快樂小藥師 Im pharmacist nichts glücklich

之前也有跟各位提過脊隨注射：

intrathecal 的藥物與用法

Case Presentation

A 61-year-old white man presents with a history of recent lower extremity pain.

The patient was diagnosed with multiple myeloma 26 months before admission and subsequently received multiple rounds of chemotherapy, including neurotoxic bortezomib and vincristine. He reports increasing bilateral lower extremity pain beginning roughly 6 months earlier, described as burning and numbing in nature. He also complains of severe sensitivity of the plantar aspect of his feet, making ambulation difficult. He has been evaluated by a neurologist and underwent an electromyographic (EMG) scan that demonstrates a mixed peripheral neuropathy and lumbar radiculopathy. Spinal magnetic resonance imaging (MRI) demonstrates multilevel lumbar degeneration. The neurosurgical consult states that the patient is not an operative candidate because of his diffuse disease. In addition, he has a history of cardiomyopathy.

The patient has been treated with multiple membrane stabilizers and tricyclic antidepressants without relief of his symptoms. His pain has also been refractory to many oral and transdermal narcotics. The patient has been admitted to the hospital by his oncologist for pain control, and pain specialists have been asked to evaluate him. He is currently receiving an intravenous (IV) basal infusion of 2 mg of morphine an hour with 2 mg available via patient-controlled analgesia every 15 minutes. He has averaged 100 mg of morphine in 24 hours. He reports 8 of 10 pain on a visual analog scale (VAS) and is experiencing some nausea.

The Pathophysiology of Pain: An Overview

As understanding of the physiology of the spinal cord has been clarified, it has become apparent that neuromodulation of the dorsal horn manipulates the perception of pain. Multiple receptors and neuromediators are involved with the activation, amplification, and inhibition of nociception. Through intrathecal (IT) delivery systems, these mediators can be used clinically to manage pain (Figure 1).

Figure 1. Systems of pain relief. Some agents act at the level of the presynaptic receptor of the primary afferent fiber, or nociceptor; others operate at the postsynaptic receptor in the dorsal horn of the spinal cord; and some work at both sites. Note that analgesics are listed according to the receptor site(s) upon which they wield their effects (SP = substance P; GLU = glutamate; NO = nitrous oxide).

Primary afferent nociceptors synapse in the dorsal horn, and this synapse is subject to significant modulation from supraspinal descending neurons, interneurons, and other primary afferents. Pain perception may be altered at each of these sites. For example, IT opioids work primarily at presynaptic levels to reduce the transmission of painful stimuli. Alpha-2 adrenergic receptors augment descending inhibitory neurons, and decrease sympathetic activity and increase depolarization thresholds of spinal neurons.^[1] The drug clonidine induces the release of spinal acetylcholine.^[2]

Intrinsic muscarinic receptors exist in the dorsal horn and are associated with inhibiting interneurons. Activation of these receptors induces analgesia, as evidenced by the injection of neostigmine, a cholinesterase inhibitor.^[3]Neostigmine prolongs the presence of acetylcholine at the receptor, causing greater descending inhibition. Local anesthetics act on sodium channels, effectively blocking neural transmission. In low concentrations, bupivacaine provides a sensory-selective block.

Adenosine binds to ligand-specific receptors in the dorsal horn. It appears to render antinociceptive effects via adrenergic mechanisms.^[2] Adenosine acts additively with clonidine.^[2]

Gamma-aminobutyric acid (GABA) has been recognized for years as an important neurotransmitter but only recently has its analgesic role in the spinal cord been examined.^[4-9] IT GABA agonists, such as baclofen, have been widely used to treat refractory spasticity, but understanding the relationship of different GABA receptors (A, B1, and B2) at the spinal cord level continues to evolve. GABA(B) receptors, important in spinally mediated pain transmission, have recently been found in lamina I.^[5] A relationship between GABA and calcium channel receptors in pain modulation has also been demonstrated in several studies.^[7,8] In an interesting study published this year, Lind and colleagues^[6]reported using IT baclofen as an adjuvant analgesic to spinal cord stimulation in 5 patients with neuropathic pain (VAS was reduced from 82 to 33). Gabapentin does not appear to bind directly to GABA receptors but may have an indirect effect either on GABA synthesis, reuptake, transporter systems, and/or inhibiting other ion channels.^[9,10] Phase 1 studies of IT gabapentin are expected to start in the near future.

Nociceptive-associated N-type calcium channels are located in the dorsal horn. A new class of peptides, known as conotoxins, block these neuronal-specific channels, inhibiting pain transmission.^[11] Ziconotide is a synthetic version of a small-molecular-weight protein produced by a giant cone snail in the South Pacific. Ziconotide blocks presynaptic calcium influx at the presynaptic terminal, thus preventing neurotransmitter vesicle fusion with the presynaptic membrane.

Clinical Advantages of IT Delivery

IT methods of controlling pain are effective and provide many clinical advantages. These include drug accountability, compliance assurance, and often a more favorable side-effect profile. Achieving satisfactory, long-term pain relief with the IT route starts with the selection of appropriate patients.

Patient Selection for IT Drug Delivery

Any patient who is being considered for implantation of an IT drug delivery system should first have failed appropriate conservative therapies. The next steps in patient selection include: confirming the indications for implantation, evaluating the psychological stability of the patient, and assessing the patient's potential to respond to this approach for pain control.

Briefly, the patient who is chosen to receive IT drug delivery for pain management should have:

• A definable cause for his or her pain;
• No surgically correctable pathology underlying the symptom(s) or risks of surgery that outweigh the potential benefit;
• Pain that has proved intractable to less complex, less invasive therapies, including conventional opioid therapy or intolerable side effects;
• Psychological clearance; and
• No contraindications to implantation.

As indicated, a comprehensive analgesic history must be part of the primary assessment of the patient. The candidate should have received appropriate analgesic trials (eg, nonsteroidal anti-inflammatory drugs for musculoskeletal pain and tricyclic antidepressants for neuropathic pain) and, if unsuccessful, treatment with opioids, titrating the dose until he or she achieves pain relief or experiences unacceptable side effects. Furthermore, combinations of opioid agents with adjuvant analgesics are often warranted before IT therapy is considered. If pain intensity continues to be unacceptable despite optimized adjuvants and opioid dose escalation, the pain is considered "intractable," and the patient can then be considered for alternative routes of drug delivery. How many opioid agents, adjuvants, combinations, and alternative therapies a patient must fail prior to consideration of IT analgesia remains a clinical decision and made on an individual basis.

Selecting the Correct Device

Selecting the correct device requires an understanding of the source of the pain. Diagnostic blocks and imaging studies can sometimes identify the specific location and source responsible for initiating the pain.

The site of the origin of the pain, along with the character, pattern, and intensity of the pain, will guide the choice of delivery system. This information is also important when choosing the pharmaceutical agent for delivery, spinal level for catheter tip location, and the method of delivery.

The commercially available devices for intraspinal access include implantable epidural and IT ports; short-term catheters with friction connectors; nonkinking, wire-supported epidural or IT catheters for prolonged intraspinal access; and long-term silicone catheters.

Catheter stiffness and stylets are important considerations because they can contribute to catheter migration from epidural to IT spaces or vice versa; stiffness may also lead to pressure at the site of delivery and nerve root paresthesias. However, device selection should be an individualized choice that concerns both the patient and the clinician. The practitioner should select the apparatus that he or she is most adept and comfortable using; this generally results in the most predictable outcomes. Advantages and disadvantages of various drug-delivery devices are listed in the Table.

Table. Pros and Cons of Selected Intraspinal Drug-Delivery Devices (Adapted From: DuPen AR, DuPen SL. Neuraxial Analgesia by Intrathecal Drug Delivery for Chronic Noncancer Pain. Medscape Neurology & Neurosurgery. December 30, 2003)

Choosing and Managing the Agents

Treatment planning is a dynamic and ongoing process. The evolving plan will be based on the patient's original pain experience and repeated assessments of the patient's responses to the treatment as it is accomplished. Individual patient responses to opioid infusions are relatively predictable; however, some patients will continue to experience pain, and a more complex treatment plan will be required in that setting. As with opioid treatments delivered systemically, patients may develop tolerance and drug doses will need to be adjusted.

As discussed, clonidine and local anesthetic agents are commonly used as adjuncts in epidural and IT analgesia.

Some medications are more suited to IT use than others. Individual suitability depends on the pharmacokinetics and pharmacodynamics of each agent, and their synergy with other drugs.

Opioids

Morphine sulfate is the most common drug used intrathecally for pain management. Both somatic and visceral types of pain are affected by IT morphine, regardless of whether the pain is nociceptive or neuropathic. Most practitioners use a 100:1 IV-to-IT dose conversion. However, larger and smaller conversions are often used, and should be titrated to efficacy. Multiple studies have demonstrated improved pain scores and quality of life with IT morphine in a variety of pain states.^[12-14]

Winkelmuller and Winkelmuller^[12] retrospectively evaluated the long-term effects of IT opioids in 120 patients with chronic nonmalignant pain, including neuropathic pain. The duration of treatment in this cohort was from 6 months to 5.7 years. They reported that 74.2% of patients experienced some pain relief from IT opioids, with an average of 67.4% reduction in pain after 6 months; 81% of their patients reported improvements in quality of life. In another study, Anderson and Burchiel^[13] implanted an intraspinal drug-delivery system in 22 patients with severe intractable nonmalignant pain. Pain types included mixed neuropathic/nociceptive, peripheral neuropathic, deafferentation, and nociceptive. During 2 years of follow-up, 50% of the patients reported a 25% reduction in VAS. Unfortunately, 20% of the patients experienced device-related complications requiring surgical intervention. A survey^[14] of 35 physicians treating 429 patients with intraspinal opioids via an implantable system found the mean percentage of pain relief to be 61%. The average dose of morphine required by patients with cancer rose quickly before leveling off; for patients with nonmalignant pain, the dose increased gradually; overall, for those analyzed at 24 months, the average doses rose no more than 2-fold after the initial titration period (from 6.84 ± .65 mg/day at 3 months to 13.19 ± 1.76 mg/day at 24 months).

Because significantly lower doses of morphine are required for IT administration, side-effect profiles are often better with IT delivery vs oral routes; however, nausea, pruritus, constipation, and urinary retention remain potential problems. One of the specific risks of IT morphine is lower extremity edema, which is correlated with a history of prepump edema. Diuretics may be required, along with support stockings and other conservative measures. Switching to another opioid may ultimately be required.

Hydromorphone is the first alternative opioid for most pain specialists.^[15] The pharmacokinetics and IT behavior of this agent are similar to that of morphine. IT hydromorphone exhibits the same expected 5:1 potency ratio as compared with morphine. All the side effects and complications seen with IT morphine have also been reported with hydromorphone, including granuloma formation.

Meperidine, methadone, and synthetic opioids have been administered successfully via the IT route; however, because of limited experience with these agents, they are usually reserved for refractory patients.

Catheter tip-associated granuloma formation is a real risk, especially when morphine concentrations above 25 mg/mL are used. This potentially devastating phenomenon must be suspected if new neurologic deficits arise or the patient experiences a sudden loss of analgesia. Human and animal studies^[16,17] found that this complication occurred only in those who had received IT opioid agents, both with and without other drugs, or in patients who were given agents that had not been approved or formulated for long-term IT use. The risk of granuloma formation rose with the opioid dose. MRI is the best modality for diagnosis. If found early, discontinuing the IT infusion can result in a reduced size or disappearance of the mass, but this can take from 2 to 5 months.^[16] If diagnosis is delayed, however, open surgical excision may be required.

Tolerance is a difficult problem with IT opioids. Tolerance appears to occur more commonly in patients with noncancer pain.^[18] A survey by Paice and colleagues^[14] found that cancer patients initiate IT opioids at a higher dose but stabilize their daily opioid requirement compared with noncancer pain patients receiving IT therapy. As mentioned, granuloma formation is correlated with rising concentrations of opioid drugs; therefore, adjuvants should be considered when higher doses are required.

Myoclonic activity has been associated with IT opioids.^[19-21] Although myoclonus is typically related to the size of the dose, considerable interpatient variability can be seen. Treatment of this complication involves discontinuing the drug, alternative treatment with GABA agonists, administering systemic opioids to prevent withdrawal, and supportive care.^[22] The addition of a systemic benzodiazepine will ease the agitation and anxiety seen with myoclonus.

Alpha-2 Agonists

Clonidine has been approved by the US Food and Drug Administration (FDA) for epidural use in patients with refractory cancer pain. This agent is an excellent adjuvant choice, especially when neuropathic complaints predominate. Doses from 1 to 2 mcg/hour are effective in combination with opioids. Titration to effective pain control may be required, usually to no more than 10 mcg/hour, although higher doses have occasionally been required.

Dry mouth, sedation, bradycardia, and hypotension are potential side effects that must be monitored. Young women and poorly controlled hypertensive patients are particularly prone to orthostatic hypotension in association with this drug. Catheter tips placed in the thoracic region promote more significant bradycardia. Patients with cardiovascular comorbidities, such as heart failure, should be trialed cautiously; personal experience with a 100-mcg bolus of IT clonidine given to an elderly gentleman who had significant cardiomyopathy required IV boluses of epinephrine in 15-mcg aliquots every 6 minutes. In this case, we initiated a dopamine infusion and successfully weaned the patient within 4 hours.

Clonidine appears to protect against morphine-associated inflammatory granuloma formation at the IT catheter tip.^[17] This makes clonidine an obvious choice for adding to highly concentrated morphine infusions. Furthermore, tolerance to prolonged IT clonidine infusions has not been reported.

Withdrawal from systemic or IT clonidine can result in life-threatening rebound hypertension. Patients receiving IT clonidine for more than 3 weeks should be withdrawn from the drug gradually or switched to systemic administration and weaned slowly. Patients who develop catheter occlusions, experience fractures, or allow their infusions to run out are at risk of rebound hypertension.

Local Anesthetics

Lower extremity and sacral complaints respond well when bupivacaine is added to the opioid infusion. Effective doses range from 0.5 to 5mg/hour, and many practitioners feel safe using bupivacaine concentrations as high as 30 mg/cc. Higher doses may result in numbness, weakness, and bowel or bladder dysfunction. In a double-blind, crossover study comparing ropivacaine and bupivacaine, ropivacaine was found to provide similar pain relief with a similar side-effect profile^[23]; however, ropivacaine cost significantly more.

Tachyphylaxis may occur with any local anesthetic infusion. Local anesthetic neurotoxicity is a concern when higher concentrations are compounded and low infusion rates are used. High tetracaine concentrations produce neurotoxicity when given as prolonged IT infusions but may be required in end-of-life situations.

Adenosine

Adenosine demonstrates antihypersensitivity and antihyperalgesic qualities. This is most evident in patients with chronic neuropathic pain, such as complex regional pain syndrome, mononeuropathy, or radiculopathy.^[24] A useful bolus dose is 1-2 mg. Experience with adenosine is limited, but we have successfully used infusions of 0.05-0.10 mg/hour. Transient back pain has been reported in patients treated with a bolus of adenosine, but interestingly, this has not occurred with healthy volunteers.^[24,25]

Cholinesterase Inhibitors

Neostigmine has been used successfully for postoperative pain.^[26] Limited experience exists with constant infusions; however, 0.5-1.0 mcg/hour have been tolerated by some patients. Nausea and vomiting limit its clinical utility.^[26]

Baclofen

For patients who have pain associated with muscle spasm and dystonia, baclofen is an effective agent either alone or in combination with other agents.^[27] Doses ranging from 3 to 20 mcg/hour have been shown to be effective in a variety of pain states, including neuropathic pain syndromes.^[28] Sedation, hypotonia with weakness, and urinary retention are possible side effects. A potentially life-threatening withdrawal syndrome has been described with abrupt cessation of IT baclofen.^[29] The symptoms are similar to neuroleptic malignant syndrome and feature fever and muscle rigidity. If this occurs, the dose should be tapered gradually and oral baclofen may be needed to mitigate the withdrawal.

Midazolam

Experience with IT midazolam in the setting of chronic pain is limited. A randomized study involving labor pain demonstrated significant efficacy when midazolam plus fentanyl was compared with fentanyl alone.^[30] Early concerns of a potential for neurotoxicity have dissuaded many from pursuing further trials. Animal studies report mixed results, with no neurotoxicity observed in cats, rats, sheep, or pigs; however, neurotoxicity was found in a rabbit model.^[31,32] A definitive, long-term infusion study by Johansen and colleagues,^[31] reported earlier this past year, found no neurotoxicity in sheep. An accompanying editorial supports the safety of IT midazolam.^[33] Thus, clinical studies have supported analgesic efficacy with midazolam but good, prospective, placebo-controlled studies are needed. Dose studies suggest that 2 mg is an appropriate bolus.^[34]

Conotoxins

Ziconitide is a potent conotoxin that has demonstrated significant analgesia when delivered spinally, which has recently been approved for marketing by the FDA. A neuronal-specific, N-gated calcium channel blocker, ziconitide works at the dorsal horn. Tolerance does not appear to develop with this agent. It has been effective in a variety of pain states, including many patients with refractory pain. A randomized, placebo-controlled trial in 111 patients with either malignant pain or AIDS-related pain demonstrated a mean pain reduction of 53% in the ziconitide group vs 18% in the placebo group.^[35] Reported side effects include nausea, urinary retention, nystagmus, ataxia, somnolence, confusion, and cranial nerve VI palsies.^[36] The probability of side effects is greatly reduced by initiating the drug at a low dose and titrating it slowly. Initial doses of 0.1 mcg/hour have been used successfully, with titration by no more than 0.5-1.0 mcg/hour each week.

Future Prospects

Cyclooxygenase Inhibitors

Cyclooxygenase (COX)-1 and COX-2 isoenzymes mediate pain and are present in the spinal cord. Ketorolac inhibits both isoenzymes. IT ketorolac studies have demonstrated a reversal of the hypersensitivity and tolerance that may develop with IT opioid administration.^[37] Intrinsic analgesia has been observed in both human and animal studies with spinal ketorolac.^[37,38] A phase 1 study in patients with chronic IT pumps reported analgesia but no dose-effect curve after receiving 0.5-, 1.0-, and 2.0-mg doses of IT ketorolac, respectively.^[39]

Gabapentin

Rodent models have demonstrated reduced mechanical allodynia and thermal hypersensitivity associated with inflammation and nerve injury.^[40] Phase 1 safety studies are expected to start in the near future. The broad success of oral gabapentin hopefully will carry over to IT applications.

Practical Algorithm

No single drug has proven effective for all pain syndromes, whether intrathecally or orally delivered. Multiple oral medications are common in pain management. IT therapy is evolving toward a polyanalgesic approach (Figure 2).

Figure 2. Update of clinical guidelines for the use of intraspinal drug infusion in pain management. Adapted from: Kang YJ, Vincler M, Li X, et al. Intrathecal ketorolac reverses hypersensitivity following acute fentanyl exposure.Anesthesiology. 2002;97:1641-1644.

Compounding

Many of the physicians who manage IT drug-delivery systems compound the drugs that are injected into the pump.^[41] With the new approval of ziconotide, it joins morphine sulfate as the only intrathecally administered drug approved for the treatment of pain. Other drugs or combinations require either compounding or off-label use.

The United States Pharmacopoeia (USP) and the American Society of Health System Pharmacists (ASHP) have published standards on compounding sterile products, which apply to the administration of neuraxial drugs.^[42,43] A compounded drug is defined as the mixing of ingredients to prepare a medication for patient use and includes admixture, dilution, repackaging, reconstitution, or other manipulation of a sterile product. For further information, the reader is referred to USP chapter 797, which became effective January 2004.^[42]

Compounding demands extremely clean facilities with personnel trained in the aseptic technique, high air-quality standards, and appropriate knowledge of sterilization and solutions stability principles. All compounded preservative-free IT preparations are classified minimally as Level 2 (medium-risk). Level 3 (high-risk) includes the preparation of all sterile solutions from nonsterile powder intended for IT use.

Other considerations for compounding include control of any bacterial endotoxins; ensuring sterility of preparation; avoiding preservatives, oxidants, and solubility enhancers; using buffers compatible with the delivery system; maintaining a physiologically appropriate pH of the solution; keeping the solution isotonic with cerebrospinal fluid; preparing the solution such that the solubility of the constituent ingredients is not affected; and verifying the chemical and physical stability of the preparation.^[42]

Special Considerations for Patients and Primary Caregivers

Most patients with IT pain pumps do not achieve complete relief of their symptoms. Rather, the goal of IT analgesia is to make the pain tolerable or manageable. VAS are helpful for looking at trends during therapy but are often incomplete for determining the efficacy of treatment. Clinically, some patients are quite content with therapy if their pain scores are at 8 on a 0-10 scale. Other patients find a score of 3 unacceptable. Similar to other pain treatment modalities, IT therapy should be individualized and titrated to effect. With pain scores, information from caregivers and family members, questionnaires, activities of daily living, and functional assessments, patients and physicians can work together to decide when they have reached a satisfactory end point vs the need to increase or decrease the daily dose, and add or remove adjuvant drugs to the delivery system.

Most IT analgesic delivery systems are managed long term by pain specialists who are familiar with the drugs and drug combinations used in these devices. During the course of therapy, some patients develop tolerance that requires either an increase in dose or change in the therapy to a different drug, or the addition of an adjuvant drug. A sudden lack of efficacy in a patient who has otherwise been stable for a prolonged period warrants further investigation. It may be that the patient has suffered an additional injury that needs further testing or evaluation of the system to make sure a disconnection, dislodgement, or kink in the catheter has not occurred. Catheter disconnections or dislodgements can be confirmed by injecting contrast directly through an exteriorized catheter or through a side port attached in an internal pump. Catheter kinks preclude injection into the catheter or side port.

Pump failures are extraordinarily rare unless battery-related. Battery function is easily tested with the programmer. The pump mechanics can be checked under fluoroscopy, looking for movement of the rotor. A rotor test provides information about the internal workings of the pump, but the rotor will continue to function in the presence of a catheter kink or disconnect.

In rare instances, loss of efficacy means the formation of an IT granuloma. In most cases, the formation of a granuloma is associated with sensory, motor, urinary, sexual, and/or bowel changes. An MRI can be performed in patients with IT catheters and pumps, although it is recommended that the pump be turned off before the test. A neurosurgical consult should be considered if a granuloma is found, although asymptomatic granulomas may resolve without surgery following discontinuation of the drug.

Case Conclusion

The patient undergoes a trial of IT morphine. He receives a single injection of 2 mg of spinal morphine. His basal IV morphine infusion is held and his patient-controlled analgesia doses are recorded. He achieves a 60% reduction in his pain, lasting 8 hours. He develops no side effects. He agrees to proceed with a permanent pump. His IT morphine infusion is started at 2.5 mg/day, and he is continued on IV morphine for breakthrough pain. His pain persists at a VAS score of greater than 4 of 10; thus, during a 4-day period his doses are titrated to 6 mg/day before he develops nausea. His pain remains 5 of 10. The pump infusion is replaced with a combination of morphine 20 mg/cc and bupivacaine 10 mg/cc. His IT infusion device is programmed to administer 5 mg of morphine/day and a resulting 2.5 mg bupivacaine/day. His pain improves substantially during the subsequent 2-day period without dose adjustment, and he currently ranks his pain 2 of 10, with resolution of his nausea. His allodynia persists, however. Adenosine is added at a dose of 0.25 mg/day, resulting in reduced sensitivity. Adenosine was chosen over clonidine because of the patient's history of cardiomyopathy. The patient remains with pain scores of 1-2 on a 0-10 VAS scale for 2 months following the change to this 3-drug IT combination.

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