Spinal analgesia for advanced cancer patients: An update

Critical Reviews in Oncology/Hematology 82 (2012) 227–232

Spinal analgesia for advanced cancer patients: An update Sebastiano Mercadante a,∗ , Giampiero Porzio b , Vittorio Gebbia c a

Anesthesia and Intensive Care Unit, Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Palermo, Italy b Department of Oncology, University of L’ Aquila, Italy c Department of Oncology, La Maddalena Cancer Center, Palermo, Italy Accepted 19 May 2011

Contents 1. 2. 3.

4.

Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Indications and frequency of use of spinal analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. IT morphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Local anesthetic–opioid combination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Thoracic–cervical IT catheter insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Specific uses of IT local anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Spinal adjuvants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract In the nineties, spinal analgesia has been described as an useful means to control pain in advanced cancer patients. The aim of this review was to update this information with a systematic analysis of studies performed in the last 10 years. 27 papers pertinent with the topic selected for review were collected according to selection criteria. Few studies added further information on spinal analgesia in last decade. Despite a lack of a clinical evidence, spinal analgesia with a combination of opioids, principally morphine, and local anesthetics may allow to achieve analgesia in patients who had been intensively treated unsuccessfully with different trials of opioids. Some adjuvant drugs such as clonidine, ketamine, betamethasone, meperidine, and ziconotide may be promising agents, but several problems have to be solved before they can be used in the daily practice. In complex pain situations, spinal analgesia should not be negated to cancer patients, and oncologists should address this group of patients to other specialists. © 2011 Elsevier Ireland Ltd. All rights reserved. Keywords: Cancer pain; Spinal analgesia; Intrathecal opioids; Local anesthetics

∗ Corresponding author at: Anesthesia and Intensive Care Unit, Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Via S.Lorenzo 312, 90146, Palermo, Italy. Tel.: +39 091 6806521; fax: +39 091 680 6906. E-mail addresses: [email protected], [email protected] (S. Mercadante).

1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2011.05.007

Most advanced cancer patients will experience painful symptoms that require opioid therapy. Even when the basic principles for the use of analgesic drugs are adhered to, some patients experience considerable side-effects from systemic opioids and/or poor pain relief. About 10–20% of patients may not respond well to standard analgesic measures, and

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thus, additional treatment options are necessary [1]. Aggressive opioid therapy using trials of different opioids in the same patient has been found to provide some benefit in pain relief [2]. However, opioid-induced hyperalgesia, particularly with increasing doses of opioids has been of concern in the last years. Moreover, some pain syndromes may strongly limit the quality of life of cancer patients. The proportion of cancer patients who may benefit from invasive therapies is small [3], but still extremely important, given the level of suffering of patients unresponsive to multiple trials of opioids, possibly receiving high doses of opioids unsuccessfully and having consistent adverse effects. Spinal analgesia may provide an useful means to control pain in such difficult situations. The rationale behind spinal opioid therapy was that administration of small amounts of opioids in close proximity to their spinal receptors would achieve high concentrations at these sites, resulting in a superior analgesia and minimization of adverse effects. Moreover, other drugs with a different mechanism, for example local anesthetics, may provide additive or synergistic analgesia. In 1999 a review on the use of spinal analgesia for the management of cancer pain provided information on status of art of this treatment, assessing the principal problems in longterm [4]. The aim of this review was to update this information with a systematic analysis of studies performed in the last 10 years. 1. Methods A systematic literature search of literature on Pub-Med database was carried out from 2000 to 2010. The terms used were “spinal” OR “intrathecal” OR “peridural” OR “neuraxial analgesia” AND “cancer pain”. Hand search of the references list of identified papers was also performed. Studies were included if performed in adult patients with chronic cancer pain. Because the expected paucity of studies available, no other limits regarding study design have been established. Case series with small number of patients were taken into consideration only when providing relevant information to be tested in larger studies. The goal was to find publications that meaningfully update the literature in the last decade as regards a previous review [4], also providing challenging new ideas to be explored in future studies. 2. Results 27 papers pertinent with the topic selected for review were collected according to selection criteria. Many papers included patients both cancer and non-malignant pain. Only one paper was a randomized-controlled trial of IT treatment with an implantable drug delivery system compared with comprehensive medical management, and two were followup analyses [5–7]. In a multicenter study, 119 cancer patients were treated with a patient-activated implanted delivery system [8].

Two retrospective studies of patients who received an implanted pump system were retrieved. A retrospective analysis was performed in 64 of 87 patients who received a trial of neuraxial analgesia, and then treated with long-term epidural and IT analgesia by an implanted pump [9]. Stability, compatibility, and safety of IT BU and opioids administered via an implantable delivery system was assessed in 56 patients with cancer pain [10]. Only three papers reported a series of cancer patients implanted with a subcutaneous port system. One reported prospective data of 55 advanced cancer patients who were unresponsive to multiple trials of systemic opioids [11], and another two were retrospective analyses of patients who were treated with IT opioids and BU [12,13] (Table 1). Fifty cancer patients who were implanted with a subcutaneous port system were assessed for risk of infection [14]. Small case reports provided interesting information about IT adjuvants. Six patients with cancer pain were included in a phase I/II study of IT clonidine [15] and a case report on the use of IT dexmedetomidine has been described [16]. Small case series dealt with the use of IT betamethasone [17,18], meperidine [19,20], and ketamine [21–23]. Controlled and double blind studies, open-label experiences as well an alarming report regarding serious toxicity have been reported on the use of IT ziconotide [24–27]. The use of cervical–thoracic catheter insertion was described in two small series [11,28]. Local anesthetics were described for breakthrough pain in patients receiving high doses of opioids intrathecally, unresponsive to systemic opioids given as breakthrough pain medication [13,29,30]. Papers were conveniently grouped for different clinical problems.

3. Discussion 3.1. Indications and frequency of use of spinal analgesia In a previous review it was stressed as in pioneer studies of spinal analgesia in cancer pain no clear indications were provided to start this complex treatment [4]. It seems that patients should optimize their treatment by using multiple trials of opioids administered by different routes and administering other indicated non-opioid analgesics and symptomatic drugs, before being defined as refractory [8,11]. After an appropriate selection, neuraxial analgesia is used in a selected number of patients with cancer pain, accounting for approximately 2% of those seen for pain consultation [9]. 3.2. IT morphine The rate and extent of opioid distribution within cerebrospinal fluid, spinal cord, epidural space, and systemic circulation after intrathecal injection has been recently assessed. Integral exposure (area under the curve divided by dose) of the spinal cord (i.e., effect compartment) to the

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Table 1 Data regarding studies of IT opioids alone or in combination with local anesthetics. Author

Design n

Protocol

Previous oral morphine equivalents (mg)

Doses at stabilization of oral morphine equivalents (mg)

Mean IT doses Initial → final

Outcome

Smith et al. [5]

Randomizedcontrolled 200

272 250

290 (4 weeks) 50

MO 2 → NA ? local anesthetics

Better P and AE after four weeks, survival at 6 months

Deer et al. [12]

Retrospective 25

Traditional management (n = 71) IT + traditional management (n = 72) IT opioids and BU

NA

NA

Improved P Less opioid consumption

Rauck et al. [8]

Open-label 149 (119) Retrospective 87 (79)

IT MO

106

NA

EP or IT (different opioids) IT MO and LBU IT opioids and BU

580

294 (8 weeks)

IT MO NA → 8 IT BU NA → 10 IT MO 1.8 → 5.1 NA

566

183 (death)

NA

NA

MO 5.7 → 19 LBU 27 → 54 MO 4.4 → 9.5 BU 8.8 → 20.5

Improved P and AE Improved P

Burton et al. [9]

Mercadante et al. [11]

55 (45)

Pasutharnchat et al. [13]

Open-label Retrospective 29

Improved P Improved P

Design: in bracket number of patients with available data. IT, intrathecal; MO, morphine; BU, bupivacaine, LBU, levobupivacaine; P, pain intensity; AE, adverse effects.

opioids was highest for morphine because of its low spinal cord distribution volume and slow clearance into plasma. The integral exposure of the spinal cord to the other opioids was relatively low, but for different reasons: alfentanil has a high clearance from spinal cord into plasma, fentanyl distributes rapidly into the epidural space and fat, and sufentanil has a high spinal cord volume of distribution [31]. Thus, morphine has the best intrathecal-systemic potency ratio and still remains the opioid of choice for IT therapy. One of the most important and controversial pieces of literature in the last decade was the only existing controlled study of an implantable system to deliver IT opioids compared with traditional pain management. This trial provided impressing data, suggesting that this method had a better clinical success, with improved pain scores, significantly reduced drug toxicity scores, and improved survival [5]. In a further analysis of patients implanted as for randomization or after failure of traditional pain management, a decrease in pain intensity and toxicity was obtained [6,7]. However, there are many limitations which render the value of this trial not extensible to daily activity. The way to administer a trial (epidural or IT, injections or infusions), lack of relevant differences in pain control, unclear use of local anesthetics and their doses, patients’ selection, concomitant treatments (chemoradiotherapy), imprecise protocols about the use of systemic opioids (with minimal increases in opioid doses in the four week period of study in the traditional arm), the entity of technique-induced complications, and some statistical considerations were considered controversial issues opening a fervid debate [32,33].

The efficacy of IT morphine given through a patientactivated implantable delivery system was assessed in a large multicenter trial. Patients underwent a trial with initial doses of IT morphine by using a conversion ratio of 1/100–200 with oral morphine equivalents. About 40% of patients experienced a 50% or greater reduction in pain from baseline, and reductions in use of systemic opioids were observed [8]. In a retrospective analysis of a large number of patients epidural or IT opioids, depending on life expectancy were administered, according an institutional protocol. Very selected patients, highly tolerant to opioids, were given a trial of epidural or IT analgesia which was successful in 88% of cases. Successful patients selected for IT analgesia were then implanted with an internal pump [9]. A relevant decrease in opioid consumption and a decrease in pain intensity were reported. Of interest, patients with implanted systems did not used local anesthetics. 3.3. Local anesthetic–opioid combination Prospective and retrospective series confirmed that data about the efficacy of a combination of IT morphine and local anesthetics given by a tunneled port system. The treatment produced an improvement in analgesia and a decrease of opioid consumption in patients who were unresponsive to systemic opioids. From a larger a population with different diagnosis, 25 cancer patients treated with a combination of local anesthetics and opioids given by an IT implanted pump, were retrospectively reviewed. However, data were not distinguishable from non cancer population and low doses of

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IT bupivacaine (BU) were given (mean of the entire sample 10 mg/day) [12]. In one retrospective study survival was short, the majority of patients dying within two weeks [13]. In a larger prospective study, where more stringent protocol were used, including a strict selection of highly tolerant patients, higher doses of local anesthetics were used. Pain intensity significantly improved as well as adverse effects. These data confirm a statement of a previous review, that is the combination of IT local anesthetics and morphine provided an indisputable synergistic analgesic effect [4]. A flow of 2 mls/h was deemed to be necessary to provide a sufficient dispersion of local anesthetic–opioid mixture. This implies a limited role of implanted pumps which does not allow for high volume-high flow rate of spinally administered drugs. 3.4. Thoracic–cervical IT catheter insertion IT catheter are usually inserted into the lumbar spine for lower limb and pelvic pain. IT lines in the cervical-upper thoracic spine have been rarely reported. Catheter were inserted at thoracic [11] and cervical level [28] successfully and safely, with the obvious intent to produce segmental analgesia with local anesthetics administered in combination with opioids. 3.5. Specific uses of IT local anesthetics The role of local anesthetics for spinal analgesia has been further assessed in extreme situations, like those occurring in highly tolerant patients receiving high doses of spinal opioids and presenting episodes of breakthrough pain (BTcP). Small doses of IT levoBU were effective in few minutes and well tolerated, after even high doses of intravenous morphine failed [29,30]. IT boluses have been also reported, although no details were provided [13]. As no experience exists in this niche of patients, this treatment should be reserved in acute units providing strict surveillance. 3.6. Complications The risk of technical complication seems to be consistent in patients who were implanted with internal pumps. In one study catheter and pump revisions were necessary in 21 patients and in nine patients, respectively [5], Serious procedure-related complications with a patient-activated implanted system, nearly all related to implant or refill, were found in 25–30% of patients. The application for market approval of this device was subsequently denied [8]. Rare but serious complications were reported in another study of implantable pumps [9]. The risk of infection was examined in patients with subcutaneous port systems for IT delivery of drugs. A very low incidence of catheter-related infection (8%) was found in 50 patients when a careful handling of the system with aseptic technique was applied [14]. Prophylactic antibiotics was not deemed to be necessary. In another experience of

subcutaneous ports, however, the prophylactic use of vancomycin limited infections in a more incisive way, recording just 2/55 septic complications [11]. In a retrospective analysis technique-related complication rate was about 15% [13]. 3.7. Spinal adjuvants No new data about cholinergic agonists, somatostatin analogue, or anti-inflammatory drugs have been produced [4], and it is likely that this class of drugs are not indicated for a daily clinical use. It is thought that IT steroids produce rapid and long-lasting analgesia. IT betamethasone in doses of 1–4 mg has been proposed in two small cases series from the same authors. In the first series a single IT steroid injection provided prompt and efficient analgesia in very advanced cancer patients [17]. In the second experience ten patients received an IT injection once a week for 4 weeks. Half of the patients achieved sufficient analgesia, and clinical signs of neurotoxicity were not evidenced [18]. The use of clonidine in combination to opioids remain controversial. Only one study dealt with IT clonidine in a small series of cancer patients who were not differently evaluated from other neuropathic non-malignant pain conditions. While a substantial percentage of patients with neuropathic pain could benefit from a continuous infusion of IT clonidine, blood pressure changes, however, can be of concern [15], confirming previous observations from a well conducted controlled study reported with epidural clonidine earlier [34]. Dexmedetomidine, a clonidine analogue was beneficial as an adjuvant in cancer pain in doses of 15 mcg/d [16]. However, there is serious concern about the neurotoxicity of the drug as it might damage myelin [35]. Although meperidine is considered an obsolete drug for cancer pain, due to neurotoxicity associated with its metabolite with prolonged administration, compared to other opioids has unique local anesthetic properties, which may render this substance useful when used spinally, as an adjuvant. There are a case report and a small series which suggest the efficacy of IT meperidine [19,20] particularly in neuropathic cancer pain, although central nervous toxicity may occur following continuous IT administration of meperidine [19]. Data regarding IT ketamine are disputable. While case reports have shown that IT ketamine added to morphine and local anesthetics [21,23] provided an important analgesic effect, many concerns have been raised for the postmortem neuropathological findings after IT administration [22]. There is indeed overwhelming evidence to show that the drug has severe neurotoxic effects4, as do all compounds with NMDA antagonistic activity [36]. The current consensus is clearly that these drugs should not be used intrathecally. In the last decade a new drug for IT delivery, acting by selectively binding to N.type voltage-sensitive calcium channels, has been marketed. In the first trial 95/111 patients with refractory cancer pain were continuously infused with IT ziconotide or placebo for 5–6 days, followed by a 5-day maintenance phase for responders and crossover of nonresponders to the

S. Mercadante et al. / Critical Reviews in Oncology/Hematology 82 (2012) 227–232 Table 2 Indications for IT therapy. Incident pain limiting movement not responsive to optimization of opioid therapy Inconvenient balance between analgesia and adverse effects with sistemic therapy, after multiple opioid trials. Opioid-induced hyperalgesia

opposite treatment group. Pain intensity significantly improved in ziconotide group [25]. A large open-label, long-term trial of patients with many neurological abnormalities, included only 16 cancer patients. Although data on cancer patients were not distinguishable from nonmalignant patients, globally, in patients receiving mean doses of 8.4 mcg/d of IT ziconotide, no significant changes in pain intensity were reported while a high discontinuation rate principally due to adverse effects or lack efficacy was recorded (about 78%) [26]. In a concomitant study, 48 patients with cancer pain were infused with IT ziconotide in dose of about 4.5 mcg/d. Significant improvement in pain intensity was reported over time. Data were grouped and no specific analysis for cancer patients was performed. However, about 40% of patients discontinued treatment because of adverse effects [27]. Regardless the promising efficacy, the need of an implanted pump, timing for dose titration in patients who are presumably suffering for poor pain relief, and the high frequency of serious adverse effects are of concern in a population affected by various co-morbidities like cancer patients. It appears that ziconotide remains active within tissue for extended periods of time [24]. 4. Conclusion Despite several attempts to provide some evidence, few studies added further information on spinal analgesia in last decade. Despite a lack of a clinical evidence, spinal analgesia with a combination of opioids, principally morphine, and local anesthetics may allow to achieve analgesia in patients who had been intensively treated unsuccessfully with different trials of opioids. Appropriate indications for IT treatment in cancer patients are reported in Table 2. In such circumstances, this procedure should be not negated to cancer patients. Some adjuvant drugs such as clonidine, ketamine, betamethasone, meperidine, and ziconotide may be promising agents, but several problems have to be solved before they can be used in the daily practice. Reviewers Edoardo Arcuri, M.D., Scientific Director, Hospice Sacro Cuore-Fondazione Roma, Anesthesiology and Palliative Care, via Poerio 100, I-00143 Rome, Italy. Eric Buchser, M.D., Responsable du Centre, Hospital of Morges, Department of Anaesthesia and Pain Management, Ch. du Crêt 2, CH-1110 Morges, Switzerland.

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Conflict of interest statement No conflict of interest declared. References [1] Cherny N, Ripamonti C, Pereira J, et al. Expert Working Group of the European Association of Palliative Care Network. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 2001;19:2542–54. [2] Mercadante S, Bruera E. Opioid switching: a systemic and critical review. Cancer Treat Rev 2006;32:304–15. [3] Mercadante S. Treatment and outcome of cancer pain in advanced cancer patients followed at home. Cancer 1999;85:1849–58. [4] Mercadante S. Problems of long-term spinal opioid treatment in advanced cancer patients. Pain 1999;79:1–13. [5] Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management of refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 2002;20:4040–9. [6] Smith T, Coyne P. Implantable drug delivery system (IDDS) after failure of comprehensive medical management (CMM) can palliate symptoms in the most refractory cancer pain patients. J Pall Med 2005;8:736–42. [7] Smith T, Coyne P, Staats P, et al. An implantable drug delivery system (IDDS) for refractory cancer pain provides sustained pain control, less drug-related toxicity, and possibly better survival compared with comprehensive medical management (CMM). Ann Oncol 2005;16:825–33. [8] Rauck R, Cherry D, Boyer M, Kosek P, Dunn J, Alo K. Long-term intrathecal opioid therapy with a patient-activated, implanted delivery system for the treatment of refractory cancer pain. J Pain 2003;4:441–7. [9] Burton A, Rajagopal A, Shah H, et al. Epidural and intrathecal analgesia is effective in treating refractory cancer pain. Pain Med 2004;5:239–47. [10] Hildebrand K, Elsberry D, Deer T. Stability, compatibility, and safety of intrathecal bupivacaine administered chronically via an implantable delivery system. Clin J Pain 2001;17:239–44. [11] Mercadante S, Intravaia G, Villari P, et al. Intrathecal treatment in cancer patients unresponsive to multiple trials of systemic opioids. Clin J Pain 2007;23:793–8. [12] Deer T, Caraway D, Kim C, Dempsey C, Stewart D, McNeil K. Clinical experience with intrathecal bupivacaine in combination with opioid for the treatment of chronic pain related to failed back surgery syndrome and metastatic cancer pain of the spine. Spine J 2002;2:274–8. [13] Pasutharnchat K, Tan K, Hadi MA, Ho K. Intrathecal analgesia in patients with cancer pain—an audit in a tertiary institution. Ann Acad Med Singapore 2009;38:943–6. [14] Holmfred A, Vikerfors T, Berggren L, Gupta A. Intrathecal catheters with subcutaneous port systems in patients with severe cancer-related pain managed out of hospital: the risk of infection. J Pain Symptom Manage 2006;31:568–72. [15] Hassenbusch S, Gunes S, Wachsman S, Willis D. Intrathecal clonidine in the treatment of intractable pain: a phase I/II study. Pain Med 2002;3:85–91. [16] Ugur F, Gulcu N, Boyaci A. Intrathecal infusion therapy with dexmedetomidine-supplemented morphine in cancer pain. Acta Anaesthesiol Scand 2007;51:388. [17] Taguchi H, Oishi K, Sakamoto S, Shingu K. Intrathecal betamethasone for cancer pain in the lower half of the body: a study of its analgesic efficacy and safety. Br J Anaesth 2007;98:385–9. [18] Taguchi H, Shingu K, Okuda H, Matsumoto H. Analgesia for pelvic and perineal cancer pain by intrathecal steroid injection. Acta Anaesthesiol Scand 2002;46:190–3. [19] Vranken JH, Van der Vegt MH, Van Kan H, Kruis M. Plasma concentrations of meperidine and normeperidine following continuous intrathecal meperidine in patients with neuropathic cancer pain. Acta Anaesthesiol Scand 2005;49:665–70.

232

S. Mercadante et al. / Critical Reviews in Oncology/Hematology 82 (2012) 227–232

[20] Souter K, Davies J, Loeser J, Fitzgibbon D. Continuous intrathecal meperidine for severe refractory cancer pain. Clin J Pain 2005;21:193–6. [21] Vranken JH, van der Vegt M, Kruis M. Treatment of neuropathic cancer pain with continuous intrathecal administration of S (+)- ketamine. Acta Anaesthesiol Scand 2004;48:249–52. [22] Vranken JH, Troost D, Wegener JT, Kruis MR, van der Vegt MH. Neuropathological findings after continuous intrathecal administration of S(+) ketamine for the management of neuropathic cancer pain. Pain 2005;117:231–5. [23] Sato C, Okabe T, Nakanishi K, Sakamoto A. A case of cancer management by long-term intrathecal PCA. J Nippon Med Sch 2010;77:333–7. [24] Penn R, Paice J. Adverse effects associated with the intrathecal administration of ziconotide. Pain 2000;85:291–6. [25] Staats P, Yearwood T, Charapata S, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer and AIDS. JAMA 2004;291:63–70. [26] Wallace M, Rauck R, Fisher R, Charapata S, Ellis D, Dissanayake S. Intrathecal ziconotide for severe chronic pain: safety and tolerability of an open-label, long-term trial. Anesth Analg 2008;106:628–37. [27] Ellis D, Dissanayake S, McGuire D, et al. Continuous intrathecal infusion for ziconotide for treatment of chronic malignant and nonmalignant pain over 12 months: a prospective, open-label study. Neuromodulation 2008;11:40–9. [28] Baker L, Balls J, Regnard C, Pridie A. Cervical intrathecal analgesia for head and neck/upper limb cancer pain: six case reports. Palliat Med 2007;21:543–5. [29] Mercadante S, Arcuri E, Ferrera P, Villari P, Mangione S. Alternative treatments of breakthrough pain in patients receiving spinal analgesics for cancer pain. J Pain Symptom Manage 2005;30:485–91. [30] Mercadante S, Ferrera P, Villari P, Arcuri E. Local anesthetics for breakthrough pain in patients receiving intrathecal treatment for cancer pain management. Anesth Analg 2005;100:1540. [31] Ummenhofer WC, Arends RH, Shen DD, Bernards CM. Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil. Anesthesiology 2000;92:739–53. [32] Davis M, Walsh D, Lagman R, LeGrand S. Randomized clinical trial o fan implantable drug delivery system. J Clin Oncol 2003;21:2800–1. [33] Ripamonti C, Brunelli C. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management of refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 2003;21:2801–2. [34] Eisenach JC, Du Pen S, Dubois M, Miguel R, Allin D. Epidural clonidine analgesia for intractable cancer pain. Pain 1995;61:391–9. [35] Konakci S, Adanir T, Yilmaz G, Rezanko T. The efficacy and neurotoxicity of dexmedetomidine administered via the epidural route. Eur J Anaesthesiol 2008;25:403–9. [36] Yaksh TL, Tozier N, Horais KA, et al. Toxicology profile of N-methyld-aspartate antagonists delivered by intrathecal infusion in the canine model. Anesthesiology 2008;108:938–49.

Biographies Sebastiano Mercadante, was born on 3rd December 1955. Doctor’s degree with full marks in 1979. Specialization in Anesthesiology (1980–1983), University of Palermo; Specialization in Science of Nutrition (1984–1987), University of Palermo. – Professor of Palliative medicine, Post-graduate Master, Univesity of Palermo. Director of Anesthesia & Intensive Care Unit, Pain Relief & Palliative Care Unit, La Maddalena Clinic for Cancer, Palermo, Italy and Professor of Palliative Medicine at University of Palermo. More than 400 hundred lectures at national and international congresses. Associated Editor, editorial Board and/or referee of more than 30 international peer-reviewed journals in the field of pain and symptom management, and anesthesiology. More than 300 papers published in peer-reviewed international journals and author of more than 40 chapters and books. Winner of award of excellence in scientific research, American Academy of Hospice and palliative medicine, Boston 2010. Giampiero Porzio was born in Chieti on 1st February 1956. Degree in Medicine and Surgery, University of Chieti and specialization in Residency in Gynaecology and Obstetrics, University of L’Aquila, 1988. Vice-Director, Chief of Supportive Care Task Force, Medical Oncology Department, “San Salvatore” Hospital, L’Aquila (Italy), and Chief, Home Care Oncological Unit, “L’Aquila per la Vita” no-profit organization, L’Aquila (Italy). He has published several papers on per-reviewed journal regarding supportive and palliatice care in oncology and serves has referee for peer-reviewed journals. Vittorio Gebbia was born in Palermo on 6th September 1959. He received the medical degree in July 1983 cum laude and the PhD in Experimental oncology and hematology in 1988 at John Hopkins Cancer center, Baltimore, Maryland, USA 1985–86. At present he is Director of the medical Oncologial unit at La Maddalena Cancer Center, Palermo, Italy, and Aggregate professor of medical oncology at the University of Palermo. He is author of more than 200 publications in International peer reviewed journals.