Ziconotide
Encyclopedia
Ziconotide is a non-opioid
and non-NSAID analgesic
agent used for the amelioration of severe and chronic pain
. Derived from Conus magus
("Cone Snail"), it is the synthetic form
of an ω-conotoxin
peptide
.
In December 2004 the Food and Drug Administration
approved ziconotide when delivered
as an infusion into the cerebrospinal fluid
using an intrathecal
pump system
.
species Conus magus
. Scientists have been intrigued by the effects of the thousands of chemicals in marine snail toxins since the initial investigations in the late 1960s by Baldomero Olivera
. Olivera, now a professor of biology in the University of Utah
, was inspired by accounts of the deadly effects of these toxins from his childhood in the Philippines. Ziconotide was discovered in the early 1980s by University of Utah research scientist Michael McIntosh, when he was barely out of high school and working with Baldomero Olivera. Ziconotide was developed into an artificially manufactured drug by Elan Corporation. It was approved for sale under the name Prialt by the U.S. Food and Drug Administration on December 28, 2004, and by the European Commission
on February 22, 2005.
blocker
. This action inhibits the release of pro-nociceptive neurochemical
s like glutamate, calcitonin gene-related peptide
(CGRP), and substance P
in the brain
and spinal cord
, resulting in pain relief.
ly (i.e. directly into the spinal fluid). As this is by far the most expensive and invasive method of drug delivery and involves additional risks of its own, ziconotide therapy is generally considered appropriate (as evidenced by the range of use approved by the FDA in US) only for “management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies or IT morphine
”. In practice, the efficacy of ziconotide in relieving neurogenic pain remains to be established according to Prescrire Int. October, 2008.Furthermore "It is better to re-examine and, if possible, correct the reasons for opiate treatment failure rather than prescribe ziconotide."
However, this must be weighed against the high level of pain management
, both in terms of degree and length, and the apparent lack of tolerance and other signs of dependence
even after extended treatment along with the need for alternatives to other therapies that have not worked for the patient. Ziconotide is also contraindicated for patients with certain preexisting mental disorders (e.g. psychosis
) due to evidence that they are more susceptible to certain severe side effects.
, confusion, nystagmus and headache
. Others may include weakness, hypertonia
, ataxia
, abnormal vision, anorexia
, somnolence
, unsteadiness on feet, vertigo
, urinary retention, pruritis, increased sweating, diarrhea
, nausea
, vomiting
, asthenia, pyrexia, rigors, sinusitis
, muscle spasms, myalgia, insomnia
, anxiety
, amnesia, nystagmus
, tremor
, memory impairment and induced psychiatric disorders. Other side effects which are less frequent but still clinically significant include auditory and visual hallucinations, thoughts of suicide
, acute renal failure, atrial fibrilation, cardiovascular accident, sepsis, new or worsening depression
, paranoia, disorientation, meningitis
and seizures. Therefore, it is contraindicated in people with a history of psychosis
, schizophrenia
, clinical depression
, and bipolar disorder
. Recent incidents suggesting a link between intrathecal ziconotide treatment and increased risk of suicide have led to calls for strict and ongoing psychiatric monitoring of patients to avoid suicide occurring in vulnerable individuals. There is no known antidote.
Some patients who received Ziconotide therapy and suffered intolerable adverse side effects continue to suffer from these same side effects many years after discontinuation of the drug therapy in the form of "flash-backs". These "flash-backs" are equivalent in intensity to those suffered while receiving the ziconotide therapy. Weight loss and the subsequent break down of fat cells seems to trigger "flash-backs".
Corporation, plc of Ireland
. U.S. patents assigned to Elan include 5,859,186, 5,795,864, 5,770,690, 5,587,454, and 5,559,095.
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
and non-NSAID analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
agent used for the amelioration of severe and chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...
. Derived from Conus magus
Conus magus
Conus magus, common name the magical cone, is a species of sea snail, a marine gastropod mollusk in the family Conidae, the cone snails and their allies.Like all species within the genus Conus, these snails are predatory and venomous...
("Cone Snail"), it is the synthetic form
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
of an ω-conotoxin
Conotoxin
A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus Conus.Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. Conotoxins have a variety of mechanisms of actions, most of...
peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
.
In December 2004 the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
approved ziconotide when delivered
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
as an infusion into the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
using an intrathecal
Intrathecal
Intrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...
pump system
Infusion pump
An infusion pump infuses fluids, medication or nutrients into a patient's circulatory system. It is generally used intravenously, although subcutaneous, arterial and epidural infusions are occasionally used....
.
Discovery
Ziconotide or Prialt is derived from the toxin of the cone snailCone snail
Conidae is a taxonomic family of minute to quite large sea snails, marine gastropod molluscs in the superfamily Conoidea.The snails within this family are sophisticated predatory animals...
species Conus magus
Conus magus
Conus magus, common name the magical cone, is a species of sea snail, a marine gastropod mollusk in the family Conidae, the cone snails and their allies.Like all species within the genus Conus, these snails are predatory and venomous...
. Scientists have been intrigued by the effects of the thousands of chemicals in marine snail toxins since the initial investigations in the late 1960s by Baldomero Olivera
Baldomero Olivera
Baldomero Olivera is a Filipino American chemist known for discovery of many cone snail toxins important for neuroscience. These molecules, called conotoxins led to a breakthrough in the study of ion channels and neuro-muscular synapses....
. Olivera, now a professor of biology in the University of Utah
University of Utah
The University of Utah, also known as the U or the U of U, is a public, coeducational research university in Salt Lake City, Utah, United States. The university was established in 1850 as the University of Deseret by the General Assembly of the provisional State of Deseret, making it Utah's oldest...
, was inspired by accounts of the deadly effects of these toxins from his childhood in the Philippines. Ziconotide was discovered in the early 1980s by University of Utah research scientist Michael McIntosh, when he was barely out of high school and working with Baldomero Olivera. Ziconotide was developed into an artificially manufactured drug by Elan Corporation. It was approved for sale under the name Prialt by the U.S. Food and Drug Administration on December 28, 2004, and by the European Commission
European Commission
The European Commission is the executive body of the European Union. The body is responsible for proposing legislation, implementing decisions, upholding the Union's treaties and the general day-to-day running of the Union....
on February 22, 2005.
Mechanism of action
Ziconotide is a hydrophilic molecule that is freely soluble in water and is practically insoluable in methyl t-butyl ether. Ziconotide acts as a selective N-type voltage-gated calcium channelN-type calcium channel
The N-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit forms the pore through which calcium enters the cell and determines most of the channel's properties...
blocker
Calcium channel blocker
A calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with...
. This action inhibits the release of pro-nociceptive neurochemical
Neurochemical
A neurochemical is an organic molecule, such as serotonin, dopamine, or nerve growth factor, that participates in neural activity. The science of neurochemistry studies the functions of neurochemicals.-Prominent neurochemicals:...
s like glutamate, calcitonin gene-related peptide
Calcitonin gene-related peptide
Calcitonin gene related peptide is a member of the calcitonin family of peptides, which in humans exists in two forms, α-CGRP and β-CGRP. α-CGRP is a 37-amino acid peptide and is formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11...
(CGRP), and substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, resulting in pain relief.
Amino Acid Sequence
H-Cys-Lys-Gly-Lys-Gly-Ala-Lys-Cys-Ser-Arg-Leu-Met-Tyr-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Arg-Ser-Gly-Lys-Cys-NH2Therapeutic use
Due to the profound side effects or lack of efficacy when delivered through more common routes, such as orally or intravenously, ziconotide must be administered intrathecalIntrathecal
Intrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...
ly (i.e. directly into the spinal fluid). As this is by far the most expensive and invasive method of drug delivery and involves additional risks of its own, ziconotide therapy is generally considered appropriate (as evidenced by the range of use approved by the FDA in US) only for “management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies or IT morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
”. In practice, the efficacy of ziconotide in relieving neurogenic pain remains to be established according to Prescrire Int. October, 2008.Furthermore "It is better to re-examine and, if possible, correct the reasons for opiate treatment failure rather than prescribe ziconotide."
However, this must be weighed against the high level of pain management
Pain management
Pain management is a branch of medicine employing an interdisciplinary approach for easing the suffering and improving the quality of life of those living with pain. The typical pain management team includes medical practitioners, clinical psychologists, physiotherapists, occupational therapists,...
, both in terms of degree and length, and the apparent lack of tolerance and other signs of dependence
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
even after extended treatment along with the need for alternatives to other therapies that have not worked for the patient. Ziconotide is also contraindicated for patients with certain preexisting mental disorders (e.g. psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
) due to evidence that they are more susceptible to certain severe side effects.
Adverse reactions
The most common side effects are dizziness, nauseaNausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, confusion, nystagmus and headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
. Others may include weakness, hypertonia
Hypertonia
Hypertonia a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by lesions to upper motor neurons in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle...
, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, abnormal vision, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, unsteadiness on feet, vertigo
Vertigo
Vertigo is a form of dizziness.Vertigo may also refer to:* Vertigo , a 1958 film by Alfred Hitchcock**Vertigo , its soundtrack** Vertigo effect, or Dolly zoom, a special effect in film, named after the movie...
, urinary retention, pruritis, increased sweating, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, asthenia, pyrexia, rigors, sinusitis
Sinusitis
Sinusitis is inflammation of the paranasal sinuses, which may be due to infection, allergy, or autoimmune issues. Most cases are due to a viral infection and resolve over the course of 10 days...
, muscle spasms, myalgia, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, amnesia, nystagmus
Nystagmus
Nystagmus is a condition of involuntary eye movement, acquired in infancy or later in life, that may result in reduced or limited vision.There are two key forms of Nystagmus: pathological and physiological, with variations within each type. Nystagmus may be caused by congenital disorders,...
, tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, memory impairment and induced psychiatric disorders. Other side effects which are less frequent but still clinically significant include auditory and visual hallucinations, thoughts of suicide
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
, acute renal failure, atrial fibrilation, cardiovascular accident, sepsis, new or worsening depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, paranoia, disorientation, meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
and seizures. Therefore, it is contraindicated in people with a history of psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, clinical depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, and bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
. Recent incidents suggesting a link between intrathecal ziconotide treatment and increased risk of suicide have led to calls for strict and ongoing psychiatric monitoring of patients to avoid suicide occurring in vulnerable individuals. There is no known antidote.
Some patients who received Ziconotide therapy and suffered intolerable adverse side effects continue to suffer from these same side effects many years after discontinuation of the drug therapy in the form of "flash-backs". These "flash-backs" are equivalent in intensity to those suffered while receiving the ziconotide therapy. Weight loss and the subsequent break down of fat cells seems to trigger "flash-backs".
Patents
The drug was patented by Neurex Corp., a U.S. company purchased in 1998 by ÉlanÉlan
Élan Corporation plc is a major drugs firm based in Athlone, County Roscommon, Ireland which has major interests in the United States. In the late 1990s its value on the Irish Stock Exchange reached over €20bn. It has secondary listings on the London Stock Exchange and the New York Stock Exchange....
Corporation, plc of Ireland
Ireland
Ireland is an island to the northwest of continental Europe. It is the third-largest island in Europe and the twentieth-largest island on Earth...
. U.S. patents assigned to Elan include 5,859,186, 5,795,864, 5,770,690, 5,587,454, and 5,559,095.
External links
- Manufacturer website
- FDA approves new drug for severe pain, a December 2004 Associated PressAssociated PressThe Associated Press is an American news agency. The AP is a cooperative owned by its contributing newspapers, radio and television stations in the United States, which both contribute stories to the AP and use material written by its staff journalists...
article - Press release announcing FDA approval from Elan
- Ziconotide Effectiveness and Safety Trial in Patients with Chronic Severe Pain