Intrathecal Ziconotide for Cancer Pain Relief: When, How and Why

Anesthesia & Clinical Research Negri et al., J Anesth Clin Res 2012, 3:8 http://dx.doi.org/10.4172/2155-6148.1000227 Rapid Communication Open Access Intrathecal Ziconotide for Cancer Pain Relief: When, How and Why Pasquale De Negri*, Tiziana Tirri, Sergio Mameli and Alfonso Papa IRCCS, Centro di Riferimento, Oncologico della, Basilicata Rionero in Vulture, Italy The Polyanalgesic Consensus Conference called the intrathecal administration of opioids and ziconotide as first-line therapy for chronic cancer pain. Morphine acts on the µ-opioid receptor, linking to calcium channels via a G protein–coupled mechanism. Ziconotide, an N-type calcium channel antagonist, effective in the treatment of neuropathic, nociceptive, and mixed neuropathic/nociceptive pain [1,2] blocks calcium influx into the presynaptic nerve terminal, preventing the release of neurotransmitters into the synapse. Unlike morphine, which acts indirectly and only partially (because some of the µ-opioid receptors are not linked to N-type calcium channels), ziconotide directly inhibits the N-type calcium channel. The phenomenon of tolerance observed with opioids, given the lack of coupling of µ-opioid receptors with calcium channels, has not been observed with ziconotide because it acts directly on calcium channels. An algorithm allowing identification of the “ideal” patient for intrathecal analgesic therapy and clear information on the use of ziconotide in cancer pain are not still available. In a conference with Italian experts on intrathecal treatment of chronic cancer pain was asked them to indicate which features would make a patient eligible to receive intrathecal treatment and predict response to intrathecal analgesia. The first aspect highlighted during the conference has been the lack of guidelines on when to discontinue systemic analgesic therapy (oral or parenteral), and when to use intrathecal therapy. Based on the clinical experience of the participants, the features of cancer patients which could be of particular importance in the decision to start intrathecal analgesic therapy include: • Lack of adequate analgesic response to opioids or the need for tightly spaced increments of systemic opioid (according to some > 25% per week) • Presence of adverse events with an unacceptable impact on the quality of life of patients • Mixed neuropathic/nociceptive pain Life expectancy has not been considered a limiting factor when considering the intrathecal route because, as shown by available data in the literature [3,4]: lifespan could be significantly prolonged by appropriate pain treatment. The consensus expert panel agrees that the amount of pain relief is more important than survival itself. In conclusion, based on the expert opinion of the panel and clinical practice, intrathecal therapy seems to be indicated in the following cases: • Patients with mixed nociceptive/neuropathic pain inadequately controlled with systemic opioids (NRS> 6-7) or with intense localized pain. • Patients with adequate pain control but with adverse effects not responding to common symptomatic treatments, reducing the quality of life. Experts agree that all candidates for intrathecal analgesia should undergo a psychological/psychiatric evaluation, regardless of the drug to be used. J Anesth Clin Res ISSN: 2155-6148 JACR an open access journal Although not supported by the international literature, the experts recommend that the desired site for the tip of the implanted subarachnoid catheter should vary according to the site of pain and should preferably be placed at the site of pain within the spinal cord [5]. Once the intrathecal route has been decided upon, the question that arises is which drug should be administered. Ziconotide has been used intrathecally for treatment of mixed neuropathic/nociceptive pain, in cancer and non cancer patients [6]. Unfortunately ziconotiderelated adverse events (AE) reported from the FDA for the five years following ziconotide approval, include those of a psychiatric nature (confusion, dissociation and hallucinatory phenomena, dizziness, gait abnormalities), nausea, elevation in creatine kinase levels and rhabdomyolysis, Ziconotide has been suggested to be associated with an increased risk of suicidality, even in patients without symptoms of depression. A previous study of ziconotide use in malignant pain, using a fast titration protocol with rapid increases in ziconotide dose over 5–10 days, reported a significant improvement in pain correlated with a high discontinuation rate in the ziconotide group [6]. Another study reporting slow ziconotide titration over 3 weeks showed a significant change in pain in the ziconotide group with a lower discontinuation rate and better tolerability [7]. In these studies, the effective analgesic dose of ziconotide varied, the duration of the titration was not specified and the analgesic efficacy could not be fully achieved for several days after ziconotide dose adjustment. On the other hand patients suffering from cancer pain require quick and adequate pain relief, which precludes the use of ziconotide as monotherapy due to time-consuming titration periods. The experts do not recommend the use of ziconotide bolus during the trialing period, due to a lack of sufficient clinical experience, and express concerns about the increased incidence of adverse events. The addition of ziconotide and other IT agents for chronic non cancer pain has been described in various paper [8-11]. The experts unanimously agree on the need to use, in patients with cancer pain, an opioid in combination with ziconotide as recommended by the 2012 Consensus Conference [2]. Experts believe, basing on actual literature, that the concomitant administration of drugs with a different mechanism of action, like opioids and ziconotide at low doses, represents a therapeutic advantage particularly in cancer pain refractory to high doses of systemic opioids, due to possible synergistic interactions, allowing a reduction in the dosage of individual drugs, a lower incidence of adverse effect and a rapid pain control. In their daily experience, the experts report the absence of breakthrough pain when using ziconotide in combination with opioids. They suggest, *Corresponding author: Pasquale De Negri, IRCCS Centro di Riferimento Oncologico della Basilicata Rionero in Vulture, Italy, E-mail: [email protected] Received April 03, 2012; Accepted August 04, 2012; Published August 10, 2012 Citation: Negri PD, Tirri T, Mameli S, Papa A (2012) Intrathecal Ziconotide for Cancer Pain Relief: When, How and Why. J Anesth Clin Res 3:227. doi:10.4172/21556148.1000227 Copyright: © 2012 Negri PD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Volume 3 • Issue 8 • 1000227 Citation: Negri PD, Tirri T, Mameli S, Papa A (2012) Intrathecal Ziconotide for Cancer Pain Relief: When, How and Why. J Anesth Clin Res 3:227. doi:10.4172/2155-6148.1000227 Page 2 of 2 based on their clinical experience, the use of a starting dose of ≤ 0.05 mcg/h or ≤ 1.2 mcg/day and to carry out ziconotide titration according to the following schedule: weekly increments of ≤ 0.05 mcg/h, always maintaining a stable dose of intrathecal opioid. In the intervals between dose adjustments, patients should have free access to the use of systemic opioids or NSAIDs/acetaminophen. In the case of failure to achieve adequate pain relief with ziconotide or in the case of side effects related to the use of ziconotide, the experts recommend increasing the dose of intrathecal opioid. However with the use of an intrathecal combination therapy, is mandatory to consider drug stability as mixing drug with low stabilities requires a more frequent pump refill: morphine apparently can interfere with ziconotide stability [12,13]. Experts point out that during continuous intrathecal administration of morphine/ziconotide at low doses and with incremental increases of low magnitude, the incidence of AE is low and the decrease in pain intensity is significant. They advise that ziconotide, anyway, should never be used in psychiatric patients (major depression, bipolar disorder, etc.) as it is not possible to exclude a possible interaction between ziconotide and psychiatric drugs, which may be used to treat major depression in cancer patients. Serious cognitive adverse events related to ziconotide have been shown to be reversible with drug withdrawal, while minor adverse events required a reduction in drug dosage [14,15]. However, the experts observe that resolution of serious adverse events related to ziconotide is not immediate, can be time-varying and sometimes prolonged [16]. The panel suggests that the appearance of ziconotideinduced adverse effects does not necessarily preclude the possibility of re-using the drug, but this must be determined on an individual basis, and the panel underlines that under these circumstances ziconotide must be re-titrated [17]. clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 20: 4040-4049. 4. Deer TR, Smith HS, Burton AW, Pope JE, Doleys DM, et al. (2011) Comprehensive consensus based guidelines on intrathecal drug delivery systems in the treatment of pain caused by cancer pain. Pain Physician 14: E283-E312. 5. DeLeón Casasola O (2010) Intrathecal therapy for cancer pain management. Rev Soc Esp Dolor 3: 162–168. 6. Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, et al. (2004) Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA 291: 63-70. 7. Rauck RL, Wallace MS, Leong MS, Minehart M, Webster LR, et al. (2006) A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage 31: 393-406. 8. Deer TR, Kim C, Bowman R, Tolentino D, Stewart C, et al. (2009) Intrathecal ziconotide and opioid combination therapy for noncancer pain: an observational study. Pain Physician 12: E291-296. 9. Saulino M, Burton AW, Danyo DA, Frost S, Glanzer J, et al. (2009) Intrathecal ziconotide and baclofen provide pain relief in seven patients with neuropathic pain and spasticity: case reports. Eur J Phys Rehabil Med 45: 61-67. 10. Saulino M (2007) Successful reduction of neuropathic pain associated with spinal cord injury via of a combination of intrathecal hydromorphone and ziconotide: a case report. Spinal Cord 45: 749-752. 11. Ruíz Ortiz S, Gálvez R, Romero Cotelo J (2009) Intrathecal ziconotide combined with two other drugs in two cases of refractory spinal cord injury pain. Eur J Pain 13: 259-260. 12. Wallace MS, Yaksh TL (2000) Long-term spinal analgesic delivery: a review of the preclinical and clinical literature. Reg Anesth Pain Med 25: 117–157. 13. Alicino I, Giglio M, Manca F, Bruno F, Puntillo F (2012) Intrathecal combination of ziconotide and morphine for refractory cancer pain: a rapidly acting and effective choice. Pain 153: 245-249. References 14. EMEA (2005) Scientific discussion of ziconotide. 1. Deer T, Krames ES, Hassenbusch SJ, Burton A, Caraway D, et al. (2007) Polyanalgesic Consensus Conference 2007: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation 10: 300-328. 15. Newcomb R, Abbruscato TJ, Singh T, Nadasdi L, Davis TP, et al. (2000) Bioavailability of Ziconotide in brain: influx from blood, stability, and diffusion. Peptides 21: 491-501. 2. Deer TR, Prager J, Levy R, Rathmell J, Buchser E, et al. (2012) Polyanalgesic Consensus Conference 2012: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel. Neuromodulation. 3. Smith TJ, Staats PS, Deer T, Stearns LJ, Rauck RL, et al. (2002) Randomized 16. Thompson JC, Dunbar E, Laye RR (2006) Treatment challenges and complications with ziconotide monotherapy in established pump patients. Pain Physician 9: 147-152. 17. Webster LR, Fisher R, Charapata S, Wallace MS (2009) Long-term intrathecal ziconotide for chronic pain: an open-label study. J Pain Symptom Manage 37: 363-372. 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