Intracerebroventricular Pain Treatment with Analgesic Mixtures including Ziconotide for Intractable Pain.

Intracerebroventricular (ICV) administration of opioids for control of intractable cancer pain has been used since 1982. We present here our experience of intracerebroventricular administration of pain treatments including ziconotide associated with morphine and ropivacaine for patients resistant to a conventional approach, with nociceptive, neuropathic, or mixed pain. These clinical cases were conducted with patients suffering from refractory pain, more than 6/10 on a numerical pain rating scale (NPRS) while on high-dose medical treatment and/or intolerance with significant side effects from oral medication. The baseline study visit included a physical examination and an assessment of pain intensity on a NPRS. Under general anesthesia, a neuronavigation device was used to place the catheter on the floor of the third ventricle, supported by an endoscope. Then, drugs were injected in the cerebroventricular system, through a pump (external or subcutaneous). The primary objective was to measure pain evaluation with ICV treatment after a complete withdrawal of other medications.Four patients were enrolled: 3 with intractable cancer pain and one with central neuropathic pain. The median NPRS at baseline was 9.5 [8.5; 19]. The mean NPRS after one month was 3.5 [3; 4.5]. Ziconotide was initiated at 0.48 µg/d and up to a median of 1.2 µg/d [1.0; 1.56]. The median dose of morphine and ropivacaine used initially was respectively 0.36 mg/d [0.24; 0.66] up to 0.6 mg/d [0.45; 4.63] and 1.2 mg/d [0; 2.4] up to 2.23 mg/d [1.2; 3.35]. Minor side effects were initially observed but transiently. One psychiatric agitation required discontinuation of ziconotide infusion. For intractable pain, using ziconotide by intracerebroventricular infusion seems safe and efficient, specifically for chronic neoplastic pain of cervicocephalic, thoracic, or diffuse origin and also for pain arising from a central neuropathic mechanism.

[1]  M. Schmelz,et al.  Local anesthetics take a central action in analgesia. , 2015, Pain.

[2]  D. Dupoiron,et al.  Rationale for Prospective Assays of Intrathecal Mixtures Including Morphine, Ropivacaine and Ziconotide: Prevention of Adverse Events and Feasibility in Clinical Practice. , 2015, Pain physician.

[3]  Darrin J. Lee,et al.  Intracerebroventricular opiate infusion for refractory head and facial pain. , 2014, World journal of clinical cases.

[4]  Blair H. Smith,et al.  Neuropathic pain in the general population: A systematic review of epidemiological studies , 2014, PAIN®.

[5]  T. Deer,et al.  Ziconotide: a clinical update and pharmacologic review , 2013 .

[6]  T. Yaksh,et al.  Pharmacokinetic Analysis of Ziconotide (SNX‐111), an Intrathecal N‐Type Calcium Channel Blocking Analgesic, Delivered by Bolus and Infusion in the Dog , 2012, Neuromodulation : journal of the International Neuromodulation Society.

[7]  M. Saulino,et al.  Polyanalgesic Consensus Conference 2012: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel , 2012, Neuromodulation : journal of the International Neuromodulation Society.

[8]  R. Raffa,et al.  Intracerebroventricular opioids for intractable pain. , 2012, British journal of clinical pharmacology.

[9]  M. Giglio,et al.  Intrathecal combination of ziconotide and morphine for refractory cancer pain: A rapidly acting and effective choice , 2012, PAIN.

[10]  D. Monnin,et al.  Ziconotide adverse events in patients with cancer pain: a multicenter observational study of a slow titration, multidrug protocol. , 2011, Pain physician.

[11]  T. Jensen,et al.  Central poststroke pain: A population-based study , 2011, PAIN®.

[12]  T. Deer,et al.  Ziconotide Combination Intrathecal Therapy: Rationale and Evidence , 2010, The Clinical journal of pain.

[13]  Jörn Lötsch,et al.  Ziconotide for treatment of severe chronic pain , 2010, The Lancet.

[14]  T. Soong,et al.  Nuclear localization of Cav2.2 and its distribution in the mouse central nervous system, and changes in the hippocampus during and after pilocarpine‐induced status epilepticus , 2010, Neuropathology and applied neurobiology.

[15]  C. Benedetti,et al.  Intracerebroventricular Morphine for Refractory Cancer Pain: Transitioning to the Home Setting , 2010, The American journal of hospice & palliative care.

[16]  C. Bernards,et al.  Cerebrospinal Fluid and Spinal Cord Distribution of Hyperbaric Bupivacaine and Baclofen during Slow Intrathecal Infusion in Pigs , 2010, Anesthesiology.

[17]  L. García-Larrea,et al.  Imagerie des réecepteurs opioїdes chez l’homme , 2009 .

[18]  G. Varrassi,et al.  Intrathecal Therapy: What Has Changed With the Introduction of Ziconotide , 2009, Pain practice : the official journal of World Institute of Pain.

[19]  A. Burton,et al.  Intrathecal Ziconotide for Neuropathic Pain: A Review , 2009, Pain practice : the official journal of World Institute of Pain.

[20]  F. De Conno,et al.  Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[21]  T. Deer,et al.  Intrathecal ziconotide and opioid combination therapy for noncancer pain: an observational study. , 2009, Pain physician.

[22]  L. Webster,et al.  Open-label, multicenter study of combined intrathecal morphine and ziconotide: addition of morphine in patients receiving ziconotide for severe chronic pain. , 2008, Pain medicine.

[23]  P. Staats,et al.  Phase II, open-label, multicenter study of combined intrathecal morphine and ziconotide: addition of ziconotide in patients receiving intrathecal morphine for severe chronic pain. , 2008, Pain medicine.

[24]  M. Wallace Ziconotide: a new nonopioid intrathecal analgesic for the treatment of chronic pain , 2006, Expert review of neurotherapeutics.

[25]  C. Bernards Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during Slow Intrathecal Infusion in Pigs , 2006, Anesthesiology.

[26]  L. Webster,et al.  A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. , 2006, Journal of pain and symptom management.

[27]  Hans-Georg Buchholz,et al.  High opiate receptor binding potential in the human lateral pain system , 2006, NeuroImage.

[28]  D. Wermeling,et al.  Ziconotide, an Intrathecally Administered N‐Type Calcium Channel Antagonist for the Treatment of Chronic Pain , 2005, Pharmacotherapy.

[29]  Frode Willoch,et al.  Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study , 2004, Pain.

[30]  P. Navarra,et al.  Electrophysiological and molecular evidence of L‐(Cav1), N‐ (Cav2.2), and R‐ (Cav2.3) type Ca2+ channels in rat cortical astrocytes , 2004, Glia.

[31]  Y. Matsuda,et al.  Effects of ablation of N- and R-type Ca2+ channels on pain transmission , 2002, Neuroscience Research.

[32]  L. Radbruch,et al.  Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology , 2001, Pain.

[33]  R. Penn,et al.  Adverse effects associated with the intrathecal administration of ziconotide , 2000, Pain.

[34]  R. Miguel,et al.  Interventional treatment of cancer pain: the fourth step in the World Health Organization analgesic ladder? , 2000, Cancer control : journal of the Moffitt Cancer Center.

[35]  P. Staats,et al.  Intrathecal drug therapy for chronic pain: from basic science to clinical practice. , 1999, Anesthesiology.

[36]  B Conrad,et al.  Central pain after pontine infarction is associated with changes in opioid receptor binding: a PET study with 11C-diprenorphine. , 1999, AJNR. American journal of neuroradiology.

[37]  G. Fountzilas,et al.  Intraventricular administration of morphine for control of intractable cancer pain in 90 patients. , 1996, Neurosurgery.

[38]  F. Mosteller,et al.  Comparative efficacy of epidural, subarachnoid, and intracerebroventricular opioids in patients with pain due to cancer. , 2013, The Cochrane database of systematic reviews.

[39]  I. Curelaru,et al.  Continuous Intracisternal and High Cervical Intrathecal Bupivacaine Analgesia in Refractory Head and Neck Pain , 1996, Anesthesiology.

[40]  T. Cramond,et al.  Intraventricular Morphine for Intractable Pain of Advanced Cancer , 1994 .

[41]  J. Guieu,et al.  Intracerebroventricular morphine, analgesia, and nociceptive spinal reflexes , 1994, The Lancet.

[42]  R. Candrina,et al.  Intraventricular octreotide for cancer pain. , 1992, Journal of neurosurgery.

[43]  S. L. Lu,et al.  Clinical application of a patient-controlled apparatus for ventricular administration of morphine in intractable pain: report of 28 cases. , 1991, Neurosurgery.

[44]  M. Debray,et al.  Morphine pharmacokinetics and pain assessment after intracerebroventricular administration in patients with terminal cancer , 1991, Clinical pharmacology and therapeutics.

[45]  J. G. Todd,et al.  Intraventricular diamorphine via an Ommaya shunt for intractable cancer pain. , 1990, British journal of anaesthesia.

[46]  T. Lee,et al.  Intraventricular morphine for intractable craniofacial pain. , 1990, Singapore medical journal.

[47]  R. Dewitty,et al.  Long-term intraventricular infusion of morphine for intractable pain in cancer of the head and neck. , 1990, Neurosurgery.

[48]  Y. Ha,et al.  Intraventricular or epidural injection of morphine for severe pain , 1989, Neurochirurgia.

[49]  F. Meyers,et al.  Intraventricular morphine administered by hospice nurses to a patient with intractable pain , 1989, The American journal of hospice care.

[50]  Y. Lazorthes Intracerebroventricular Administration of Morphine for Control of Irreducible Cancer Pain , 1988, Annals of the New York Academy of Sciences.

[51]  Victor W. Pike,et al.  Regional cerebral opioid receptor studies with [11C]diprenorphine in normal volunteers , 1988, Journal of Neuroscience Methods.

[52]  C. Su,et al.  Intraventricular morphine produces pain relief, hypothermia, hyperglycaemia and increased prolactin and growth hormone levels in patients with cancer pain , 1987, Journal of Neurology.

[53]  P. Hole,et al.  [Management of pain in cancer patients by intraventricular administration of morphine]. , 1987, Ugeskrift for laeger.

[54]  R. Lobato,et al.  Intraventricular morphine for intractable cancer pain: rationale, methods, clinical results , 1987, Acta anaesthesiologica Scandinavica. Supplementum.

[55]  A. Caraceni,et al.  A validation study of the WHO method for cancer pain relief , 1987, Cancer.

[56]  M. Leavens,et al.  Intraventricular morphine administration for control of chronic cancer pain , 1987, Pain.

[57]  F. Rychlicki,et al.  [Epidural and intraventricular morphine therapy in the treatment of cancer pain]. , 1986, Minerva anestesiologica.

[58]  G. Nurchi Use of intraventricular and intrathecal morphine in intractable pain associated with cancer. , 1985, Neurosurgery.

[59]  G. Marini,et al.  Intraventricular morphine in paraneoplastic painful syndrome of the cervicofacial region: experience in thirty-eight cases. , 1985, Neurosurgery.

[60]  P. Frérebeau,et al.  Intraventricular administration of morphine in patients with neoplastic intractable pain. , 1984, Surgical neurology.

[61]  R. Lobato,et al.  Intraventricular morphine for control of pain in terminal cancer patients. , 1983, Journal of neurosurgery.

[62]  J. Weston,et al.  Intrathecal and intraventricular morphine for pain in cancer patients: initial study. , 1983, Journal of neurosurgery.

[63]  M. Kuhar,et al.  Autoradiographic localization of opiate receptors in rat brain. II. The brain stem , 1977, Brain Research.

[64]  M. Kuhar,et al.  Autoradiographic localization of opiate receptors in rat brain. I. Spinal cord and lower medulla , 1977, Brain Research.

[65]  S. Snyder,et al.  Regional Distribution of Opiate Receptor Binding in Monkey and Human Brain , 1973, Nature.

[66]  A. Ommaya Subcutaneous reservoir and pump for sterile access to ventricular cerebrospinal fluid. , 1963, Lancet.

[67]  S. Abram Intrathecal combination of ziconotide and morphine for refractory cancer pain: A rapidly acting and effective choice , 2012 .

[68]  M. Smith,et al.  Cerebrospinal fluid and plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in patients before and after initiation of intracerebroventricular morphine for cancer pain management. , 1999, Anesthesia and analgesia.

[69]  F. Alesch,et al.  [Intraventricular morphine administration as a treatment possibility for patients with intractable pain]. , 1996, Wiener klinische Wochenschrift.

[70]  P. Ince,et al.  Distribution of alpha 1A, alpha 1B and alpha 1E voltage-dependent calcium channel subunits in the human hippocampus and parahippocampal gyrus. , 1996, Neuroscience.

[71]  F. Bonnet,et al.  [Cephalic cancer pain controlled by intraventricular administration of morphine and clonidine]. , 1995, Annales francaises d'anesthesie et de reanimation.

[72]  J. Hell,et al.  Biochemical properties and subcellular distribution of an N-type calcium channel alpha 1 subunit. , 1992, Neuron.

[73]  J. Opavský,et al.  Intracerebroventricular application of morphine in the treatment of intractable malignant pain. , 1990, Acta Universitatis Palackianae Olomucensis Facultatis Medicae.

[74]  S. Blond,et al.  [Intracerebroventricular morphine therapy. Apropos of 79 patients]. , 1989, Neuro-chirurgie.

[75]  Y. Lazorthes,et al.  Intracerebroventricular morphinotherapy for control of chronic cancer pain. , 1988, Progress in brain research.

[76]  R. Franco-Bourland,et al.  Intraventricular somatostatin-14, arginine vasopressin, and oxytocin: analgesic effect in a patient with intractable cancer pain. , 1987, Applied neurophysiology.

[77]  F. Mundinger,et al.  Continuous intraventricular morphine- or peptide-infusion for intractable cancer pain. , 1987, Acta neurochirurgica. Supplementum.

[78]  R. Badenes,et al.  [Intraventricular administration of morphine in the treatment of pain of neoplastic origin. Cooperative study]. , 1986, Revista espanola de anestesiologia y reanimacion.

[79]  Y. Lazorthes,et al.  Spinal versus intraventricular chronic opiate administration with implantable drug delivery devices for cancer pain. , 1985, Applied neurophysiology.

[80]  C. Batier,et al.  [Value of intraventricular morphine analgesia in intractable neoplasm pain. Apropos of 8 cases with self-administration in 4]. , 1983, Neuro-chirurgie.