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Long-term management of patients with interspinal drug delivery systems
Seminars in Pain Medicine Vol. 2 No. 1 2004
Long-Term Management of Patients With Interspinal Drug Delivery Systems JAMAL TAHA, MD,* and NAGY A. MEKHAIL, MD, PhD†
ABSTRACT Interspinal drug delivery via pump for chronic pain and spasticity is only part of a more comprehensive patient management program for the long-term success of therapy. This therapy should not be relied upon solely, but rather used in conjunction with other rehabilitative modalities during long-term patient management. Physicians who manage these devices should be able to answer questions that arise from patients or other health-care providers regarding activity restrictions or other limitations imposed by this therapy. They should be able to recognize and treat side effects that arise from drugs used in the pump and complications related to the pump system. Physicians should also have a clear plan of action for patients whose symptoms are not well controlled. This review assesses the long-term management of patients who receive this therapy. Key words: interspinal drug delivery, complications, trouble shooting, patient management.
could be related to the implanted pump. Therefore, proper communication with the primary-care physician is essential to provide better overall care and to avoid duplication of efforts or potential conflicts. This investigation reviews the long-term management of patients with implanted intraspinal drugdelivery systems, specifically with regard to issues related to patient activities and restrictions, adjustment of oral and intraspinal medications, troubleshooting drug- or pump-related complications, and management of pain recurrence.
Introduction Implantation of a pump for intraspinal drug delivery is the beginning of a long-term relationship between the health-care team and the patient. Preoperative patient education should emphasize that this therapy is only part of a comprehensive treatment program in which the patient should play an active role. The goal of intraspinal drug delivery is to reduce pain to a level that allows the patient to engage in physical reconditioning and integration back into society as well as participation in social activities and, possibly, gainful employment. The patient not assume a passive role during this treatment, because this would only result in long-term failure of therapy; therefore, it is important that both patient and physician discuss the timetable for engaging in different therapy programs after the pump is implanted. Frequent follow-ups and reevaluations are necessary to adjust the treatment algorithm. Outcome expectations should be realistic and discussed before the pump is implanted. The ultimate goal of this therapy should be to improve function and quality of life rather than merely decreasing pain. Patients with implantable pumps frequently consider the managing pain physician their new primarycare doctor. They may call the managing physician for every medical development that arises, fearing that it
Activity and Restrictions Patient Rehabilitation Patients are encouraged to engage in most activities with minimal restrictions. Physical and psychoFrom the *Taha Neurosurgical Clinic, Kettering, OH; and †Department of Pain Management, Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Jamal Taha, MD, Taha Neurosurgical Clinic, 3533 Southern Boulevard, Suite 3000, Kettering, OH 45429. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 1537-5897/04/0201-0003/$30.00/0 doi:10.1016/j.spmd.2004.02.001
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logic rehabilitation are essential for the long-term success of this therapy in patients with chronic pain as well as patients with spasticity. Intrathecal drug delivery in chronic pain management should be viewed as a temporary measure to help the patient start on the path toward recovery. It is important to get the patient engaged in this activity as soon as possible. Sports. Most patients with chronic pain or spasticity usually do not participate in sports, although this question frequently arises, particularly with regard to golf, bowling, and swimming. Patients often ask whether sports activities disrupt the function of the pump or cause catheter dislodgement. Although activities are somewhat restricted immediately after pump implant, the present investigator encourages patients to participate in sports activities long term. Restrictions are usually not imposed if the activity is well tolerated by the patient; however, I advise against engagement in “extreme” sports (eg, skydiving, bungee jumping) and contact sports (eg, football, wrestling). Air travel and diving. The function of implantable pumps is affected by atmospheric pressure; however, various pumps are affected differently, depending on the type of the pump (constant flow vs programmable) and the pump model. The specific information can be obtained from the pump manufacturer. In general, patients with constant-flow pumps are advised against diving. The function of programmable pumps is usually affected when pumps are submerged in ⬎30 feet of water. In general, patients with implantable pumps can travel by air without problems. However, patients should show their implant cards when they pass through airport security checks. Driving. Patients who can safely drive on oral opioid treatment should be able to drive safely after a pump is implanted. Drugs delivered intrathecally theoretically result in fewer systemic side effects than drugs delivered systemically.1 Sedation that may occur after opioids are first administered intrathecally is usually transient and should not persist long term. Nevertheless, concerns regarding safe driving should be addressed. This is especially true if the patient’s occupation primarily involves driving. Patients can be referred to a rehabilitative facility where reflexes necessary for safe driving are formally tested. The need for these measures should be assessed on an individual basis. Work. Patients are encouraged to return to work. A referral for a formal evaluation of functional capacity, work hardening, and job training may be necessary to define the level of activity and type of work to which patients are best suited. Some types of work may require further evaluation if safety is an issue
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(eg, machine operator, construction worker). When safety is an issue, a formal evaluation of patient reflexes, such as that discussed with driving, is recommended. Surgery and Invasive Procedure A frequent question asked of the managing physician is whether patients with implanted pumps require prophylactic antibiotics or have certain restrictions when they undergo dental or other surgical procedures. The present investigator usually does not recommend prophylactic antibiotics or offer specific restrictions. If a lumbar puncture is performed, I advise that this be done under fluoroscopy to avoid the risk of injuring the catheter. Incisions for a surgical procedure should be performed away from the pump system to avoid damage to the pump or infection. Intraoperative X-rays and cauterization intraoperatively are allowed. Imaging and Radiation Magnetic resonance imaging (MRI) can be performed safely in patients with most pump implants. It is usually advised that a programmable pump be interrogated before and after the MRI. However, I have never encountered a case in which the pump program changed after MRI was performed. The magnetic field of MRI will temporarily stop the rotor of a programmable pump and suspend drug infusion for the duration of MRI exposure; thereafter, the pump resumes normal operation. Therefore, it is not necessary to empty a programmable pump from its mediations during MRI. Computed tomography (CT) scans, plain X-rays, and nuclear studies can be performed safely with all pump implants. If radiation treatment is administered, it is advised that ports of radiation that traverse a programmable pump be limited to avoid possible pump damage. Postmortem Patients with implanted pumps should not be cremated before the pump is explanted. After death, programmable pumps may alarm once they reach a low reservoir. The patient’s family should be aware of this possibility. Adjustment of Oral and Intrathecal Medications Most patients who undergo pump implant would still be receiving oral medications in the periopera-
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Fig 1. Guidelines for intraspinal drug delivery (adapted and modified from Bennett et al4).
tive period. One of the goals of long-term intraspinal drug delivery is to eliminate or reduce the need for oral pain medications. This may or may not be achievable. Many patients will still require oral opiates as an adjuvant or for breakthrough pain. Many further patients will still require adjuvant non-opiate medications. The issue of when and how to receive oral medications after a pump is implanted should be discussed preoperatively with the patient and other caregivers to establish a timetable and a strategy for adjusting systemic medications. Systemic opiates or baclofen medications should be decreased gradually as intrathecal medications are increased. Intrathecal Medications in Chronic Pain Morphine is the only medication approved by the Food and Drug Administration (FDA) for intrathecal use via implantable pump. A broad consensus exists within the pain management medical community that intrathecal opiates should be prescribed and
maintained at the lowest effective dose for as long as possible.2 It is common for patients to require an increase in their daily morphine dose in the first 6 months after pump implantation, sometimes at twoto threefold the initial dose.3 Thereafter, most patients remain on a stable daily dose, although others require further escalation of morphine dose. Clinical guidelines have been published for the most common medications used in the pump as well as guidelines for their selection (Fig 1).4 These guidelines were based on an internet survey, literature review, and the clinical experience of an expert panel. A four-tier therapy approach was recommended: Tier I approaches gain clear support from data of available literature and extensive clinical experience; Tier II approaches have limited supporting data but are commonly applied, supported by extensive clinical experience; Tier III approaches have limited empirical data, although they are considered reasonable on the basis of sufficient clinical experience; and Tier IV approaches are rarely utilized based on limited safety data.
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Morphine is the most common initially used medication in pumps for all kinds of pain, both nociceptive as well as neuropathic, and is considered the first-tier therapy.4,5 The dose of morphine is usually escalated before other medications are considered; however, the threshold dose of morphine that should be reached before first-tier therapy is changed is not agreed on.6 Several studies have demonstrated that the higher the morphine dose, the higher the risk for morphine-induced hyperalgesia, myoclonus, opioid tolerance, and development of catheter-related inflammatory masses. The usual maximum compounded concentration of morphine is 50 mg/ mL. Some physicians escalate the morphine intrathecal dose to 20 mg/day before they consider changing or adding other medications. This upper dose limit was selected based on some studies showing that the risk of morphine-induced hyperalgesia is high at above this dose.4,7 In addition, morphine doses of ⬎20 mg/day shorten the intervals between pump refills, which may be inconvenient to the patient and expensive to the payer.4 Other physicians change first-tier therapy when the intrathecal morphine dose reaches only a few milligrams per day.8 In one survey,9 the mean dose of intrathecal morphine was 9.2 mg/day at 1 year for patients with chronic noncancer pain and 14.2 mg/day at 1 year for patients with cancer pain. Dose escalation is usually done in increments of 15% to 50%. Patients with nociceptive pain who require escalated doses of intrathecal morphine or who develop morphine-related side effects may benefit from second-tier therapy, whereby morphine is substituted with hydromorphone. The starting dose of hydromorphone is usually 20% that of morphine. If symptoms persist, a third-tier therapy can be used where hydromorphone is substituted with a lipophilic medication, such as fentanyl or sufentanil. The usual starting dose of fentanyl is 50 to 75 g/day, whereas that of sufentanil is 10 g/day.10 Patients with neuropathic pain who require an escalated dose of morphine or who suffer from morphine-related side effects may benefit from the addition of bupivacaine or clonidine as a second-tier therapy. The combination of morphine and clonidine has been shown to be stable in the pump.11 The usual starting dose for clonidine is 50 to 75 g/day whereas that of bupivacaine is 2 to 4 mg/day.10 If symptoms or side effects persist, a mixture of opioid, bupivacaine, and clonidine is a thirdtier therapy. Second- and third-tier therapies described for the treatment of neuropathic pain can be also applied for the treatment of nociceptive pain when other measures fail.12
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Fourth-tier therapies are best considered in several categories: Group I includes meperidine, methadone, ropivacaine, neostigmine, and droperidol. The intrathecal administration of these medications has some limited data supporting safety, but little information about efficacy. Physicians should consider an approved institutional protocol before offering these medications on a routine basis. Group II includes the use of intrathecal baclofen for pain. There is anecdotal evidence that intrathecal baclofen can help pain related to spasticity but evidence that it has a broader analgesic effect is lacking. Adding intrathecal baclofen in small doses (ie, 25 to 50 g/day) to morphine can sometimes help relieve the pain of muscle spasms associated with back pain. Group III includes tetracaine, midazolam and Nmethyl-D-aspartate (NMDA) antagonists, such as dextrorphan, dextromethorphan, memantine, and ketamine. These medications have unresolved questions concerning safety, and some reports have associated their intrathecal administration to spinal cord toxicity.4 Such medications should be reserved for special circumstances or research protocols. A change from one tier-therapy to another or a change from one therapeutic approach to another within the same tier level is predicated on the assessment of therapeutic failure. An intraspinal therapy fails if pain is not well controlled, if intolerable side effects develop, or if doses of a specific treatment are required that exceed those conventionally used. When this occurs, patients should be reevaluated to clarify the etiology of the inadequate response and to determine the appropriate next step.
Intrathecal Medications for Spasticity Baclofen is the only FDA-approved medication for intrathecal use through an implantable pump for spasticity. It is not infrequent for patients to require an increase in the daily dose of intrathecal baclofen to control spasticity during the first 6 months after pump implant. Patients with spasticity related to central nervous system pathology (eg, cerebral palsy, brain or spinal cord injuries, dystonia) usually require higher dosages of intrathecal baclofen than patients with spasticity secondary to multiple sclerosis. Patients with a progressive pathology (eg, multiple sclerosis) frequently require further increases in the daily baclofen dose months to years after pump implant compared to patients with nonprogressive pathology (eg, spinal cord injury).13
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Fig 2. Side effects of intrathecal opioids.
Troubleshooting Drug-Related Complications Complications related to the medications used in the pump include side effects of drugs administered intrathecally, drug overdose, and drug withdrawal. The following is a discussion of these complications.
Side Effects of Opioids Administered Intrathecally Most side effects of intrathecally administered opioids are transient. These include sedation, nausea and vomiting, urinary retention, constipation, and pruritis. The treatment of these side effects is summarized in Figure 2. These side effects are treated
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symptomatically until they abate spontaneously. They rarely require long-term management.14 Side effects that usually persist long term include peripheral edema, myoclonus, hormonal changes, and the development of granuloma. The following is a discussion of these side effects. Peripheral edema. Patients receiving intrathecal opiates therapy may develop peripheral edema, which is believed to result from vasopressin release due to cephalad spread of the opiate in the cerebrospinal fluid (CSF) and interaction with receptors in the posterior pituitary.15 Preexisting pedal edema and venous stasis before pump implant seem to be risk factors for development of this complication.16 Patients who develop peripheral edema should be evaluated for other causes. Intrathecal administration of opioids may occasionally unmask a preexisting condition such as sleep apnea or congestive heart failure. The patient may very well be developing a medical condition that causes peripheral edema independent of opioid administration. Peripheral edema can be initially treated symptomatically. Elastic stockings and diuretics may reduce symptoms. Reduction of daily opioid dose or switching to another opiate may help. Myoclonus. Clinical reports have suggested a relationship between the occurrence of myoclonus and the use of high doses of morphine.7 An elevated concentration of morphine-3-glucuronide (M3G) in the spinal fluid is believed to be responsible for the development of myoclonus.17 Symptomatic treatment includes administration of oral or intravenous muscle relaxants such as benzodiazepines. Management should include lowering the daily dose of morphine or substituting morphine with another opiate. In one study of patients receiving long-term oral opiate treatment, myoclonus was more likely to occur in those taking antidepressant or antipsychotic drugs as antiemetics or as adjuvant agents or nonsteroidal anti-inflammatory drugs for additional analgesia.18 It is possible that discontinuing supplemental medications helps to reduce myoclonus in patients receiving intrathecal opioids, but further studies are required. Hormonal changes. Long-term administration of intrathecal opiates can result in various hormonal changes in both men and women. In one study, most men and all women receiving intrathecal opioids developed hypogonadotropic hypogonadism, about 15% of patients developed central hypocorticism, and about 15% of patients developed growth hormone deficiency.19 Some female patients may develop amenorrhea after the administration of intrathecal morphine.20 These findings suggest that further investigations are required to determine the
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need for systematic endocrine work-up in these patients and the possible need for substitutive therapy. Some male patients have complained of decreased libido after long-term intrathecal administration of opioids. Several animal and human studies demonstrated that opioids lower testosterone levels and suppress penile erectile reflexes.21,22 Patients who suffer from decreased libido should be tested for low testosterone levels. These patients may respond to a decrease in their daily morphine dose or to testosterone replacement. Granuloma. Granulomas are inflammatory masses that occur at the tip of the intrathecal catheter. In general, granulomas develop infrequently and are usually discovered several months or years after implanting an intrathecal pump system that delivers opioids. Depending on their size and rate of formation, they may be discovered incidentally or after they cause symptoms of neural compression to nerve rootlets or to the spinal cord. They are usually reported with pumps delivering morphine and have not been reported in association with pumps delivering baclofen.23,24 Drug overdose. Symptoms of drug overdose should be known to physicians. Symptoms of opioid overdose include respiratory depression with or without concomitant central nervous system depression, including dizziness, sedation, euphoria, anxiety, seizures, and respiratory arrest. Symptoms of baclofen overdose include drowsiness, light-headedness, dizziness, somnolence, respiratory depression, seizure, rostral progression of hypotonia, and loss of consciousness progressing to coma. The treatment of drug overdose must be prompt (Fig 3). Attention should be directed first to support the respiratory and circulatory systems. The patient should be monitored closely, preferably in the intensive care unit. The pump should be stopped immediately. Emptying a programmable pump alone may not be adequate as the drug remaining in the tubing will continue to be delivered into the intrathecal space; however, aspirating the drug from the catheter through a pump side port ensures that no further medication is delivered into the CSF. A large volume of CSF (30 to 40 mL) should be aspirated through the pump side port or through a lumbar puncture to decrease the concentration of the drug in the intrathecal space.14 In morphine overdose, naloxone 0.4 to 2 mg intravenously (IV) is administered as intermittent bolus repeated every 2 to 3 minutes to a total of 10 mg or as a continuous drip depending on the severity of symptoms. Because the duration of the effect of IV naloxone is shorter than that of intrathecal morphine, it is important to closely monitor the patient
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Fig 3. Etiology and treatment of intrathecal drug overdose.
for symptom recurrence; repeated administration of naloxone may be necessary. There is no specific antidote for treating overdose of baclofen; however, anecdotal reports have suggested that physostigmine may reverse central side effects, notably drowsiness and respiratory depression. In adults, physostigmine is administered at 0.5 to 1 mg intramuscularly (IM) or IV, not to exceed 1 mg/min, and can be repeated every 10 to 30 minutes. In children, physostigmine is administered at 0.02 mg/kg IM or IV, not to exceed 0.5 mg/min, and can be repeated every 5 to 10 minutes, up to a maximum of 2 mg. Once treatment of overdose is instituted, investigation should be carried out to determine the cause and correct it accordingly. Drug overdose can result from several factors, which are discussed in what follows. Injection of drug through the side port: During pump refill, injecting the drug into a side port when present results in the administration of a large amount of the drug directly into the spinal fluid. This complication should be avoided if the physician carefully follows the manufacturer’s instructions for pump refill. Specifically, needles that can penetrate the screen applied over the side port should be avoided. Injection of drug into the subcutaneous tissue: Injecting the drug into the subcutaneous tissue may occur inadvertently in obese patients. If this happens, symptoms may not develop immediately after pump refill but several hours or days later. This complication should be avoided by carefully following the manufacturer’s instructions for pump refill.
During the dye study: When pump side ports are accessed for a dye study, it is important to aspirate ⬎0.5 mL through the side port before injecting the dye. This is necessary to avoid pushing the drug retained in the catheter into the spinal fluid. If aspiration cannot be achieved, the procedure should be terminated. Dose calculations: Drug overdose may result from wrong dose calculations during bridge bolus, change of drug concentration, and programming. It is important for two staff members to independently review calculations to avoid this complication. Revision of pump malfunction or change of drug in pump: Poor pain control as a result of pump malfunction or as a result of tolerance to an opioid requires escalation of the drug dose before the pump system is revised or before the opioid is replaced by a different opioid. In all cases, intrathecal drug delivery should be restarted at a lower dose of opioid, or its theoretical equianalgesic, dose to compensate for the corrected drug delivery or incomplete crosstolerance. Iatrogenic: Physicians should always question whether patients are receiving systemic medications above and beyond what is discussed. There are case reports of patients aspirating the opioid medication from the pump for systemic use.
Drug Withdrawal Symptoms of drug withdrawal should be well known to physicians managing the pump. This is especially true for baclofen-filled pumps, where drug
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Fig 4. Treatment of intrathecal baclofen drug withdrawal. Asterisk: airway, breathing, circulation.
withdrawal can be life-threatening. The treatment of drug withdrawal is twofold: (1) to treat the patient’s symptoms; and (2) to investigate the cause of withdrawal. Figs 4 and 5. Opioid withdrawal. Withdrawal symptoms of opioids include pain, insomnia, irritability, and autonomic signs, such as hypertension, tachycardia, tachypnea, diarrhea, and piloerection.25 Opioid withdrawal can be treated by oral, intramuscular, or intravenous replacement of morphine. Clonidine (oral or patch) can decrease symptoms of sympathetic hyperactivity associated with opioid withdrawal.
Baclofen withdrawal. Baclofen withdrawal can be serious and even life-threatening.26 Symptoms of baclofen withdrawal include increased spasticity, pruritis without rash, paresthesias, fever, and altered mental state. In advanced cases, patients may have exaggerated rebound spasticity and muscle rigidity, rhabdomyolysis, and multiple-organ failure. The condition may resemble autonomic dysreflexia, sepsis, malignant hyperthermia, and neuroleptic-malignant syndrome. Several physicians routinely replace programmable pumps filled with baclofen as these pumps approach their life expectancy and before symptoms develop.
Fig 5. Causes of drug withdrawal.
16 Seminars in Pain Medicine Vol. 2 No. 1 March 2004 When baclofen withdrawal is suspected, treatment should be prompt. Depending on the severity of clinical symptoms, the following measures are needed: (1) cardiopulmonary and respiratory support, as the patient should be followed closely in a monitored setting or the intensive care unit; (2) reinstitution of baclofen intrathecally through an indwelling catheter; (3) administration of intravenous benzodiazepines and sometimes dantrolene if rigidity is present; and (4) close follow-up for the development of myoglobinuria. Serial creatinine phosphokinase (CPK) measurements and renal function tests are recommended to monitor for the development of renal failure. Administration of mannitol may be necessary to perfuse the kidneys.21 Once the treatment of drug withdrawal is instituted, the physician should investigate causal factors. These are discussed in what follows. Expired battery (pump interrogation): Interrogating the pump can help determine whether there is a problem with drug delivery. An expired battery is easily detected. Low alarm volume: The present investigator has frequently observed that some patients develop symptoms of drug withdrawal as the pump approaches an alarm residual volume of 2 mL. It appears that drug delivery may decrease at drug residual volumes of between 2 and 4 mL in some programmable pumps. An increase in the alarm volume to 4 mL in these patients prevents symptoms from recurring. Pump malfunction: Pump malfunction should be suspected in patients with a stable course of pain control and who suddenly or gradually develop symptoms of drug withdrawal. Pump malfunction can result from the catheter migrating or breaking, the catheter leaking or disconnecting, or the pump battery expiring or malfunctioning. Drug delivery may also be blocked from a kink in the catheter. To investigate pump malfunction the physician should obtain a plain X-ray of the system, which can help identify catheter migration, kink, or disconnection. The physician should be aware of the model and type of the implanted system to avoid misinterpreting the X-ray finding. For example, in some pump models, the connector between the intrathecal catheter and the pump is partially radiolucent, giving a false impression that the intrathecal catheter is disconnected. A drug residual volume that exceeds the expected drug residual volume by ⬎25% implies that the drug is not delivered as determined. When pump malfunction is suspected and imaging studies do not show abnormal findings, a dye study of the pump can be done. However, a dye study requires that a side port for the pump is available. It must be em-
phasized that the contrast should never be injected into the side port without first aspirating the drug within the catheter. Aspirating 1 mL through the side port ensures that no drug in the catheter is pushed into the intrathecal space as the contrast is injected. If a malfunction of a programmable pump itself is suspected, a rotor test can determine whether there is an internal mechanical failure. The details on performing a rotor test can be obtained from the manufacturer.
Troubleshooting Pump-Related Complications Long-term complications related to the pump include swelling around the pump and esthetic/irritation problems related to the position of the pump.
Swelling Around the Pump Implant Swelling that develops long term around a pump is usually secondary to either hygroma or infection. Hygroma is suspected if the swelling is not accompanied by tenderness, erythema, or fever. Hygroma. Most CSF leaks occur during the postoperative period; however, some patients may have symptoms related to CSF leak thereafter if the catheter is disconnected, broken, migrated, or punctured during pump refill. Unlike CSF leaks that occur postoperatively, CSF leaks that occur long term invariably require surgical revision of the pump system. The system needs to be investigated by plain X-ray or dye study to identify the source of the leak. Until the pump is revised, symptoms are treated symptomatically. Patients who have headache may benefit from laying down flat with hydration and some caffeine. Any leakage of spinal fluid outside the skin should be treated aggressively. Patients should either be taken to the operating room to revise the pump system or at least have the wound resutured, then be started on antibiotics until the system is surgically revised (Fig 6). Infection. Infection of the pump system rarely occurs beyond the perioperative period. Nevertheless, infections infrequently occur long term after pump refills or for no obvious reason. Infections that occur beyond the perioperative period are rarely simple superficial wound infections and most commonly require aggressive treatment. Patients who develop swelling around the pump associated with tenderness and possibly mild fever should be treated with intravenous antibiotics. The pump pocket can be aspirated and fluid sent for culture. The pump itself, however, should not be accessed to avoid introduc-
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Fig 6. Treatment of swelling around the pump.
ing bacteria into the pump and thereafter into the spinal fluid from an infected surrounding pocket. Patients who are febrile, have a stiff neck or headache, and appear ill should be treated for meningitis. A spinal tap will confirm the diagnosis. Meningitis is best treated by explanting the pump and administering IV antibiotics. Although there have been case reports of patients successfully treated for spinal meningitis with intrathecal antibiotics administered through the pump side port, the present investigator recommends explanting the system as a more definitive and safer approach (Fig 6). The timing for reimplanting a pump system after explanting an infected system depends on the severity of the infection and the clinical symptoms. A new pump system can be implanted on the opposite side of the abdominal wall as early as 2 weeks after explanting an infected pump and administering IV antibiotics. I recommend against implanting a new pump system within the same pocket of previous infection. If this must be done, I further recommend waiting at least 6 months after the infection is cleared before implanting the new pump. Pump Malposition Some patients, especially those who lose weight, may complain that the pump is unsightly, painful as it pushes against the skin or rib, or flips within the
wound. Pumps that flip need to be reanchored to the fascia with nonabsorbable sutures. Pumps that push against the rib, iliac crest, or skin should be repositioned. Occasionally, pumps need to be repositioned underneath the fascia of the abdominal muscles to reduce the high profile of the pump. Management of Pain Recurrence Pain that occurs long term could be recurrence of the old pain or the development of a new pain. Sometimes the distinction is not clear. Loss of pain relief. It is not uncommon for patients with opioid- or baclofen-filled pumps to require escalation of their daily drug dose for few months after surgery.27,28 Depending on the patient’s pathologic condition, some increases in the daily dose thereafter may still be required, as discussed previously. Physicians should have a clear plan regarding drug escalation and mixture to control pain, also discussed previously. Physicians should also have a clear plan regarding when to investigate for a cause for loss of pain or spasticity relief. When pain is not well controlled, physicians should treat the pain symptomatically as directed by published algorithms noted earlier. There are no specific rules that define the threshold before investigating the cause for inadequate pain relief. Guidelines that should alert the physician to look for a cause
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Fig 7. Investigation and management of pain recurrence.
include: (1) pain that suddenly recurs after a period of good pain control; (2) new characters of pain; (3) persistent pain despite “reasonable” changes in drugs; (4) rapid escalation of pain; (5) increased pain with dose escalation; and (6) new neurologic findings. In what follows are possible causes of loss of pain relief (Fig 7). Tolerance: Tolerance can occur for both opioids as well as baclofen.27,28 Tolerance may be treated by drug “holidays”29; however, it is my experience that this is rarely beneficial for long-term management. I believe that, at present, opioid tolerance is best treated by changing the opioid or by adding other non-opioid drugs, as discussed earlier. Baclofen can be substituted with morphine and then resumed. Pump system failure: Pump failure can be investigated by first interrogating the pump to assess the status of the battery. A residual volume that differs by ⬎25% of the volume of the drug aspirated should alert for a possible block in the system. Plain X-ray can delineate a kink, disconnection, or migration of the catheter. Injection of a nonionic contrast or radionuclide through the pump side port (dye study) may reveal a partial occlusion or a leak in the catheter or at a connection. A rotor test as recommended by the manufacturer may demonstrate a malfunction of some pumps. Pumps that malfunction need to be revised accordingly.
Granuloma: Granulomas have been associated with intrathecal opioid administration but not baclofen. Granulomas were discussed earlier. Structural: Patients who have loss of pain relief that is not managed by “reasonable” measures, occur without an inciting factor, or are associated with new neurologic findings should be investigated for a structural pathology that is progressing or developing. Management is planned accordingly. Patients with recurrent spasticity should be first investigated for factors that induce spasticity such as fever, urinary retention, bowel obstruction, and development of bed sores. Spasticity can improve by treating these conditions first rather than escalating the dose of baclofen. New pain. New pain should always be investigated promptly. Causes of new pain include drug-induced, granuloma, and structural causes (Fig 8). The latter two causes were discussed earlier. Opioid-induced hyperalgesia should be suspected when patients receive a high dose of opioid and investigation demonstrates no other cause. Opioidinduced hyperalgesia has been reported with the use of high-dose morphine and sometimes hydromorphone, but not with the use of lipophilic opioids such as fentanyl and sefentanil.4 Risk factors include the pre-existence of pathologic changes of the spine before intrathecal drug delivery.30 The clinical symp-
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Fig 8. Investigation and management of new pain.
toms are usually characterized by acute onset of severe pain, hypersensitivity, autonomic abnormalities below the waist, and occasionally segmental myoclonus and piloerection.7 The syndrome is dose-related and can occur suddenly. It is postulated that it is related to high concentration of M3G metabolite, which acts on the glycine receptor, producing a strychnine-like action.7,17 Patients with suspected morphine-induced hyperalgesia should be weaned off intrathecal morphine and started on IV benzodiazepines. Supplemental oral morphine may be necessary as a temporary measure. Morphine may be restarted at a lower dose or substituted with another opioid, such as fentanyl. I believe that the development of hyperalgesia syndrome in some patients who receive small amounts of opioids can still occur if there is a partial block of CSF flow around the catheter. If this is the case, revising the catheter should help relieve symptoms. This theory remains to be proven. Bupivacaine can also cause new pain, characteristically dysesthetic and burning. This usually occurs if high concentrations of 3% to 4% intrathecal bupivacaine are used. References 1. Onofrio BM, Yaksh TL: Long-term pain relief produced by intrathecal morphine infusion in 53 patients. J Neurosurg 72:200-209, 1990 2. Yaksh TL, Onofrio BM: Retrospective consideration of the doses of morphine given intrathecally by chronic infusion in 163 patients by 19 physicians. Pain 31:211223, 1987 3. Paice JA, Penn RD, Shott S: Intraspinal morphine for chronic pain: a retrospective, multicenter study. J Pain Sympt Manag 11:71-80, 1996 4. Bennett G, Burchiel K, Buchser E, et al: Clinical guide-
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lines for intraspinal infusion: report of an expert panel. J Pain Sympt Manag 20:S37-S43, 2000 (suppl) 5. Hassenbusch SJ, Stanton-Hicks M, Covington EC, et al: Long-term intraspinal infusions of opioids in the treatment of neuropathic pain. J Pain Sympt Manag 10:527543, 1995 6. Portenoy RK, Savage SR: Clinical realities and economic considerations: special therapeutic issues in intrathecal therapy—tolerance and addiction. J Pain Sympt Manag 14:S27-S35, 1997 (suppl) 7. Parkinson SK, Bailey SL, Little WL, et al: Myoclonic seizure activity with chronic high-dose spinal opioid administration. Anesthesiology 72:743-745, 1990 8. Hassenbusch SJ, Portenoy RK: Current practices in intraspinal therapy—a survey of clinical trends and decision making. J Pain Sympt Manag 20:S4-S11, 2000 (suppl) 9. Paice J, Winkelmuller M, Burchiel K, et al: Clinical realities and economic considerations: efficacy of intrathecal pain therapy. J Pain Sympt Manag 14:S14-S26, 1997 (suppl) 10. Bennett G, Serafini M, Burchiel K, et al: Evidencebased review of the literature on intrathecal delivery of pain medication. J Pain Sympt Manag 20:S12-S36, 2000 (suppl) 11. Hildebrand KR, Elsberry DD, Hassenbusch SJ: Stability and compatibility of morphine– clonidine admixtures in an implantable infusion system. J Pain Sympt Manag 25:464-471, 2003 12. Rainov NG, Heidecke V, Burkert W: Long-term intrathecal infusion of drug combinations for chronic back and leg pain. J Pain Sympt Manag 22:862-871, 2001 13. Ordia JI, Fischer E, Adamski E, et al: Chronic intrathecal delivery of baclofen by a programmable pump for the treatment of severe spasticity. J Neurosurg 85:452-457, 1996 14. Chaney MA: Side effects of intrathecal and epidural opioids. Can J Anaesthesiol 42:891-903, 1995 15. Simantov R, Snyder SH: Opiate receptor binding in the pituitary gland. Brain Res 124:178-184, 1977 16. Aldrete JA, Couto da Silva JM: Leg edema from intrathecal opiate infusions. Eur J Pain 4:361-365, 2000 17. Sjogren P, Thunedborg LP, Christrup L, et al: Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? Six case histories. Acta Anaesthesiol Scand 42: 1070-1075, 1998 18. Potter JM, Reid DB, Shaw RJ, et al: Myoclonus associated with treatment with high doses of morphine: the role of supplemental drugs. BMJ 299:150-153, 1989 19. Abs R, Verhelst J, Maeyaert J, et al: Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab 75:2215-2222, 2000 20. Paice JA, Penn RD: Amenorrhea associated with intraspinal morphine. J Pain Sympt Manag 10:582-583, 1995 21. Gomez-Marrero J, Feria M, Mas M: Stimulation of opioid receptors suppresses penile erectile reflexes and seminal emission in rats. Pharmacol Biochem Behav 31: 393-396, 1988 22. Paice JA, Penn RD, Ryan WG: Altered sexual func-
20 Seminars in Pain Medicine Vol. 2 No. 1 March 2004 tion and decreased testosterone in patients receiving intraspinal opioids. J Pain Sympt Manag 9:126-131, 1994 23. Hassenbusch S, Burchiel K, Coffey RJ, et al: Management of intrathecal catheter-tip inflammatory masses: a consensus statement. Pain Med 3:313-323, 2002 24. Yaksh T, Hassenbusch S, Burchiel K, et al: Inflammatory masses associated with intrathecal drug infusion: a review of preclinical evidence and human data. Pain Med 3:300-312, 2002 25. Savage SR: Addiction in the treatment of pain: significance, recognition, and management. J Pain Sympt Manag 8:265-278, 1993 26. Coffey RJ, Ridgely PM: Abrupt intrathecal baclofen withdrawal: management of potentially life-threatening sequelae. Neuromodulation 4:142-146, 2001
27. Ali NM, Hoffman JS: Tolerance during long-term administration of intrathecal morphine. Conn Med 53: 266-268, 1989 28. Nielsen JF, Hansen HJ, Sunde N, et al: Evidence of tolerance to baclofen in treatment of severe spasticity with intrathecal baclofen. Clin Neurol Neurosurg 104:142-145, 2002 29. Winkelmuller M, Winkelmuller W: Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology. J Neurosurg 85:458-467, 1996 30. Kloke M, Bingel U, Seeber S: Complications of spinal opioid therapy: myoclonus, spastic muscle tone and spinal jerking. Support Care Cancer 2:249-252, 1994
Long-Term Management of Patients With Interspinal Drug Delivery Systems JAMAL TAHA, MD,* and NAGY A. MEKHAIL, MD, PhD†
ABSTRACT Interspinal drug delivery via pump for chronic pain and spasticity is only part of a more comprehensive patient management program for the long-term success of therapy. This therapy should not be relied upon solely, but rather used in conjunction with other rehabilitative modalities during long-term patient management. Physicians who manage these devices should be able to answer questions that arise from patients or other health-care providers regarding activity restrictions or other limitations imposed by this therapy. They should be able to recognize and treat side effects that arise from drugs used in the pump and complications related to the pump system. Physicians should also have a clear plan of action for patients whose symptoms are not well controlled. This review assesses the long-term management of patients who receive this therapy. Key words: interspinal drug delivery, complications, trouble shooting, patient management.
could be related to the implanted pump. Therefore, proper communication with the primary-care physician is essential to provide better overall care and to avoid duplication of efforts or potential conflicts. This investigation reviews the long-term management of patients with implanted intraspinal drugdelivery systems, specifically with regard to issues related to patient activities and restrictions, adjustment of oral and intraspinal medications, troubleshooting drug- or pump-related complications, and management of pain recurrence.
Introduction Implantation of a pump for intraspinal drug delivery is the beginning of a long-term relationship between the health-care team and the patient. Preoperative patient education should emphasize that this therapy is only part of a comprehensive treatment program in which the patient should play an active role. The goal of intraspinal drug delivery is to reduce pain to a level that allows the patient to engage in physical reconditioning and integration back into society as well as participation in social activities and, possibly, gainful employment. The patient not assume a passive role during this treatment, because this would only result in long-term failure of therapy; therefore, it is important that both patient and physician discuss the timetable for engaging in different therapy programs after the pump is implanted. Frequent follow-ups and reevaluations are necessary to adjust the treatment algorithm. Outcome expectations should be realistic and discussed before the pump is implanted. The ultimate goal of this therapy should be to improve function and quality of life rather than merely decreasing pain. Patients with implantable pumps frequently consider the managing pain physician their new primarycare doctor. They may call the managing physician for every medical development that arises, fearing that it
Activity and Restrictions Patient Rehabilitation Patients are encouraged to engage in most activities with minimal restrictions. Physical and psychoFrom the *Taha Neurosurgical Clinic, Kettering, OH; and †Department of Pain Management, Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Jamal Taha, MD, Taha Neurosurgical Clinic, 3533 Southern Boulevard, Suite 3000, Kettering, OH 45429. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 1537-5897/04/0201-0003/$30.00/0 doi:10.1016/j.spmd.2004.02.001
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logic rehabilitation are essential for the long-term success of this therapy in patients with chronic pain as well as patients with spasticity. Intrathecal drug delivery in chronic pain management should be viewed as a temporary measure to help the patient start on the path toward recovery. It is important to get the patient engaged in this activity as soon as possible. Sports. Most patients with chronic pain or spasticity usually do not participate in sports, although this question frequently arises, particularly with regard to golf, bowling, and swimming. Patients often ask whether sports activities disrupt the function of the pump or cause catheter dislodgement. Although activities are somewhat restricted immediately after pump implant, the present investigator encourages patients to participate in sports activities long term. Restrictions are usually not imposed if the activity is well tolerated by the patient; however, I advise against engagement in “extreme” sports (eg, skydiving, bungee jumping) and contact sports (eg, football, wrestling). Air travel and diving. The function of implantable pumps is affected by atmospheric pressure; however, various pumps are affected differently, depending on the type of the pump (constant flow vs programmable) and the pump model. The specific information can be obtained from the pump manufacturer. In general, patients with constant-flow pumps are advised against diving. The function of programmable pumps is usually affected when pumps are submerged in ⬎30 feet of water. In general, patients with implantable pumps can travel by air without problems. However, patients should show their implant cards when they pass through airport security checks. Driving. Patients who can safely drive on oral opioid treatment should be able to drive safely after a pump is implanted. Drugs delivered intrathecally theoretically result in fewer systemic side effects than drugs delivered systemically.1 Sedation that may occur after opioids are first administered intrathecally is usually transient and should not persist long term. Nevertheless, concerns regarding safe driving should be addressed. This is especially true if the patient’s occupation primarily involves driving. Patients can be referred to a rehabilitative facility where reflexes necessary for safe driving are formally tested. The need for these measures should be assessed on an individual basis. Work. Patients are encouraged to return to work. A referral for a formal evaluation of functional capacity, work hardening, and job training may be necessary to define the level of activity and type of work to which patients are best suited. Some types of work may require further evaluation if safety is an issue
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(eg, machine operator, construction worker). When safety is an issue, a formal evaluation of patient reflexes, such as that discussed with driving, is recommended. Surgery and Invasive Procedure A frequent question asked of the managing physician is whether patients with implanted pumps require prophylactic antibiotics or have certain restrictions when they undergo dental or other surgical procedures. The present investigator usually does not recommend prophylactic antibiotics or offer specific restrictions. If a lumbar puncture is performed, I advise that this be done under fluoroscopy to avoid the risk of injuring the catheter. Incisions for a surgical procedure should be performed away from the pump system to avoid damage to the pump or infection. Intraoperative X-rays and cauterization intraoperatively are allowed. Imaging and Radiation Magnetic resonance imaging (MRI) can be performed safely in patients with most pump implants. It is usually advised that a programmable pump be interrogated before and after the MRI. However, I have never encountered a case in which the pump program changed after MRI was performed. The magnetic field of MRI will temporarily stop the rotor of a programmable pump and suspend drug infusion for the duration of MRI exposure; thereafter, the pump resumes normal operation. Therefore, it is not necessary to empty a programmable pump from its mediations during MRI. Computed tomography (CT) scans, plain X-rays, and nuclear studies can be performed safely with all pump implants. If radiation treatment is administered, it is advised that ports of radiation that traverse a programmable pump be limited to avoid possible pump damage. Postmortem Patients with implanted pumps should not be cremated before the pump is explanted. After death, programmable pumps may alarm once they reach a low reservoir. The patient’s family should be aware of this possibility. Adjustment of Oral and Intrathecal Medications Most patients who undergo pump implant would still be receiving oral medications in the periopera-
10 Seminars in Pain Medicine Vol. 2 No. 1 March 2004
Fig 1. Guidelines for intraspinal drug delivery (adapted and modified from Bennett et al4).
tive period. One of the goals of long-term intraspinal drug delivery is to eliminate or reduce the need for oral pain medications. This may or may not be achievable. Many patients will still require oral opiates as an adjuvant or for breakthrough pain. Many further patients will still require adjuvant non-opiate medications. The issue of when and how to receive oral medications after a pump is implanted should be discussed preoperatively with the patient and other caregivers to establish a timetable and a strategy for adjusting systemic medications. Systemic opiates or baclofen medications should be decreased gradually as intrathecal medications are increased. Intrathecal Medications in Chronic Pain Morphine is the only medication approved by the Food and Drug Administration (FDA) for intrathecal use via implantable pump. A broad consensus exists within the pain management medical community that intrathecal opiates should be prescribed and
maintained at the lowest effective dose for as long as possible.2 It is common for patients to require an increase in their daily morphine dose in the first 6 months after pump implantation, sometimes at twoto threefold the initial dose.3 Thereafter, most patients remain on a stable daily dose, although others require further escalation of morphine dose. Clinical guidelines have been published for the most common medications used in the pump as well as guidelines for their selection (Fig 1).4 These guidelines were based on an internet survey, literature review, and the clinical experience of an expert panel. A four-tier therapy approach was recommended: Tier I approaches gain clear support from data of available literature and extensive clinical experience; Tier II approaches have limited supporting data but are commonly applied, supported by extensive clinical experience; Tier III approaches have limited empirical data, although they are considered reasonable on the basis of sufficient clinical experience; and Tier IV approaches are rarely utilized based on limited safety data.
Long-Term Management
Morphine is the most common initially used medication in pumps for all kinds of pain, both nociceptive as well as neuropathic, and is considered the first-tier therapy.4,5 The dose of morphine is usually escalated before other medications are considered; however, the threshold dose of morphine that should be reached before first-tier therapy is changed is not agreed on.6 Several studies have demonstrated that the higher the morphine dose, the higher the risk for morphine-induced hyperalgesia, myoclonus, opioid tolerance, and development of catheter-related inflammatory masses. The usual maximum compounded concentration of morphine is 50 mg/ mL. Some physicians escalate the morphine intrathecal dose to 20 mg/day before they consider changing or adding other medications. This upper dose limit was selected based on some studies showing that the risk of morphine-induced hyperalgesia is high at above this dose.4,7 In addition, morphine doses of ⬎20 mg/day shorten the intervals between pump refills, which may be inconvenient to the patient and expensive to the payer.4 Other physicians change first-tier therapy when the intrathecal morphine dose reaches only a few milligrams per day.8 In one survey,9 the mean dose of intrathecal morphine was 9.2 mg/day at 1 year for patients with chronic noncancer pain and 14.2 mg/day at 1 year for patients with cancer pain. Dose escalation is usually done in increments of 15% to 50%. Patients with nociceptive pain who require escalated doses of intrathecal morphine or who develop morphine-related side effects may benefit from second-tier therapy, whereby morphine is substituted with hydromorphone. The starting dose of hydromorphone is usually 20% that of morphine. If symptoms persist, a third-tier therapy can be used where hydromorphone is substituted with a lipophilic medication, such as fentanyl or sufentanil. The usual starting dose of fentanyl is 50 to 75 g/day, whereas that of sufentanil is 10 g/day.10 Patients with neuropathic pain who require an escalated dose of morphine or who suffer from morphine-related side effects may benefit from the addition of bupivacaine or clonidine as a second-tier therapy. The combination of morphine and clonidine has been shown to be stable in the pump.11 The usual starting dose for clonidine is 50 to 75 g/day whereas that of bupivacaine is 2 to 4 mg/day.10 If symptoms or side effects persist, a mixture of opioid, bupivacaine, and clonidine is a thirdtier therapy. Second- and third-tier therapies described for the treatment of neuropathic pain can be also applied for the treatment of nociceptive pain when other measures fail.12
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Fourth-tier therapies are best considered in several categories: Group I includes meperidine, methadone, ropivacaine, neostigmine, and droperidol. The intrathecal administration of these medications has some limited data supporting safety, but little information about efficacy. Physicians should consider an approved institutional protocol before offering these medications on a routine basis. Group II includes the use of intrathecal baclofen for pain. There is anecdotal evidence that intrathecal baclofen can help pain related to spasticity but evidence that it has a broader analgesic effect is lacking. Adding intrathecal baclofen in small doses (ie, 25 to 50 g/day) to morphine can sometimes help relieve the pain of muscle spasms associated with back pain. Group III includes tetracaine, midazolam and Nmethyl-D-aspartate (NMDA) antagonists, such as dextrorphan, dextromethorphan, memantine, and ketamine. These medications have unresolved questions concerning safety, and some reports have associated their intrathecal administration to spinal cord toxicity.4 Such medications should be reserved for special circumstances or research protocols. A change from one tier-therapy to another or a change from one therapeutic approach to another within the same tier level is predicated on the assessment of therapeutic failure. An intraspinal therapy fails if pain is not well controlled, if intolerable side effects develop, or if doses of a specific treatment are required that exceed those conventionally used. When this occurs, patients should be reevaluated to clarify the etiology of the inadequate response and to determine the appropriate next step.
Intrathecal Medications for Spasticity Baclofen is the only FDA-approved medication for intrathecal use through an implantable pump for spasticity. It is not infrequent for patients to require an increase in the daily dose of intrathecal baclofen to control spasticity during the first 6 months after pump implant. Patients with spasticity related to central nervous system pathology (eg, cerebral palsy, brain or spinal cord injuries, dystonia) usually require higher dosages of intrathecal baclofen than patients with spasticity secondary to multiple sclerosis. Patients with a progressive pathology (eg, multiple sclerosis) frequently require further increases in the daily baclofen dose months to years after pump implant compared to patients with nonprogressive pathology (eg, spinal cord injury).13
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Fig 2. Side effects of intrathecal opioids.
Troubleshooting Drug-Related Complications Complications related to the medications used in the pump include side effects of drugs administered intrathecally, drug overdose, and drug withdrawal. The following is a discussion of these complications.
Side Effects of Opioids Administered Intrathecally Most side effects of intrathecally administered opioids are transient. These include sedation, nausea and vomiting, urinary retention, constipation, and pruritis. The treatment of these side effects is summarized in Figure 2. These side effects are treated
Long-Term Management
symptomatically until they abate spontaneously. They rarely require long-term management.14 Side effects that usually persist long term include peripheral edema, myoclonus, hormonal changes, and the development of granuloma. The following is a discussion of these side effects. Peripheral edema. Patients receiving intrathecal opiates therapy may develop peripheral edema, which is believed to result from vasopressin release due to cephalad spread of the opiate in the cerebrospinal fluid (CSF) and interaction with receptors in the posterior pituitary.15 Preexisting pedal edema and venous stasis before pump implant seem to be risk factors for development of this complication.16 Patients who develop peripheral edema should be evaluated for other causes. Intrathecal administration of opioids may occasionally unmask a preexisting condition such as sleep apnea or congestive heart failure. The patient may very well be developing a medical condition that causes peripheral edema independent of opioid administration. Peripheral edema can be initially treated symptomatically. Elastic stockings and diuretics may reduce symptoms. Reduction of daily opioid dose or switching to another opiate may help. Myoclonus. Clinical reports have suggested a relationship between the occurrence of myoclonus and the use of high doses of morphine.7 An elevated concentration of morphine-3-glucuronide (M3G) in the spinal fluid is believed to be responsible for the development of myoclonus.17 Symptomatic treatment includes administration of oral or intravenous muscle relaxants such as benzodiazepines. Management should include lowering the daily dose of morphine or substituting morphine with another opiate. In one study of patients receiving long-term oral opiate treatment, myoclonus was more likely to occur in those taking antidepressant or antipsychotic drugs as antiemetics or as adjuvant agents or nonsteroidal anti-inflammatory drugs for additional analgesia.18 It is possible that discontinuing supplemental medications helps to reduce myoclonus in patients receiving intrathecal opioids, but further studies are required. Hormonal changes. Long-term administration of intrathecal opiates can result in various hormonal changes in both men and women. In one study, most men and all women receiving intrathecal opioids developed hypogonadotropic hypogonadism, about 15% of patients developed central hypocorticism, and about 15% of patients developed growth hormone deficiency.19 Some female patients may develop amenorrhea after the administration of intrathecal morphine.20 These findings suggest that further investigations are required to determine the
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need for systematic endocrine work-up in these patients and the possible need for substitutive therapy. Some male patients have complained of decreased libido after long-term intrathecal administration of opioids. Several animal and human studies demonstrated that opioids lower testosterone levels and suppress penile erectile reflexes.21,22 Patients who suffer from decreased libido should be tested for low testosterone levels. These patients may respond to a decrease in their daily morphine dose or to testosterone replacement. Granuloma. Granulomas are inflammatory masses that occur at the tip of the intrathecal catheter. In general, granulomas develop infrequently and are usually discovered several months or years after implanting an intrathecal pump system that delivers opioids. Depending on their size and rate of formation, they may be discovered incidentally or after they cause symptoms of neural compression to nerve rootlets or to the spinal cord. They are usually reported with pumps delivering morphine and have not been reported in association with pumps delivering baclofen.23,24 Drug overdose. Symptoms of drug overdose should be known to physicians. Symptoms of opioid overdose include respiratory depression with or without concomitant central nervous system depression, including dizziness, sedation, euphoria, anxiety, seizures, and respiratory arrest. Symptoms of baclofen overdose include drowsiness, light-headedness, dizziness, somnolence, respiratory depression, seizure, rostral progression of hypotonia, and loss of consciousness progressing to coma. The treatment of drug overdose must be prompt (Fig 3). Attention should be directed first to support the respiratory and circulatory systems. The patient should be monitored closely, preferably in the intensive care unit. The pump should be stopped immediately. Emptying a programmable pump alone may not be adequate as the drug remaining in the tubing will continue to be delivered into the intrathecal space; however, aspirating the drug from the catheter through a pump side port ensures that no further medication is delivered into the CSF. A large volume of CSF (30 to 40 mL) should be aspirated through the pump side port or through a lumbar puncture to decrease the concentration of the drug in the intrathecal space.14 In morphine overdose, naloxone 0.4 to 2 mg intravenously (IV) is administered as intermittent bolus repeated every 2 to 3 minutes to a total of 10 mg or as a continuous drip depending on the severity of symptoms. Because the duration of the effect of IV naloxone is shorter than that of intrathecal morphine, it is important to closely monitor the patient
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Fig 3. Etiology and treatment of intrathecal drug overdose.
for symptom recurrence; repeated administration of naloxone may be necessary. There is no specific antidote for treating overdose of baclofen; however, anecdotal reports have suggested that physostigmine may reverse central side effects, notably drowsiness and respiratory depression. In adults, physostigmine is administered at 0.5 to 1 mg intramuscularly (IM) or IV, not to exceed 1 mg/min, and can be repeated every 10 to 30 minutes. In children, physostigmine is administered at 0.02 mg/kg IM or IV, not to exceed 0.5 mg/min, and can be repeated every 5 to 10 minutes, up to a maximum of 2 mg. Once treatment of overdose is instituted, investigation should be carried out to determine the cause and correct it accordingly. Drug overdose can result from several factors, which are discussed in what follows. Injection of drug through the side port: During pump refill, injecting the drug into a side port when present results in the administration of a large amount of the drug directly into the spinal fluid. This complication should be avoided if the physician carefully follows the manufacturer’s instructions for pump refill. Specifically, needles that can penetrate the screen applied over the side port should be avoided. Injection of drug into the subcutaneous tissue: Injecting the drug into the subcutaneous tissue may occur inadvertently in obese patients. If this happens, symptoms may not develop immediately after pump refill but several hours or days later. This complication should be avoided by carefully following the manufacturer’s instructions for pump refill.
During the dye study: When pump side ports are accessed for a dye study, it is important to aspirate ⬎0.5 mL through the side port before injecting the dye. This is necessary to avoid pushing the drug retained in the catheter into the spinal fluid. If aspiration cannot be achieved, the procedure should be terminated. Dose calculations: Drug overdose may result from wrong dose calculations during bridge bolus, change of drug concentration, and programming. It is important for two staff members to independently review calculations to avoid this complication. Revision of pump malfunction or change of drug in pump: Poor pain control as a result of pump malfunction or as a result of tolerance to an opioid requires escalation of the drug dose before the pump system is revised or before the opioid is replaced by a different opioid. In all cases, intrathecal drug delivery should be restarted at a lower dose of opioid, or its theoretical equianalgesic, dose to compensate for the corrected drug delivery or incomplete crosstolerance. Iatrogenic: Physicians should always question whether patients are receiving systemic medications above and beyond what is discussed. There are case reports of patients aspirating the opioid medication from the pump for systemic use.
Drug Withdrawal Symptoms of drug withdrawal should be well known to physicians managing the pump. This is especially true for baclofen-filled pumps, where drug
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Fig 4. Treatment of intrathecal baclofen drug withdrawal. Asterisk: airway, breathing, circulation.
withdrawal can be life-threatening. The treatment of drug withdrawal is twofold: (1) to treat the patient’s symptoms; and (2) to investigate the cause of withdrawal. Figs 4 and 5. Opioid withdrawal. Withdrawal symptoms of opioids include pain, insomnia, irritability, and autonomic signs, such as hypertension, tachycardia, tachypnea, diarrhea, and piloerection.25 Opioid withdrawal can be treated by oral, intramuscular, or intravenous replacement of morphine. Clonidine (oral or patch) can decrease symptoms of sympathetic hyperactivity associated with opioid withdrawal.
Baclofen withdrawal. Baclofen withdrawal can be serious and even life-threatening.26 Symptoms of baclofen withdrawal include increased spasticity, pruritis without rash, paresthesias, fever, and altered mental state. In advanced cases, patients may have exaggerated rebound spasticity and muscle rigidity, rhabdomyolysis, and multiple-organ failure. The condition may resemble autonomic dysreflexia, sepsis, malignant hyperthermia, and neuroleptic-malignant syndrome. Several physicians routinely replace programmable pumps filled with baclofen as these pumps approach their life expectancy and before symptoms develop.
Fig 5. Causes of drug withdrawal.
16 Seminars in Pain Medicine Vol. 2 No. 1 March 2004 When baclofen withdrawal is suspected, treatment should be prompt. Depending on the severity of clinical symptoms, the following measures are needed: (1) cardiopulmonary and respiratory support, as the patient should be followed closely in a monitored setting or the intensive care unit; (2) reinstitution of baclofen intrathecally through an indwelling catheter; (3) administration of intravenous benzodiazepines and sometimes dantrolene if rigidity is present; and (4) close follow-up for the development of myoglobinuria. Serial creatinine phosphokinase (CPK) measurements and renal function tests are recommended to monitor for the development of renal failure. Administration of mannitol may be necessary to perfuse the kidneys.21 Once the treatment of drug withdrawal is instituted, the physician should investigate causal factors. These are discussed in what follows. Expired battery (pump interrogation): Interrogating the pump can help determine whether there is a problem with drug delivery. An expired battery is easily detected. Low alarm volume: The present investigator has frequently observed that some patients develop symptoms of drug withdrawal as the pump approaches an alarm residual volume of 2 mL. It appears that drug delivery may decrease at drug residual volumes of between 2 and 4 mL in some programmable pumps. An increase in the alarm volume to 4 mL in these patients prevents symptoms from recurring. Pump malfunction: Pump malfunction should be suspected in patients with a stable course of pain control and who suddenly or gradually develop symptoms of drug withdrawal. Pump malfunction can result from the catheter migrating or breaking, the catheter leaking or disconnecting, or the pump battery expiring or malfunctioning. Drug delivery may also be blocked from a kink in the catheter. To investigate pump malfunction the physician should obtain a plain X-ray of the system, which can help identify catheter migration, kink, or disconnection. The physician should be aware of the model and type of the implanted system to avoid misinterpreting the X-ray finding. For example, in some pump models, the connector between the intrathecal catheter and the pump is partially radiolucent, giving a false impression that the intrathecal catheter is disconnected. A drug residual volume that exceeds the expected drug residual volume by ⬎25% implies that the drug is not delivered as determined. When pump malfunction is suspected and imaging studies do not show abnormal findings, a dye study of the pump can be done. However, a dye study requires that a side port for the pump is available. It must be em-
phasized that the contrast should never be injected into the side port without first aspirating the drug within the catheter. Aspirating 1 mL through the side port ensures that no drug in the catheter is pushed into the intrathecal space as the contrast is injected. If a malfunction of a programmable pump itself is suspected, a rotor test can determine whether there is an internal mechanical failure. The details on performing a rotor test can be obtained from the manufacturer.
Troubleshooting Pump-Related Complications Long-term complications related to the pump include swelling around the pump and esthetic/irritation problems related to the position of the pump.
Swelling Around the Pump Implant Swelling that develops long term around a pump is usually secondary to either hygroma or infection. Hygroma is suspected if the swelling is not accompanied by tenderness, erythema, or fever. Hygroma. Most CSF leaks occur during the postoperative period; however, some patients may have symptoms related to CSF leak thereafter if the catheter is disconnected, broken, migrated, or punctured during pump refill. Unlike CSF leaks that occur postoperatively, CSF leaks that occur long term invariably require surgical revision of the pump system. The system needs to be investigated by plain X-ray or dye study to identify the source of the leak. Until the pump is revised, symptoms are treated symptomatically. Patients who have headache may benefit from laying down flat with hydration and some caffeine. Any leakage of spinal fluid outside the skin should be treated aggressively. Patients should either be taken to the operating room to revise the pump system or at least have the wound resutured, then be started on antibiotics until the system is surgically revised (Fig 6). Infection. Infection of the pump system rarely occurs beyond the perioperative period. Nevertheless, infections infrequently occur long term after pump refills or for no obvious reason. Infections that occur beyond the perioperative period are rarely simple superficial wound infections and most commonly require aggressive treatment. Patients who develop swelling around the pump associated with tenderness and possibly mild fever should be treated with intravenous antibiotics. The pump pocket can be aspirated and fluid sent for culture. The pump itself, however, should not be accessed to avoid introduc-
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Fig 6. Treatment of swelling around the pump.
ing bacteria into the pump and thereafter into the spinal fluid from an infected surrounding pocket. Patients who are febrile, have a stiff neck or headache, and appear ill should be treated for meningitis. A spinal tap will confirm the diagnosis. Meningitis is best treated by explanting the pump and administering IV antibiotics. Although there have been case reports of patients successfully treated for spinal meningitis with intrathecal antibiotics administered through the pump side port, the present investigator recommends explanting the system as a more definitive and safer approach (Fig 6). The timing for reimplanting a pump system after explanting an infected system depends on the severity of the infection and the clinical symptoms. A new pump system can be implanted on the opposite side of the abdominal wall as early as 2 weeks after explanting an infected pump and administering IV antibiotics. I recommend against implanting a new pump system within the same pocket of previous infection. If this must be done, I further recommend waiting at least 6 months after the infection is cleared before implanting the new pump. Pump Malposition Some patients, especially those who lose weight, may complain that the pump is unsightly, painful as it pushes against the skin or rib, or flips within the
wound. Pumps that flip need to be reanchored to the fascia with nonabsorbable sutures. Pumps that push against the rib, iliac crest, or skin should be repositioned. Occasionally, pumps need to be repositioned underneath the fascia of the abdominal muscles to reduce the high profile of the pump. Management of Pain Recurrence Pain that occurs long term could be recurrence of the old pain or the development of a new pain. Sometimes the distinction is not clear. Loss of pain relief. It is not uncommon for patients with opioid- or baclofen-filled pumps to require escalation of their daily drug dose for few months after surgery.27,28 Depending on the patient’s pathologic condition, some increases in the daily dose thereafter may still be required, as discussed previously. Physicians should have a clear plan regarding drug escalation and mixture to control pain, also discussed previously. Physicians should also have a clear plan regarding when to investigate for a cause for loss of pain or spasticity relief. When pain is not well controlled, physicians should treat the pain symptomatically as directed by published algorithms noted earlier. There are no specific rules that define the threshold before investigating the cause for inadequate pain relief. Guidelines that should alert the physician to look for a cause
18 Seminars in Pain Medicine Vol. 2 No. 1 March 2004
Fig 7. Investigation and management of pain recurrence.
include: (1) pain that suddenly recurs after a period of good pain control; (2) new characters of pain; (3) persistent pain despite “reasonable” changes in drugs; (4) rapid escalation of pain; (5) increased pain with dose escalation; and (6) new neurologic findings. In what follows are possible causes of loss of pain relief (Fig 7). Tolerance: Tolerance can occur for both opioids as well as baclofen.27,28 Tolerance may be treated by drug “holidays”29; however, it is my experience that this is rarely beneficial for long-term management. I believe that, at present, opioid tolerance is best treated by changing the opioid or by adding other non-opioid drugs, as discussed earlier. Baclofen can be substituted with morphine and then resumed. Pump system failure: Pump failure can be investigated by first interrogating the pump to assess the status of the battery. A residual volume that differs by ⬎25% of the volume of the drug aspirated should alert for a possible block in the system. Plain X-ray can delineate a kink, disconnection, or migration of the catheter. Injection of a nonionic contrast or radionuclide through the pump side port (dye study) may reveal a partial occlusion or a leak in the catheter or at a connection. A rotor test as recommended by the manufacturer may demonstrate a malfunction of some pumps. Pumps that malfunction need to be revised accordingly.
Granuloma: Granulomas have been associated with intrathecal opioid administration but not baclofen. Granulomas were discussed earlier. Structural: Patients who have loss of pain relief that is not managed by “reasonable” measures, occur without an inciting factor, or are associated with new neurologic findings should be investigated for a structural pathology that is progressing or developing. Management is planned accordingly. Patients with recurrent spasticity should be first investigated for factors that induce spasticity such as fever, urinary retention, bowel obstruction, and development of bed sores. Spasticity can improve by treating these conditions first rather than escalating the dose of baclofen. New pain. New pain should always be investigated promptly. Causes of new pain include drug-induced, granuloma, and structural causes (Fig 8). The latter two causes were discussed earlier. Opioid-induced hyperalgesia should be suspected when patients receive a high dose of opioid and investigation demonstrates no other cause. Opioidinduced hyperalgesia has been reported with the use of high-dose morphine and sometimes hydromorphone, but not with the use of lipophilic opioids such as fentanyl and sefentanil.4 Risk factors include the pre-existence of pathologic changes of the spine before intrathecal drug delivery.30 The clinical symp-
Long-Term Management
Fig 8. Investigation and management of new pain.
toms are usually characterized by acute onset of severe pain, hypersensitivity, autonomic abnormalities below the waist, and occasionally segmental myoclonus and piloerection.7 The syndrome is dose-related and can occur suddenly. It is postulated that it is related to high concentration of M3G metabolite, which acts on the glycine receptor, producing a strychnine-like action.7,17 Patients with suspected morphine-induced hyperalgesia should be weaned off intrathecal morphine and started on IV benzodiazepines. Supplemental oral morphine may be necessary as a temporary measure. Morphine may be restarted at a lower dose or substituted with another opioid, such as fentanyl. I believe that the development of hyperalgesia syndrome in some patients who receive small amounts of opioids can still occur if there is a partial block of CSF flow around the catheter. If this is the case, revising the catheter should help relieve symptoms. This theory remains to be proven. Bupivacaine can also cause new pain, characteristically dysesthetic and burning. This usually occurs if high concentrations of 3% to 4% intrathecal bupivacaine are used. References 1. Onofrio BM, Yaksh TL: Long-term pain relief produced by intrathecal morphine infusion in 53 patients. J Neurosurg 72:200-209, 1990 2. Yaksh TL, Onofrio BM: Retrospective consideration of the doses of morphine given intrathecally by chronic infusion in 163 patients by 19 physicians. Pain 31:211223, 1987 3. Paice JA, Penn RD, Shott S: Intraspinal morphine for chronic pain: a retrospective, multicenter study. J Pain Sympt Manag 11:71-80, 1996 4. Bennett G, Burchiel K, Buchser E, et al: Clinical guide-
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lines for intraspinal infusion: report of an expert panel. J Pain Sympt Manag 20:S37-S43, 2000 (suppl) 5. Hassenbusch SJ, Stanton-Hicks M, Covington EC, et al: Long-term intraspinal infusions of opioids in the treatment of neuropathic pain. J Pain Sympt Manag 10:527543, 1995 6. Portenoy RK, Savage SR: Clinical realities and economic considerations: special therapeutic issues in intrathecal therapy—tolerance and addiction. J Pain Sympt Manag 14:S27-S35, 1997 (suppl) 7. Parkinson SK, Bailey SL, Little WL, et al: Myoclonic seizure activity with chronic high-dose spinal opioid administration. Anesthesiology 72:743-745, 1990 8. Hassenbusch SJ, Portenoy RK: Current practices in intraspinal therapy—a survey of clinical trends and decision making. J Pain Sympt Manag 20:S4-S11, 2000 (suppl) 9. Paice J, Winkelmuller M, Burchiel K, et al: Clinical realities and economic considerations: efficacy of intrathecal pain therapy. J Pain Sympt Manag 14:S14-S26, 1997 (suppl) 10. Bennett G, Serafini M, Burchiel K, et al: Evidencebased review of the literature on intrathecal delivery of pain medication. J Pain Sympt Manag 20:S12-S36, 2000 (suppl) 11. Hildebrand KR, Elsberry DD, Hassenbusch SJ: Stability and compatibility of morphine– clonidine admixtures in an implantable infusion system. J Pain Sympt Manag 25:464-471, 2003 12. Rainov NG, Heidecke V, Burkert W: Long-term intrathecal infusion of drug combinations for chronic back and leg pain. J Pain Sympt Manag 22:862-871, 2001 13. Ordia JI, Fischer E, Adamski E, et al: Chronic intrathecal delivery of baclofen by a programmable pump for the treatment of severe spasticity. J Neurosurg 85:452-457, 1996 14. Chaney MA: Side effects of intrathecal and epidural opioids. Can J Anaesthesiol 42:891-903, 1995 15. Simantov R, Snyder SH: Opiate receptor binding in the pituitary gland. Brain Res 124:178-184, 1977 16. Aldrete JA, Couto da Silva JM: Leg edema from intrathecal opiate infusions. Eur J Pain 4:361-365, 2000 17. Sjogren P, Thunedborg LP, Christrup L, et al: Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? Six case histories. Acta Anaesthesiol Scand 42: 1070-1075, 1998 18. Potter JM, Reid DB, Shaw RJ, et al: Myoclonus associated with treatment with high doses of morphine: the role of supplemental drugs. BMJ 299:150-153, 1989 19. Abs R, Verhelst J, Maeyaert J, et al: Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab 75:2215-2222, 2000 20. Paice JA, Penn RD: Amenorrhea associated with intraspinal morphine. J Pain Sympt Manag 10:582-583, 1995 21. Gomez-Marrero J, Feria M, Mas M: Stimulation of opioid receptors suppresses penile erectile reflexes and seminal emission in rats. Pharmacol Biochem Behav 31: 393-396, 1988 22. Paice JA, Penn RD, Ryan WG: Altered sexual func-
20 Seminars in Pain Medicine Vol. 2 No. 1 March 2004 tion and decreased testosterone in patients receiving intraspinal opioids. J Pain Sympt Manag 9:126-131, 1994 23. Hassenbusch S, Burchiel K, Coffey RJ, et al: Management of intrathecal catheter-tip inflammatory masses: a consensus statement. Pain Med 3:313-323, 2002 24. Yaksh T, Hassenbusch S, Burchiel K, et al: Inflammatory masses associated with intrathecal drug infusion: a review of preclinical evidence and human data. Pain Med 3:300-312, 2002 25. Savage SR: Addiction in the treatment of pain: significance, recognition, and management. J Pain Sympt Manag 8:265-278, 1993 26. Coffey RJ, Ridgely PM: Abrupt intrathecal baclofen withdrawal: management of potentially life-threatening sequelae. Neuromodulation 4:142-146, 2001
27. Ali NM, Hoffman JS: Tolerance during long-term administration of intrathecal morphine. Conn Med 53: 266-268, 1989 28. Nielsen JF, Hansen HJ, Sunde N, et al: Evidence of tolerance to baclofen in treatment of severe spasticity with intrathecal baclofen. Clin Neurol Neurosurg 104:142-145, 2002 29. Winkelmuller M, Winkelmuller W: Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology. J Neurosurg 85:458-467, 1996 30. Kloke M, Bingel U, Seeber S: Complications of spinal opioid therapy: myoclonus, spastic muscle tone and spinal jerking. Support Care Cancer 2:249-252, 1994