CASE REPORT For reprint orders, please contact: [email protected]
The use of combined spinal–epidural technique to compare intrathecal ziconotide and epidural opioids for trialing intrathecal drug delivery
Practice Points
Amitabh Gulati*1, Jeffrey Loh2, Vinay Puttanniah1 & Vivek Malhotra1 For trialing purposes, a combined spinal–epidural technique can be used to compare ziconotide to an
epidural regimen when deciding which medications to use for intrathecal drug delivery. The combined spinal–epidural technique presented requires a hospital admission for up to 4 days. The combined spinal–epidural technique is a stepwise technique introducing intrathecal ziconotide at
day 1, and epidural opioids on day 2, with the addition of local anesthetic on day 3. If the patient benefits from ziconotide at day 1, this medication can be considered for intrathecal drug
delivery after implantation of the device. Usually, a 5-µg dose of intrathecal ziconotide is delivered at the trial. If a patient has a life expectancy of less than 6 months, but benefited from the ziconotide trial, intrathecal
ziconotide can be considered as a single-dose regimen for patients with an intrathecal drug device in a severe pain crisis.
SUMMARY Choosing the initial medications for intrathecal delivery is often confu sing and not standardized. We describe a novel way for using a combined spinal–epidural technique to compare two first-line medications for intrathecal delivery; ziconotide and morphine (or hydromorphone). Five patients with intractable chronic or cancer pain were elected to have an intrathecal drug delivery system implanted for pain management. Each patient was given a 3-day inpatient trial with the combined spinal–epidural technique. The Visual Analog Scale, Numerical Rating Scale, short-term McGill questionnaire and opioid consumption were monitored daily. The results were used to develop a paradigm to describe how ziconotide can be used in practice. The use of an intrathecal drug delivery system may assist in managing pain in patients with uncontrolled pain [1–3] . It is important to note that intrathecal trialing is not without controversy and, even in the new PCC guidelines, there is no consensus for trialing for cancer patients.
Currently, three medications; morphine, baclofen and ziconotide, are approved for intrathecal use by the US FDA. While baclofen is generally reserved for spasticity, both morphine and ziconotide are considered to be first-line medications for chronic and cancer pain [4] .
Department of Anesthesiology & Critical Care, Memorial Sloan–Kettering Cancer Center M308, New York, NY 10065, USA Department of Anesthesiology, Weill Medical College, Cornell University, New York, NY, USA *Author for correspondence: Tel.: +1 212 639 6851; Fax: +1 212 717 3206; [email protected] 1 2
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Pain Manage. (2013) 3(2), 123–128
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CASE REPORT Gulati, Loh, Puttanniah & Malhotra Both ziconotide and morphine, alone and in combination, are efficacious in relieving pain when administered intrathecally to chronic and cancer pain patients [5–7] . Ziconotide, a peptide antagonizing the entry of calcium into neuronal N-type voltage-sensitive calcium channels, produces potent antinociceptive effects when injected intrathecally and may have a potency 1000-fold greater than that of morphine [8,9] . However, choosing the initial medication and starting dose remains an art, with many different techniques available for the clinician [1] . Thus far, comparing the selection for the first-line use of intrathecal opioid versus ziconotide has not been reported. While there have been consensus guidelines for medications selecting and trialing patients suffering neuropathic and nociceptive pain for intrathecal drug delivery, guidelines for intrathecal drug choices and trialing remain largely anecdotal [10,11] . We present a case series detailing a novel method, using a combined spinal–epidural (CSE) technique for inpatients to select whether an opioid or ziconotide should be initially infused through an intrathecal drug delivery system. Methods Five patients suffering from severe, chronic or cancer pain were offered an intrathecal pump for pain management. The patient’s demographics and history are described in Table 1. Each patient’s pain was not well managed with escalating systemic opioids and adjuvant medications. At our institution, an epidural trial with local anesthestic and opioid for 2–3 days is the usual trialing method. We have found improvement of pain scales or reduction in medicationrelated toxicity to be sufficient indicators for
improvement of pain in patients receiving an intrathecal pump. Each patient was admitted for a 3-day trial for an intrathecal drug delivery system. After educating the patients about the potential benefits and possible side effects of ziconotide, epidural opioids, clonidine and local anesthetic, each patient was offered a CSE technique to deliver ziconotide intrathecally and an epidural trial of opioids/anesthetics. All patients had their intravenous patient-controlled analgesia or oral regimen reduced by half on the day of the trial (day 0), and the patient-controlled analgesia was weaned off by the beginning of the epidural regimen (day 1). Written consent was obtained from all patients. Institutional review board approval was obtained for a retrospective review of the collected data. Under sterile conditions, each patient was given 3–5 µg of ziconotide intrathecally through a spinal injection, at either L2–L3 or L3–L4 (day 1), via a 27-gauge spinal needle. Following ziconotide administration, an epidural catheter, under loss of resistance to air technique, was placed (at the corresponding level where the patient’s pain was primarily located, see Table 2), but was not used until 24 h after ziconotide administration. Patients 1 and 5 received lower zicontide doses owing to their history of nausea with opioid therapy. The epidural was started on day 2 with a continuous infusion of epidural opioids. To determine the starting dose of the epidural opioid regimen, the systemic opioid regimen was calculated in morphine equivalents and then converted to an hourly equivalent epidural rate. If the patient was using morphine systemically, this was the epidural medication of choice, otherwise hydromorphone was
Table 1. Demographics of five patients undergoing a combined spinal–epidural trial for intrathecal pump placement†. Patient Age (years)/sex
Disease
Pain description
1
48/male
Klippel–Trenaunay syndrome
2
61/female
3
54/male
4
53/female
5
48/male
Metastatic NSC lung cancer to the right lobe and right ribs (7 through to 10) Metastatic melanoma to the sacrum and pelvis Metastatic pancreatic cancer to the abdomen Metastatic melanoma to the abdomen
Neuropathic pain of the left lower extremity; opioids (morphine, hydromorphone and methadone) were ineffective and caused side effects Right chest wall pain worse with inspiration, requiring methadone therapy. Sedation became a significant side effect requiring an epidural trial Right buttock, inguinal and thigh pain; hydromorphone iv. PCA with minimal relief. Morphine and fentanyl were not tolerated well Mid-abdominal and back pain with side effects from opioid therapy. iv. dilaudid and morphine were used prior to epidural trial Low pubic and abdominal pain requiring methadone iv. PCA pain control. Methadone and morphine both caused intractable nausea
A noncancer patient has been included to better illustrate the use of the combined spinal–epidural technique in decision-making for the use of ziconotide. iv.: Intravenous; NSC: Non-small-cell; PCA: Patient-controlled analgesia. †
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Combined spinal–epidural technique to compare intrathecal ziconotide & epidural opioids chosen. At 48 h after the initial ziconotide dose, local anesthetic was added to the opioid dosage. If necessary, at 72 h, based on the pain response of each patient, the epidural opioid dosage was increased (we doubled the opioid concentration and maintained the current opioid flow rate) or clonidine was added to the infusion of epidural opioid and local anesthetic (Figure 1) . Epidural flow rates were titrated to effect based on Numerical Rating Scale (NRM) pain scores obtained every 4 h by the nursing services during the epidural infusion trial. Patients were asked to complete a standard questionnaire at our institution, consisting of the short-form McGill (a set of 15 neuropathic pain symptoms in the following scale; none/mild/moderate/severe), NRM (for pain level) and Visual Analog Scale (VAS; for pain level), 24 h prior to intrathecal pump trialing and in 24-h intervals. Daily opioid consumption was recorded and reported as daily intravenous morphine equivalents. A physician, not involved in the dosing regimen, recorded daily patient responses. If a patient was using opioids at baseline (day 0), the baseline and breakthrough doses (whether intravenous or by mouth) were reduced by 50% (patient 1 only had breakthrough
CASE REPORT
medications at day 0). The oral opioid regimen was weaned off as soon as possible during the trial period, usually between days 1 and 2. Adjuvant medications were unchanged during the trialing period. Following the 3-day CSE trial course, each patient’s pain response to administration of neuraxial medications was evaluated and used to decide the initial intrathecal solution and dosage for an implanted intrathecal drug delivery system. Results At the end of the trial period, four out of five patients described improvement in their pain control, with one patient reporting an improvement in toxicity (nausea). Table 3 details the NRM, VAS, short-form McGill scores and opioid consumption for all patients from day 0 through day 3 (day 4 was not included since not all patients underwent the fourth day). All five patients had minimal side effects to ziconotide (there was no nausea, dizziness or confusion reported). Patients 1, 2 and 4 showed significant pain relief with ziconotide treatment. Effectiveness was defined as a reduction in VAS or NRM scores by 50% from baseline. Patient 1 showed improvement until the third day, at which point the epidural regimen
Table 2. Initial trial doses and outcomes during combined spinal–epidural trial and follow-up. Patient Epidural/ spinal level
Ziconotide, day 1 (µg)
Narcotic, day 2
Bupivacaine, Intrathecal pump Outcome day 3 (%) medication
1
L3–L4/ L3–L4
3
Hydromorphone 0.05
2
T8–T9/ L2–L3
5
Morphine
3
L3–L4/ L3–L4
5
Hydromorphone 0.05
4
T9–T10/ L2–L3
5
Hydromorphone 0.05
5
T9–T10/ L2–L3
3
Morphine
0.05
0.075
Ziconotide
Intrathecal ziconotide 1.8 µg/day at 3 months Update: NRM 1–2/10 at 1 year Morphine Morphine 13.5 mg/day + bupivacaine 13.5 mg/ + bupivacaine day at 4 months, patient passed away comfortably with additional morphine intermediate-release tablets for breakthrough pain Hydromorphone + Hydromorphone 3 mg/day + bupivacaine bupivacaine 5 mg/day at 2 months, patient passed away comfortably with no systemic opioids Hydromorphone + Hydromorphone 3 mg/day + bupivacaine bupivacaine 12 mg/day at 2 months, patient passed away comfortably with no systemic opioids Morphine Morphine 35 mg/day + bupivacaine Bupivacaine discontinued at 3 months, patient passed away comfortably but required fentanyl iv. PCA and Ativan for comfort and end-of-life care during the last 2 weeks
Each patient’s trial dosing of ziconotide and medications used in the epidural regimen is presented. The intrathecal pump regimen after a few months of therapy and titration are also listed in the outcomes section. None of the patients had complications during both the trial and intrathecal drug delivery, no side effects occurred that were directly attributable to the intrathecal medications or device. iv.: Intravenous; L: Lumbar vertebral level; NRM: Numerical Rating Scale; PCA: Patient-controlled analgesia; T: Thoracic vertebral level.
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CASE REPORT Gulati, Loh, Puttanniah & Malhotra
Paradigm g Day 1
Ziconotide 3–5 µg
Day 2
Epidural–opioid infusion
Day 3
Epidural opioid increased or epidural opioid + local anesthetic
Day 4
Epidural opioid increased or epidural opioid + local anesthetic + clonidine
Figure 1. Flowchart representing the combined spinal–epidural trial and the changes made on a daily basis for a recommended 4-day inpatient trial for intrathecal pump placement.
was insufficient to control his pain. Patient 2 still showed some improvement with the epidural opioid regimen. Patient 3 did not show improvement of pain control until the addition of local anesthetic. Patient 4 showed similar improvements with all regimens. Finally, patient 5 did not show any significant improvement during our assessments, but when the epidural was discontinued, the patient reported that his pain was better controlled with the epidural infusion when compared with the intravenous patient-controlled analgesia and noted that his nausea was improved during the trial period. Patient 1 elected to have an intrathecal drug delivery system infused with intrathecal ziconotide as the initial medication. Although patient 2 responded better to ziconotide, she elected to have bupivacaine and morphine as her initial intrathecal medication due to her good response and comfort with opioids. Patient 3 received an intrathecal drug delivery system with intrathecal hydromorphone and bupivacaine as the initial medication. Patient 4 elected to have hydromorphone and bupivacaine as her initial intrathecal medication, even though she had a good response to ziconotide. Patient 5 chose to try management with intrathecal morphine and bupivacaine, with clonidine. He had decreased nausea when compared with systemic opioids and decided to have an intrathecal pump implant. The results are summarized in Table 2 .
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Discussion An inpatient, CSE technique allows us to compare a patient’s response to neuraxial ziconotide and opioids for the treatment of intractable pain. Since intrathecal ziconotide has a half-life of 4.2–5.3 h, being cleared effectively from the cerebrospinal f luid within 1 day, a single intrathecal injection of ziconotide, followed by the epidural administration of morphine or local anesthetics 24–48 h later allows for an active comparison between ziconotide and opioids, and has led to our initial intrathecal regimen shown in Table 4 [8] . It is acknowledged that the effects of ziconotide may last beyond its degradation (as observed in our clinic, perhaps in patient 1, and reported anecdotally). While a washout period may be warranted, for example 1 week between ziconotide treatment and epidural opioids, this would delay the implantation of the device in our cancer patients. Alternatively, intrathecal ziconotide could be delivered after the epidural is removed, but this would require two procedures. We have decided that obtaining information regarding effectiveness as quickly as possible so that an intrathecal drug delivery device can be appropriately placed and dosed is more important that waiting for a drug washout period, especially in patients with high tumor burden and life expectancies under 6 months. It is important to note that a cancer patient population may not respond to ziconotide as a noncancer patient population would. Furthermore, a direct comparison could be achieved with a spinal catheter and intrathecal drug administration. The effects of epidural administration of local anesthetic and opioid may not directly correspond to spinal administration via a catheter, and it can be argued that ziconotide and opioids can be better assessed with a spinal catheter. However, epidurals can be safely placed at the level of pain (i.e., at the thoracic level for chest wall pain), whereas spinal catheters may be more difficult to place at thoracic level (this is not a routine procedure given the risk of injuring the spinal cord with puncture of the dura mater). It is acknowledged that there may be some systemic effect of opioids from an epidural infusion of opioids; nonetheless, we have found the information useful in determining spinal effects of intrathecal infusion of opioids. Some patients may require a higher ziconotide dose or prolonged exposure to have effective pain control. Trialing ziconotide is not without controversy; however, when deciding how
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Combined spinal–epidural technique to compare intrathecal ziconotide & epidural opioids to choose intrathecal medications, we try to optimize the approach to the patient population we are testing [11–14] . Neurologic and psychiatric complications may occur at higher initial doses and prolonged exposure, although studies have shown ziconotide being safely used in cancer patients [7,15–17] . Boluses of ziconotide (as low as 3 or 4 µg) may lead to significant, but usually transient, side effects in our cancer patients. Since our initial experience with ziconotide, we consistently use 5-µg boluses for initial evaluation. Owing to the narrow therapeutic window of ziconotide, we start intrathecal ziconotide at a low infusion dose (0.5–1.0 µg per day) and titrate slowly over several weeks [14] . As a result, cancer patients may have a delay in receiving adequate pain relief, and we have tended to use intrathecal opioids. This was evident in patients 2 and 4 who wanted pain relief quickly and did not want to endure a titration period. Further exploration could include ziconotide combinations or two delivery systems. Optimally, patients who benefited from ziconotide in the trial would choose ziconotide, but we find that our patients with high tumor burden opt against the titration period, which can last for weeks. Both the sideeffect profile and the long titration period may hinder the use of ziconotide in patients with short life expectancies and in patients with already significant side effects from cancer treatments. The use of CSE has also led to an interesting development in our pain practice. In the event that a patient benefits from both the intrathecal ziconotide and epidural morphine (or hydromorphone), the opioid was selected as our initial intrathecal medication. However, these patients have responded to intrathecal ziconotide boluses through the intrathecal drug delivery device. This may be especially useful in a pain crisis that does not resolve with opioid management. Thus, in patients with high tumor burden and short life expectancy, we may consider an intrathecal ziconotide bolus to treat a pain crisis after intrathecal pump implantation.
CASE REPORT
Table 3. Outcome measures during combined spinal–epidural trial. Patient
Day
VAS
NRM
Short-form McGill
Opioid consumption (mg)
1
0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3
63.5 6.3 7.3 79.2 81.3 8.3 44.8 40 57.3 57.3 57.9 9.4 95.8 21.9 28.1 18.8 68.8 82.3 71.9 75
6 1 2 8 5 3 4 4 10 8 8 2 8 3 3 3 8 9 8 8
12/1/2/0 15/0/0/0 12/3/0/0 11/0/0/4 11/1/3/0 10/4/1/0 11/1/3/0 13/1/1/0 4/6/2/3 2/6/5/2 4/5/5/1 1/9/2/3 11/0/0/4 10/5/0/0 6/7/1/2 12/3/0/0 8/0/4/3 10/3/2/0 9/1/3/2 14/1/0/0
13 0 90 93.6 600 300 960 1035 101 75 57.6 115.6 250 120 310 260 4120 3670 3980 3480
2
3
4
5
Assessment of each patient’s daily pain using VAS (0–100), NRS (0–10), short-form McGill (none/mild/ moderate/severe neuropathic symptoms) and daily opioid consumption (reported as intravenous morphine daily equivalents in milligrams). Day 0 corresponds to preassessment and day 1 corresponds to administration of intrathecal ziconotide (after 24 h). Note, the intrathecal opioid regimen used the same medication as the epidural trial (maximum morphine equivalents prior to epidural trials are presented). NRM: Numerical Rating Scale; VAS: Visual Analog Scale.
We have reported follow-up for our patients after the trialing period with regard to their current intrathecal medication; however, we report a small sample size that was retrospectively reviewed and not blinded. Ideally, future research may involve comparing an infusion of ziconotide intrathecally for 1 month followed by an opioid regimen for 1 month. This could allow analysis for the CSE technique as a predictor of intrathecal infusion choice. Further research may elucidate the reduction of opioids or symptom improvement with intrathecal ziconotide administration. In addition, as we have progressed in developing our intrathecal trialing protocol, we have added an additional day for epidural use of clonidine.
Table 4. The use of ziconotide in patients with a newly implanted intrathecal pump, either as the initial medication or bolus dose using the intrathecal drug delivery system. Medication
Opioid effective
Opioid ineffective
Ziconotide effective
Choose opioid as initial intrathecal medication May use ziconotide for breakthough pain Choose opioid as initial intrathecal medication
Choose ziconotide as initial intrathecal medication
Ziconotide ineffective
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Continue epidural with adjuvant medications; change opioid, add clonidine or increase local anesthetic
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CASE REPORT Gulati, Loh, Puttanniah & Malhotra Thus, 72 h after ziconotide is administered, clonidine could be added to the opioid and local anesthetic solution. Additionally, clonidine could be combined with opioids or used as monotherapy. While there is no current standard in trialing medications for intrathecal pump, the CSE technique is the first comparison of opioids and ziconotide in neuroaxial management of pain syndromes. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a finan cial interest in or financial conflict with the subject matter
References 1
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Christo PJ, Mazloomdoost D. Cancer pain and analgesia. Ann. NY Acad. Sci. 1138, 278–298 (2008).
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Bannwarth B. Risk-benefit assessment of opioids in chronic noncancer pain. Drug Saf. 21(4), 283–296 (1999).
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Kumar K, Kelly M, Pirlot T. Continuous intrathecal morphine treatment for chronic pain of nonmalignant etiology: long-term benefits and efficacy. Surg. Neurol. 55(2), 79–86 (2001).
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Smith HS, Deer TR, Staats PS, Singh V, Sehgal N, Cordner H. Intrathecal drug delivery. Pain Physician 11(2 Suppl.) S89–S104 (2008). Wallace MS, Kosek PS, Staats P, Fisher R, Schultz DM, Leong M. Phase II, open-label, multicenter study of combined intrathecal morphine and ziconotide: addition of ziconotide in patients receiving intrathecal morphine for severe chronic pain. Pain Med. 9(3), 271–281 (2008). Webster LR, Fakata KL, Charapata S, Fisher R, MineHart M. Open-label, mulitcenter study of combined intrathecal morphine and ziconotide: addition of morphine in patients receiving ziconotide for severe chronic pain. Pain Med. 9(3), 282–290 (2008).
or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research The authors state that they have obtained appropriate insti tutional review board approval or have followed the princi ples outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.
Alicino I, Giglio M, Manca F, Bruno F, Puntillo F. Intrathecal combination of ziconotide and morphine for refractory cancer pain: a rapidly acting and effective choice. Pain 153(1), 245–249 (2012).
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Wermeling D. Ziconotide, an intrathecally administered N-type calcium channel antagonist for the treatment of chronic pain. Pharmacotherapy 25(8), 1084–1094 (2005).
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Staats PS, Yearwood T, Charapata SG et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer of AIDS: a randomized controlled trial. JAMA 291(1), 63–70 (2004).
10 Deer TR, Prager J, Levy R et al. Poly-
analgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation 15(5), 436–466 (2012). 11 Deer TR, Prager J, Levy R et al. Polyanalgesic
Consensus Conference-2012: recommendations on trialing for intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation 15(5), 420–435 (2012). 12 Rosenblum, SM. A randomized, multidose,
double-blind study to evaluate the analgesic response and safety of ziconotide intrathecal bolus injection in patients with severe chronic
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pain. Presented at: North American Neuromodulation Society Meeting. Las Vegas, NV, USA, December 2007 (Absract). 13 Okano D, Akbik H, Zollet R, Khan M,
Munir M. Single-shot intrathecal ziconotide to predict its pump infusion effect. Presented at: The 24th Annual Meeting of the American Academy of Pain Medicine. Orlando, FL, USA, 13–16 February 2008 (Abstract 162). 14 Burton AW, Deer T, Wallace MS, Rauck RL,
Grigsby E. Considerations and methodology for trialing ziconotide. Pain Physician 13, 23–33 (2010). 15 Rauck RL, Wallace MS, Leong MS et al.
A randomized, double-blind, placebocontrolled study of intrathecal ziconotide in adults with severe chronic pain. J. Pain Symptom Manage. 31(5), 393–406 (2006). 16 Wallace MS, Rauck RL, Fisher R,
Charapata SG, Ellis D, Dissanayake S. Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial. Anesth. Analg. 106, 628–637 (2008). 17 Dupoiron D, Bore F, Lefebvre-Kuntz D et al.
Ziconotide adverse events in patients with cancer pain: a multicenter observational study of a slow titration, multidrug protocol. Pain Physician 15(5), 395–403 (2012).
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The use of combined spinal–epidural technique to compare intrathecal ziconotide and epidural opioids for trialing intrathecal drug delivery
Practice Points
Amitabh Gulati*1, Jeffrey Loh2, Vinay Puttanniah1 & Vivek Malhotra1 For trialing purposes, a combined spinal–epidural technique can be used to compare ziconotide to an
epidural regimen when deciding which medications to use for intrathecal drug delivery. The combined spinal–epidural technique presented requires a hospital admission for up to 4 days. The combined spinal–epidural technique is a stepwise technique introducing intrathecal ziconotide at
day 1, and epidural opioids on day 2, with the addition of local anesthetic on day 3. If the patient benefits from ziconotide at day 1, this medication can be considered for intrathecal drug
delivery after implantation of the device. Usually, a 5-µg dose of intrathecal ziconotide is delivered at the trial. If a patient has a life expectancy of less than 6 months, but benefited from the ziconotide trial, intrathecal
ziconotide can be considered as a single-dose regimen for patients with an intrathecal drug device in a severe pain crisis.
SUMMARY Choosing the initial medications for intrathecal delivery is often confu sing and not standardized. We describe a novel way for using a combined spinal–epidural technique to compare two first-line medications for intrathecal delivery; ziconotide and morphine (or hydromorphone). Five patients with intractable chronic or cancer pain were elected to have an intrathecal drug delivery system implanted for pain management. Each patient was given a 3-day inpatient trial with the combined spinal–epidural technique. The Visual Analog Scale, Numerical Rating Scale, short-term McGill questionnaire and opioid consumption were monitored daily. The results were used to develop a paradigm to describe how ziconotide can be used in practice. The use of an intrathecal drug delivery system may assist in managing pain in patients with uncontrolled pain [1–3] . It is important to note that intrathecal trialing is not without controversy and, even in the new PCC guidelines, there is no consensus for trialing for cancer patients.
Currently, three medications; morphine, baclofen and ziconotide, are approved for intrathecal use by the US FDA. While baclofen is generally reserved for spasticity, both morphine and ziconotide are considered to be first-line medications for chronic and cancer pain [4] .
Department of Anesthesiology & Critical Care, Memorial Sloan–Kettering Cancer Center M308, New York, NY 10065, USA Department of Anesthesiology, Weill Medical College, Cornell University, New York, NY, USA *Author for correspondence: Tel.: +1 212 639 6851; Fax: +1 212 717 3206; [email protected] 1 2
10.2217/PMT.13.4 © 2013 Future Medicine Ltd
Pain Manage. (2013) 3(2), 123–128
part of
ISSN 1758-1869
123
CASE REPORT Gulati, Loh, Puttanniah & Malhotra Both ziconotide and morphine, alone and in combination, are efficacious in relieving pain when administered intrathecally to chronic and cancer pain patients [5–7] . Ziconotide, a peptide antagonizing the entry of calcium into neuronal N-type voltage-sensitive calcium channels, produces potent antinociceptive effects when injected intrathecally and may have a potency 1000-fold greater than that of morphine [8,9] . However, choosing the initial medication and starting dose remains an art, with many different techniques available for the clinician [1] . Thus far, comparing the selection for the first-line use of intrathecal opioid versus ziconotide has not been reported. While there have been consensus guidelines for medications selecting and trialing patients suffering neuropathic and nociceptive pain for intrathecal drug delivery, guidelines for intrathecal drug choices and trialing remain largely anecdotal [10,11] . We present a case series detailing a novel method, using a combined spinal–epidural (CSE) technique for inpatients to select whether an opioid or ziconotide should be initially infused through an intrathecal drug delivery system. Methods Five patients suffering from severe, chronic or cancer pain were offered an intrathecal pump for pain management. The patient’s demographics and history are described in Table 1. Each patient’s pain was not well managed with escalating systemic opioids and adjuvant medications. At our institution, an epidural trial with local anesthestic and opioid for 2–3 days is the usual trialing method. We have found improvement of pain scales or reduction in medicationrelated toxicity to be sufficient indicators for
improvement of pain in patients receiving an intrathecal pump. Each patient was admitted for a 3-day trial for an intrathecal drug delivery system. After educating the patients about the potential benefits and possible side effects of ziconotide, epidural opioids, clonidine and local anesthetic, each patient was offered a CSE technique to deliver ziconotide intrathecally and an epidural trial of opioids/anesthetics. All patients had their intravenous patient-controlled analgesia or oral regimen reduced by half on the day of the trial (day 0), and the patient-controlled analgesia was weaned off by the beginning of the epidural regimen (day 1). Written consent was obtained from all patients. Institutional review board approval was obtained for a retrospective review of the collected data. Under sterile conditions, each patient was given 3–5 µg of ziconotide intrathecally through a spinal injection, at either L2–L3 or L3–L4 (day 1), via a 27-gauge spinal needle. Following ziconotide administration, an epidural catheter, under loss of resistance to air technique, was placed (at the corresponding level where the patient’s pain was primarily located, see Table 2), but was not used until 24 h after ziconotide administration. Patients 1 and 5 received lower zicontide doses owing to their history of nausea with opioid therapy. The epidural was started on day 2 with a continuous infusion of epidural opioids. To determine the starting dose of the epidural opioid regimen, the systemic opioid regimen was calculated in morphine equivalents and then converted to an hourly equivalent epidural rate. If the patient was using morphine systemically, this was the epidural medication of choice, otherwise hydromorphone was
Table 1. Demographics of five patients undergoing a combined spinal–epidural trial for intrathecal pump placement†. Patient Age (years)/sex
Disease
Pain description
1
48/male
Klippel–Trenaunay syndrome
2
61/female
3
54/male
4
53/female
5
48/male
Metastatic NSC lung cancer to the right lobe and right ribs (7 through to 10) Metastatic melanoma to the sacrum and pelvis Metastatic pancreatic cancer to the abdomen Metastatic melanoma to the abdomen
Neuropathic pain of the left lower extremity; opioids (morphine, hydromorphone and methadone) were ineffective and caused side effects Right chest wall pain worse with inspiration, requiring methadone therapy. Sedation became a significant side effect requiring an epidural trial Right buttock, inguinal and thigh pain; hydromorphone iv. PCA with minimal relief. Morphine and fentanyl were not tolerated well Mid-abdominal and back pain with side effects from opioid therapy. iv. dilaudid and morphine were used prior to epidural trial Low pubic and abdominal pain requiring methadone iv. PCA pain control. Methadone and morphine both caused intractable nausea
A noncancer patient has been included to better illustrate the use of the combined spinal–epidural technique in decision-making for the use of ziconotide. iv.: Intravenous; NSC: Non-small-cell; PCA: Patient-controlled analgesia. †
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Pain Manage. (2013) 3(2)
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Combined spinal–epidural technique to compare intrathecal ziconotide & epidural opioids chosen. At 48 h after the initial ziconotide dose, local anesthetic was added to the opioid dosage. If necessary, at 72 h, based on the pain response of each patient, the epidural opioid dosage was increased (we doubled the opioid concentration and maintained the current opioid flow rate) or clonidine was added to the infusion of epidural opioid and local anesthetic (Figure 1) . Epidural flow rates were titrated to effect based on Numerical Rating Scale (NRM) pain scores obtained every 4 h by the nursing services during the epidural infusion trial. Patients were asked to complete a standard questionnaire at our institution, consisting of the short-form McGill (a set of 15 neuropathic pain symptoms in the following scale; none/mild/moderate/severe), NRM (for pain level) and Visual Analog Scale (VAS; for pain level), 24 h prior to intrathecal pump trialing and in 24-h intervals. Daily opioid consumption was recorded and reported as daily intravenous morphine equivalents. A physician, not involved in the dosing regimen, recorded daily patient responses. If a patient was using opioids at baseline (day 0), the baseline and breakthrough doses (whether intravenous or by mouth) were reduced by 50% (patient 1 only had breakthrough
CASE REPORT
medications at day 0). The oral opioid regimen was weaned off as soon as possible during the trial period, usually between days 1 and 2. Adjuvant medications were unchanged during the trialing period. Following the 3-day CSE trial course, each patient’s pain response to administration of neuraxial medications was evaluated and used to decide the initial intrathecal solution and dosage for an implanted intrathecal drug delivery system. Results At the end of the trial period, four out of five patients described improvement in their pain control, with one patient reporting an improvement in toxicity (nausea). Table 3 details the NRM, VAS, short-form McGill scores and opioid consumption for all patients from day 0 through day 3 (day 4 was not included since not all patients underwent the fourth day). All five patients had minimal side effects to ziconotide (there was no nausea, dizziness or confusion reported). Patients 1, 2 and 4 showed significant pain relief with ziconotide treatment. Effectiveness was defined as a reduction in VAS or NRM scores by 50% from baseline. Patient 1 showed improvement until the third day, at which point the epidural regimen
Table 2. Initial trial doses and outcomes during combined spinal–epidural trial and follow-up. Patient Epidural/ spinal level
Ziconotide, day 1 (µg)
Narcotic, day 2
Bupivacaine, Intrathecal pump Outcome day 3 (%) medication
1
L3–L4/ L3–L4
3
Hydromorphone 0.05
2
T8–T9/ L2–L3
5
Morphine
3
L3–L4/ L3–L4
5
Hydromorphone 0.05
4
T9–T10/ L2–L3
5
Hydromorphone 0.05
5
T9–T10/ L2–L3
3
Morphine
0.05
0.075
Ziconotide
Intrathecal ziconotide 1.8 µg/day at 3 months Update: NRM 1–2/10 at 1 year Morphine Morphine 13.5 mg/day + bupivacaine 13.5 mg/ + bupivacaine day at 4 months, patient passed away comfortably with additional morphine intermediate-release tablets for breakthrough pain Hydromorphone + Hydromorphone 3 mg/day + bupivacaine bupivacaine 5 mg/day at 2 months, patient passed away comfortably with no systemic opioids Hydromorphone + Hydromorphone 3 mg/day + bupivacaine bupivacaine 12 mg/day at 2 months, patient passed away comfortably with no systemic opioids Morphine Morphine 35 mg/day + bupivacaine Bupivacaine discontinued at 3 months, patient passed away comfortably but required fentanyl iv. PCA and Ativan for comfort and end-of-life care during the last 2 weeks
Each patient’s trial dosing of ziconotide and medications used in the epidural regimen is presented. The intrathecal pump regimen after a few months of therapy and titration are also listed in the outcomes section. None of the patients had complications during both the trial and intrathecal drug delivery, no side effects occurred that were directly attributable to the intrathecal medications or device. iv.: Intravenous; L: Lumbar vertebral level; NRM: Numerical Rating Scale; PCA: Patient-controlled analgesia; T: Thoracic vertebral level.
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125
CASE REPORT Gulati, Loh, Puttanniah & Malhotra
Paradigm g Day 1
Ziconotide 3–5 µg
Day 2
Epidural–opioid infusion
Day 3
Epidural opioid increased or epidural opioid + local anesthetic
Day 4
Epidural opioid increased or epidural opioid + local anesthetic + clonidine
Figure 1. Flowchart representing the combined spinal–epidural trial and the changes made on a daily basis for a recommended 4-day inpatient trial for intrathecal pump placement.
was insufficient to control his pain. Patient 2 still showed some improvement with the epidural opioid regimen. Patient 3 did not show improvement of pain control until the addition of local anesthetic. Patient 4 showed similar improvements with all regimens. Finally, patient 5 did not show any significant improvement during our assessments, but when the epidural was discontinued, the patient reported that his pain was better controlled with the epidural infusion when compared with the intravenous patient-controlled analgesia and noted that his nausea was improved during the trial period. Patient 1 elected to have an intrathecal drug delivery system infused with intrathecal ziconotide as the initial medication. Although patient 2 responded better to ziconotide, she elected to have bupivacaine and morphine as her initial intrathecal medication due to her good response and comfort with opioids. Patient 3 received an intrathecal drug delivery system with intrathecal hydromorphone and bupivacaine as the initial medication. Patient 4 elected to have hydromorphone and bupivacaine as her initial intrathecal medication, even though she had a good response to ziconotide. Patient 5 chose to try management with intrathecal morphine and bupivacaine, with clonidine. He had decreased nausea when compared with systemic opioids and decided to have an intrathecal pump implant. The results are summarized in Table 2 .
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Pain Manage. (2013) 3(2)
Discussion An inpatient, CSE technique allows us to compare a patient’s response to neuraxial ziconotide and opioids for the treatment of intractable pain. Since intrathecal ziconotide has a half-life of 4.2–5.3 h, being cleared effectively from the cerebrospinal f luid within 1 day, a single intrathecal injection of ziconotide, followed by the epidural administration of morphine or local anesthetics 24–48 h later allows for an active comparison between ziconotide and opioids, and has led to our initial intrathecal regimen shown in Table 4 [8] . It is acknowledged that the effects of ziconotide may last beyond its degradation (as observed in our clinic, perhaps in patient 1, and reported anecdotally). While a washout period may be warranted, for example 1 week between ziconotide treatment and epidural opioids, this would delay the implantation of the device in our cancer patients. Alternatively, intrathecal ziconotide could be delivered after the epidural is removed, but this would require two procedures. We have decided that obtaining information regarding effectiveness as quickly as possible so that an intrathecal drug delivery device can be appropriately placed and dosed is more important that waiting for a drug washout period, especially in patients with high tumor burden and life expectancies under 6 months. It is important to note that a cancer patient population may not respond to ziconotide as a noncancer patient population would. Furthermore, a direct comparison could be achieved with a spinal catheter and intrathecal drug administration. The effects of epidural administration of local anesthetic and opioid may not directly correspond to spinal administration via a catheter, and it can be argued that ziconotide and opioids can be better assessed with a spinal catheter. However, epidurals can be safely placed at the level of pain (i.e., at the thoracic level for chest wall pain), whereas spinal catheters may be more difficult to place at thoracic level (this is not a routine procedure given the risk of injuring the spinal cord with puncture of the dura mater). It is acknowledged that there may be some systemic effect of opioids from an epidural infusion of opioids; nonetheless, we have found the information useful in determining spinal effects of intrathecal infusion of opioids. Some patients may require a higher ziconotide dose or prolonged exposure to have effective pain control. Trialing ziconotide is not without controversy; however, when deciding how
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Combined spinal–epidural technique to compare intrathecal ziconotide & epidural opioids to choose intrathecal medications, we try to optimize the approach to the patient population we are testing [11–14] . Neurologic and psychiatric complications may occur at higher initial doses and prolonged exposure, although studies have shown ziconotide being safely used in cancer patients [7,15–17] . Boluses of ziconotide (as low as 3 or 4 µg) may lead to significant, but usually transient, side effects in our cancer patients. Since our initial experience with ziconotide, we consistently use 5-µg boluses for initial evaluation. Owing to the narrow therapeutic window of ziconotide, we start intrathecal ziconotide at a low infusion dose (0.5–1.0 µg per day) and titrate slowly over several weeks [14] . As a result, cancer patients may have a delay in receiving adequate pain relief, and we have tended to use intrathecal opioids. This was evident in patients 2 and 4 who wanted pain relief quickly and did not want to endure a titration period. Further exploration could include ziconotide combinations or two delivery systems. Optimally, patients who benefited from ziconotide in the trial would choose ziconotide, but we find that our patients with high tumor burden opt against the titration period, which can last for weeks. Both the sideeffect profile and the long titration period may hinder the use of ziconotide in patients with short life expectancies and in patients with already significant side effects from cancer treatments. The use of CSE has also led to an interesting development in our pain practice. In the event that a patient benefits from both the intrathecal ziconotide and epidural morphine (or hydromorphone), the opioid was selected as our initial intrathecal medication. However, these patients have responded to intrathecal ziconotide boluses through the intrathecal drug delivery device. This may be especially useful in a pain crisis that does not resolve with opioid management. Thus, in patients with high tumor burden and short life expectancy, we may consider an intrathecal ziconotide bolus to treat a pain crisis after intrathecal pump implantation.
CASE REPORT
Table 3. Outcome measures during combined spinal–epidural trial. Patient
Day
VAS
NRM
Short-form McGill
Opioid consumption (mg)
1
0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3
63.5 6.3 7.3 79.2 81.3 8.3 44.8 40 57.3 57.3 57.9 9.4 95.8 21.9 28.1 18.8 68.8 82.3 71.9 75
6 1 2 8 5 3 4 4 10 8 8 2 8 3 3 3 8 9 8 8
12/1/2/0 15/0/0/0 12/3/0/0 11/0/0/4 11/1/3/0 10/4/1/0 11/1/3/0 13/1/1/0 4/6/2/3 2/6/5/2 4/5/5/1 1/9/2/3 11/0/0/4 10/5/0/0 6/7/1/2 12/3/0/0 8/0/4/3 10/3/2/0 9/1/3/2 14/1/0/0
13 0 90 93.6 600 300 960 1035 101 75 57.6 115.6 250 120 310 260 4120 3670 3980 3480
2
3
4
5
Assessment of each patient’s daily pain using VAS (0–100), NRS (0–10), short-form McGill (none/mild/ moderate/severe neuropathic symptoms) and daily opioid consumption (reported as intravenous morphine daily equivalents in milligrams). Day 0 corresponds to preassessment and day 1 corresponds to administration of intrathecal ziconotide (after 24 h). Note, the intrathecal opioid regimen used the same medication as the epidural trial (maximum morphine equivalents prior to epidural trials are presented). NRM: Numerical Rating Scale; VAS: Visual Analog Scale.
We have reported follow-up for our patients after the trialing period with regard to their current intrathecal medication; however, we report a small sample size that was retrospectively reviewed and not blinded. Ideally, future research may involve comparing an infusion of ziconotide intrathecally for 1 month followed by an opioid regimen for 1 month. This could allow analysis for the CSE technique as a predictor of intrathecal infusion choice. Further research may elucidate the reduction of opioids or symptom improvement with intrathecal ziconotide administration. In addition, as we have progressed in developing our intrathecal trialing protocol, we have added an additional day for epidural use of clonidine.
Table 4. The use of ziconotide in patients with a newly implanted intrathecal pump, either as the initial medication or bolus dose using the intrathecal drug delivery system. Medication
Opioid effective
Opioid ineffective
Ziconotide effective
Choose opioid as initial intrathecal medication May use ziconotide for breakthough pain Choose opioid as initial intrathecal medication
Choose ziconotide as initial intrathecal medication
Ziconotide ineffective
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Continue epidural with adjuvant medications; change opioid, add clonidine or increase local anesthetic
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127
CASE REPORT Gulati, Loh, Puttanniah & Malhotra Thus, 72 h after ziconotide is administered, clonidine could be added to the opioid and local anesthetic solution. Additionally, clonidine could be combined with opioids or used as monotherapy. While there is no current standard in trialing medications for intrathecal pump, the CSE technique is the first comparison of opioids and ziconotide in neuroaxial management of pain syndromes. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a finan cial interest in or financial conflict with the subject matter
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