference between the dose required for analgesia and the dose required to produce side effects. Reported side effects include dizziness, confusion, gait ataxia, memory impairment, nystagmus, dysmetria, sedation, agitation, hallucinations, nausea, vomiting, urinary retention, somnolence, and coma. Elevated

uric acid, lactate dehydrogenase, and creatine kinase levels have also been reported. These side effects can cause serious psychiatric and neurologic impairment. They seem to occur most often when high doses are used at the initiation of therapy or when dose is increased quickly. On the other hand, ziconotide therapy can be abruptly terminated without withdrawal effects. Despite the severity of the side-effect profile, it has been demonstrated that adverse effects need to resolve fully after the cessation of drug infusion. To prevent the occurrence of these side effects, it is recommended that infusion start with the lowest possible dose and then is titrated slowly to effect. Ziconotide should not be offered to patients with complicated psychiatric profiles or a history of psychotic episodes. Clinicians should be vigilant for complications of ziconotide in their patients from the time of treatment onset. As this time, there are no data on the long-term use of ziconotide;36 nonetheless, it is the most studied intrathecal agent for the management of refractory chronic pain of both malignant and nonmalignant origin. While clinicians must be aware of the limitations of ziconotide (its narrow therapeutic window and high rate of adverse effects), with careful use it has significant efficacy and has been designated a first line intrathecal agent for neuropathic pain.21

NEWER DRUGS Although only morphine, baclofen, clonidine, and ziconotide have been approved by the FDA for chronic intraspinal use, the clinical practice of pain management involves in a majority of cases the “off label” use of agents alone and in combination. Currently, opioids, nonmorphine opioids, nonopioids, and combinations of these drugs are routinely being delivered intraspinally. Adenosine, baclofen, gabapentin, nonsteroidal antiinflammatory agents, midazolam, neostigmine, somatostatin37 and its analogue, octreotide, cholera toxin, botulinum, and a host of conopeptides inspired by the success with ziconotide have all been studied at some level for the intrathecal pharmacotherapy of intractable pain. Many are in the early development phase. Others have shown promise in human subjects. Clearly, our ability to provide relief for patients in pain will be enhanced with the wider availability of multiple intrathecal analgesic agents; however, more careful, controlled trials are needed to establish efficacy, long-term toxicity, and compatibility of these agents before they are introduced to our clinical armamentarium.

COMPLICATIONS Although implanted drug delivery systems offer a unique method of pain control in selected patients, they are not without significant complications. The risk of infection is common to all implanted drug delivery devices. Percutaneous catheters and implanted reservoirs appear particularly susceptible to infection because of their communication with the skin or frequent access through the skin. Infection may involve the surgical wound or the subcutaneous region surrounding the hardware. This is effectively treated by removal of all implanted hardware and the administration of appropriate intravenous antibiotics;



CHAPTER 63  Implanted Drug Delivery Systems for the Control of Chronic Pain

cure is seldom accomplished without hardware externalization. Re-implantation of the drug delivery system is usually delayed for at least three months after completion of antibiotic therapy. Infusion of contaminated drug solution is of great concern as this may lead to potentially life-threatening meningitis. The risk of this complication can be limited by the use of an in-line bacteriostatic filter; unfortunately, not all systems allow for or provide such filters. Early recognition and treatment of meningitis is critical. Erosion of the hardware through the skin is a less common complication, and may occur especially in cachectic, poorly nourished patients. This risk can be limited by placing the implant in a deep pocket, by ensuring the hardware does not lie directly under the incision, and by performing a meticulous multilayer closure. The most frequently observed complication involves failure of the system itself. Failure of the pump itself is uniquely uncommon but may occur, particularly with the complex electronics of programmable pumps. Catheter problems, however, are most common, reported in 25% of patients; the range of catheter problems is great and some centers have reported catheter complications in 50% or more of patients. These complications include kinking, obstruction, disconnection, or shearing of the catheter. There are several techniques to limit the risk of catheter failure and include the use of fluoroscopy during catheter placement to confirm the absence of loops, partial kinks, or malposition in a dural nerve root sheath. Observation of cerebrospinal fluid flow during each stage of implantation helps detect catheter obstruction during surgery. The paraspinous approach limits the sharp angle of the catheter as it enters and exits the interspinous ligament and guards against shearing at these sites. Securing the catheter with a purse string suture as it exits the interspinous ligament and again with a silastic fixation device also helps prevent cerebrospinal fluid leak and migration of the catheter out of the subarachnoid space. A loop of catheter distal to this point relieves strain on the catheter and prevents catheter migration or dislocation. Finally, dissection of a small space above the fascia in which the catheter comfortably rests will help prevent kinking when the wound is closed. Despite great care during catheter implantation, these problems may still occur. Patients with drug delivery system failure usually present with increased pain or with subcutaneous fluid accumulation. Initial evaluation includes the comparison of the expected and true residual volume in the pump reservoir; a significant disparity warrants further investigation. Plain radiologic evaluation of the entire system may reveal catheter disconnection and may also demonstrate kinking or migration of the catheter from the subarachnoid space. Occasionally, the instillation and attempted intrathecal delivery of iodinated contrast material via the pump may be helpful in differentiating between catheter or pump failure. Quantitative nuclear medicine studies may also be helpful; the pump can be filled with dilute solutions of radioactive material and the delivery of these materials can be followed over time. Even these diagnostic tests may be equivocal, requiring surgical exploration and revision of the pump or catheter or both. With such a rigorous approach, virtually all such mechanical problems can be corrected and pain relief restored.

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Another problem common to all implanted drug delivery systems is the potential for overdose. With an externalized system, this may result from improper setting of the external drug pump or improper dilution of the infusate by the pharmacy. Great care must be used to ensure appropriate drug concentration and delivery. Far more insidious can be the incorrect reprogramming of indwelling drug pumps or injection of the refill volume into the subcutaneous space, as these errors are potentially subtle and not immediately recognized. Such drug overdoses resulting from refill errors, programming errors, or incorrect infusate concentrations have occurred with devastating results. A further risk is created by the presence, in some pumps, of a side port intended for bolus drug injection or for testing catheter patency. There are two reported deaths resulting from accidental access of this side port rather than the refill port, resulting in the entire refill volume of the drug infusing into the CSF. Modifications have been made to prevent access to the bolus port by needles intended for pump refilling; nonetheless, great care must be exercised to avoid this potentially life-threatening complication.

INTRATHECAL GRANULOMAS (CATHETER TIP INFLAMMATORY MASS) The development of inflammatory masses (so-called catheter tip granulomas) at the terminal end of the intrathecal catheter within the subarachnoid space has become an increasingly well recognized complication of intrathecal drug infusion systems. While the first reported case was almost 20 years ago, the exact incidence and prevalence of catheter granulomas in patients receiving intrathecal pharmacotherapy is unknown. While initially thought to be an extremely rare event, most recent data suggests that it may occur in as many as one in twenty patients treated with intrathecal opioids. If the intrathecal granuloma becomes sufficiently large, spinal cord and nerve root compression may occur and result in new or worsening neuropathic pain, weakness, numbness, loss of bowel and bladder function, and even paralysis. It has been postulated that catheter tip granulomas represent indolent, local infections. However, they tend to occur only at catheter tips where drug is infused, rather than along any other part of the catheter length were microorganisms could theoretically be stationed. Furthermore, catheter tips and granulomas have been sent for pathologic and microbiologic studies and only three granulomas have been reported to harbor microorganisms in their center, despite many more being sterile compositions of chronic, inflammatory cells. In two of these three cases contaminants were suspected. Additionally, polymorphonuclear leukocytes (PMNs) are rarely seen in such granulomas. Some conjecture that granulomas are hypersensitivity reactions to the silicone in catheters. Others suggest granulomas may form in predisposed individuals with prior anatomic damage to neural tissues, previous or simultaneous exposure to other intraspinal devices such as spinal cord stimulators, or as direct result of the surgery necessary for catheter implantation. At this time, however,

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the most plausible explanation is that they are local, chronic inflammatory reactions related to dural based mast cell degranulation in response to the very drug infused. They occur where drug is most concentrated at its exit from the catheter lumen before it can disperse throughout the CSF. Despite the mechanism, there is strong evidence that the regional cerebrospinal fluid flow dynamics play a primary role in granuloma formation. Granuloma formation seems to occur more often in the longest and narrowest portion of the spinal canal, the thoracic spinal cistern. This region has the most stagnant CSF flow during the cardiac cycle and it tends to be the target for the catheter tip in most current pump placement operations. What results is the infusion of drug into the intrathecal space where the highest relative concentration is possible: a tight space with poor flow. If granuloma formation is directly related to drug flow, then the thoracic cord is an ideal candidate. The risk of catheter-associated granuloma formation is highest with opioids, with the exception of fentanyl. Interestingly, unlike other tested opioids, fentanyl does not cause dural mast cell degranulation. There seems to be a direct relationship between both the concentration of opioid in the infused solution and the rate at which it is infused with the likelihood that a granuloma will form. Interestingly, granulomas have often been seem to form in patients who have poor pain control and require higher daily doses of intrathecal opioids. It was long thought that granuloma formation with intrathecal baclofen was not possible. However, at least two recent case reports demonstrate the contrary. Nevertheless, the paucity of such data does support that baclofen associated granulomas are rare. Granulomas are more common in patients with nonmalignant pain as opposed to those being treated for cancer pain. They are more often seen in younger patients as well. It could be deduced that because these groups have longer life expectancies, they are exposed to greater concentrations of opioids and subsequently are more likely to develop granulomas. This adds support for the dose-dependent relationship of intrathecal drugs and granuloma formation mentioned earlier. If granulomas are discovered before they are symptomatic, discontinuation of drug infusion is often all that is necessary. Stabilization and even regression of granulomas has been shown after drug infusion ceases. Another suggested strategy is the infusion of hypertonic saline after discontinuing opioid infusion, and good results are available in the literature. The problem with these management strategies is that they result in the return of pain in nearly all patients. Another option is to replace morphine infusion with another opioid such as hydromorphone. This was reported in one case, and the patient’s granuloma remained stable without regression over time. It must be kept in mind, however, that all opioids have the potential for granuloma formation. Possibly the most common strategy for the treatment of asymptomatic catheter tip granulomas is the withdrawal of the catheter one to two spinal levels. The granuloma frequently resolves and allows for continued analgesic infusion, although at a lesser dose and rate or with another agent less likely to produce catheter tip granulomas.

When catheter tip granulomas enlarge to the size where frank spinal cord compression occurs and when patients have become symptomatic, surgical decompression and resection is often required. The results of surgical therapy, in patients who have already developed a neurologic deficit, are not perfect. While nearly one third of reported patients make a complete recovery and another one third remain ambulatory, one third of patients remain paralyzed or nonambulatory. The requirement for increasing opioid doses should raise suspicion for the formation of catheter tip granulomas. The appearance of new or altered pain sensations in a dermatomal distribution near the known location of the catheter tip, or new radicular pain or numbness is also suspect. In addition to following a patient’s pain, experts recommend close neurological follow up of all patients treated with intrathecal drug administration. Motor examination should be a routine part of every clinic visit. As catheter tip granulomas develop slowly, attention to subtle changes in physical examination may be an indication for MRI imaging or CT myelography. It has also been suggested that routine MRI imaging be instituted in all patients undergoing intrathecal morphine therapy or at least in patients at high risk, including those using high doses or high concentration of intrathecal opioids. Now that granulomas are well established complications of intrathecal drug infusion and that these complications can be extremely devastating, clinicians should have a low threshold for their development, should take all measures to diagnose them promptly and should use appropriate means to treat them once diagnosis is confirmed.

MORTALITY WITH INTRATHECAL OPIOIDS FOR NONCANCER PAIN New disturbing data has very recently been published that has demonstrated that both the initial implantation and the routine maintenance of intrathecal drug delivery systems for the treatment of chronic nonmalignant pain carry an increased risk of patient mortality. In February 2006, experts noticed a cluster of three deaths, all seemingly opioid related, that occurred within one day of opioid pump implantation for noncancer pain. Initial review of these pump manufacturers records and those of insurance providers, the Social Security Death Master File, and the Centers for Medicare and Medicaid Services databases identified nine total deaths within three days of pump implantation or pump revision in the four-month period surrounding these three “sentinel cases.” The cause of death in all causes was likely the respiratory depressant effect of opioids on the central nervous system. A more comprehensive age and gender-adjusted comparison of mortality at three days, thirty days, and one year for patients with implantation drug delivery systems was carried out using spinal cord stimulator implantation as a control, as both surgical implantation procedures are similar. For completeness, in-hospital mortality rates after lumbosacral spine surgery in Medicare beneficiaries and after discectomy in a nationwide community hospital sample were also included for comparison. Mortality within three days after intrathecal opioid system implantation was 0.88 per 100038. This figure is



CHAPTER 63  Implanted Drug Delivery Systems for the Control of Chronic Pain

higher than in-hospital mortality following discectomy operations (0.59 per 1000), but lower than more complex lumbar spine surgery (5.2 per 1000). It is also eight times higher than the reported 0.11 per 1000 deaths seen within three days of spinal cord stimulator implantation. The mortality rates one month and one year after pump implantation remained higher (0.39% at 1 month, and 3.89% at one year) albeit by lower proportions, when compared to spinal cord stimulation implantation.38 It can be said with confidence that early death within 24 hours after pump implantation or refill is likely related to opioid overdose and fatal respiratory depression. The cause for late death (thirty days and one year) was more difficult to discern. In many cases, no details or data exist to provide any information about circumstances surrounding the deaths. The authors suggest that device malfunction can be considered unlikely as a direct cause of death, because safe-guard mechanisms related to device programming may actually decrease drug administration if a pump malfunctions in situ.38 Logically, however, device malfunction may have resulted in increased oral opioid intake and indirectly caused unintentional overdose because of poor pain control. Of note, they mention that over 90% of delivery devices were not investigated after patients’ deaths. They also reject the notion that patients who receive opioid pump systems are sicker, on the whole, than patients who undergo stimulator system placement or lumbosacral surgery and tried to control for this variable. Drug pumps require frequent maintenance, refills, dose changes, and more revision operations compared to stimulator systems. This introduces many potential variables that could result in increased mortality. In light of this new recognition that pump implantation carries with it a higher risk of death, it must be stressed that every clinician be vigilant in every step of the process after pump initiation or replacement. The lowest possible dose and drug concentration should be used to initiate therapy. The clinician should be an expert in the technological capabilities and limitations of the device they choose, and they should feel comfortable in all steps of device refilling and programming.

large-scale trials are lacking; until such evidence is available, use in this setting should not be considered routine therapy. Second, patient selection criteria need to be better defined and validated. In particular, the psychosocial evaluation and specific pain states responsive to this intervention need better characterization. In light of the cost and invasiveness of this approach, we must pay great attention to refining our patient selection criteria to ensure the best chance of obtaining pain relief. Finally, and perhaps most significantly, further development in analgesic pharmacology needs to be applied to intraspinal drug therapy. Although there are currently dozens of available analgesic agents for oral or parenteral use capitalizing on the complex neurochemistry of pain transmission and modulation pathways, few are validated and FDA approved for intraspinal use. With the development of newer and more specific agents, and with the utilization of agents active at a number of receptor systems involved in pain perception, intraspinal drug administration may help limit the suffering of many more people with otherwise intractable pain.

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FUTURE DIRECTIONS While tremendous progress has been made in the use of intraspinal analgesics for the treatment of intractable pain, there are several areas that need to be addressed before the technique is more widely accepted and can be of broader clinical use. First, although its efficacy in the treatment of pain secondary to malignancy appears clear, the efficacy of intraspinal drug administration for pain of nonmalignant origin remains to be fully elucidated. Properly controlled,

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Intraspinal therapy restricts drug effects to regions associated with the source of the nociceptive input. Morphine and hydromorphone are well suited for intrathecal use in view of their hydrophilicity and slow absorption from the cerebrospinal fluid. Morphine, hydromorphone, and ziconotide are the first-line agents in intrathecal drug therapy. The inclusion of ziconotide as a first line drug is secondary to the randomized, double-blind placebo-controlled studies showing its efficacy in cancer-related pain and inadequately managed noncancer pain. Bupivacaine is the most commonly used intrathecal local anesthetic. Its addition to intrathecal opioids generally results in better pain control, less opioid use, and improved quality of life. Intrathecal granulomas are more common in patients with noncancer pain and younger patients, i.e., patients with longer life expectancies. The mortality from intrathecal opioids is higher than in patients who have discectomy or complex spine surgery and in patients who have spinal cord stimulators. The exact causes of the patients’ deaths remain to be determined.

REFERENCES Access the reference list online at http://www.expertconsult. com