Chronic Pain Update: Ziconotide - A New Class of Pharmacologic Agent

1) It is the first FDA-approved agent (approved in 2000) in a promising class of drugs called the conotoxins and its release carries the specific indication for intrathecal use in patients with severe chronic pain;

2) It belongs to a unique class of peptide drugs derived from the neurotoxic venom of cone-snails; and,

3) It is a 25-amino acid neuropeptide (endorphins also fall into this category) that is pharmacologically distinct from the opioid/narcotics, local or general anesthetics, and is neither a salicylate nor an NSAID. In addition, it is not a hypnotic or a tranquilizer, an anti-depressant or anti-seizure drug and, most importantly for the clinician, it appears to be quite effective in alleviating severe chronic pain through a CNS mechanism that is unique to its own pharmacologic class.

Conotoxins
I became acquainted with conotoxins in the Spring 2000 when teaching at the University in Florida. There I met Dr. Frank Mari, a molecular biochemist. Doctor Mari had been investigating possible medicinal uses of naturally occurring neurotoxins for some years. He pointed out that conotoxins are comprised of a spectrum of neuropeptides active on conducting both nerve and muscle tissue.

Alpha-conotoxins block neuromuscular and neuronal subtypes of nicotinic acetylcholine receptors. Thus, they may prove useful in drugs to treat schizophrenia, some neuromuscular disorders and/or bladder dysfunction.

Delta-conotoxins activate neuronal sodium channels and are highly toxic to non-mammalian animal systems, and thus may prove useful as pesticides.

Kappa-conotoxins target the voltage-sensitive K ion channel and under investigation as a class of future cardiovascular and gastrointestinal agents.

Mu-conotoxins block the voltage-dependent sodium channels in muscle tissue and may result in future muscle relaxant and antiseizure compounds.

The omega-conotoxins (including Ziconotide) inhibit presynaptic voltage-gated calcium channels and thus neurotransmission across nerve synapses. With the role of the omega-conotoxins in treating severe chronic pain, this class of biochemicals is also under investigation in the possible development of a drug to treat brain injury secondary to ischemic stroke and hypoxia where there is some evidence that Ca channel blockade may be therapeutic.

Unlike Salicylates, NSAIDs, Local Anesthetics
Unlike salicylates, NSAIDs and local anesthetics that exert analgesic effects (mostly through peripheral nerve/nociceptors) and unlike opioids and general anesthetics (act primarily at the level of the brain to obliterate pain and consciousness as well), the mechanism of therapeutic action of Ziconotide is through its capacity to bind to the N-type calcium channel receptor. The N-type calcium channel receptor is located on the primary nociceptive A-delta and C-slow fiber pain fibers (nociceptors) within the superficial posterior Rexed's laminae I and II of the spinal cord.

While local anesthetics and several opioids have been and currently are administered via a spinal route for a few decades, their use has been more practical during surgical anesthesia (operating room) and in postoperative hospital pain management than for live-at-home, ambulatory patients who engages in (or wishes to resume) normal activities of daily life with no more than a periodic visit to the doctor's office.

Potent Analgesic Effect
At recommended therapeutic dose ranges, it appears that Ziconotide is fairly specific in exerting its potent analgesic effect by inhibiting the firing of sensory fibers entering the dorsal laminae of the spinal grey matter. Motor fibers appear to be spared. To the pain management clinician, Ziconotide has a near-ideal mechanism of action as a drug for out-patient, ambulating patients with chronic extremity pain. For example, when RSD affects a patient's limb or in cases of chronic low back and leg pain with multiple surgeries and so called "failed back syndrome". Now, it appears that Ziconotide is non-addictive (at least in recommended dosages) and does not depress consciousness and respiration as opioids do whether administered orally, intravenously, or intrathecally.

Intrathecal Administration
Ziconotide must be administered intrathecally. While future isolates of the conotoxins may be suitable for oral or intravenous administration, Ziconotide must be administered directly to the spinal cord by introduction into the patient's cerebrospinal fluid through an in-dwelling catheter. The catheter is tunneled subcutaneously and attached to a pump that is similarly implanted into the flank or buttock region. Intrathecal drug delivery technology has been available for decades (for example, Medtronic and CADD® (Smiths Medical MD) implantable pump systems).

Thus, committing a chronic pain patient to treatment with Ziconotide does involve a small operative procedure to implant the pump delivery system, which may be done on an ambulatory surgery basis. Patients return to have the pump medication reservoir refilled using a sterile syringe and skin needle-puncture once every 40 to 60 days. Obviously, this treatment is appropriate when long-term or permanent therapy of chronic pain states is anticipated and the clinical situation has proved refractory to existing, more conservative pain treatments.

Side Effects
Ziconotide does have a fairly high rate of undesirable side effects, which are dose-related and reportedly clear up fairly rapidly when discontinued. However, relative contraindications exist especially at higher dosages and occasionally at therapeutic dosages. A certain incidence of drug-induced cognitive impairment has been reported and a lower incidence of drug-induced hallucinations and related psychotic symptoms. In a study of 1254 patients, the most often reported adverse side effects included, in order of frequency: confusion (33%), memory impairment (22%), speech disorder (14%), aphasia (12%), and hallucinations (12%).

Measurement of the serum CK every other week for the first month, and then once a month thereafter is recommended. This recommendation is made as one open-label study reported a 40% elevation of the CK and a three-fold elevation of the CK in as many as 11% of patients; more commonly among male patients, those on antiepileptic, antidepressant or those on concomitant IT (intrathecal) morphine. There have been two reports of acute renal failure secondary to rhabdomyolysis with extremely elevated CK levels (>17,000 IU/L). However, many commonly used drugs have the potential to cause drug-induced psychosis and CNS impairment, especially at high doses, including atropine, corticosteroids, and certain tricyclic antidepressants.

Therefore it is good practice with patients on Ziconotide (or other CNS-active drugs) to question patients using a simple 10-minute, mini-mental status examination. Such an exam is a useful screening test for cognition, memory, mood and affect. Fortunately, Ziconotide-induced cognitive impairment and/or the less common drug-induced psychosis, was reported as both temporary and reversible within 3-15 days. Whenever it is necessary to stop Ziconotide administration abruptly, no opioid-like withdrawal syndrome has been reported.

Given the fact that Ziconotide has a fairly high incidence of undesirable side effects, we can see why the drug is administered intrathecally by a pump. A potent drug with a high incidence of undesirable side effects is one that need not be re-introduced into the body through the GI tract or bloodstream several times a day but is already within the body. A programmable pump is capable of delivering extremely small quantities of a pharmacologic agent that will maintain a steady concentration of the drug within the desired body compartment (CSF in this case). Here, the drug delivery system is designed -- in part, to minimize the incidence of side effects by keeping the quantity of drug delivered to the absolute minimum needed.

Conclusion
To summarize, in intrathecal Ziconotide we appear to have the first of a new class of neuropeptide pharmaceuticals with potent pain-relieving properties and a relatively safe profile free from addictive properties and depression of consciousness and respiration. The side effect profile, while not life-threatening, is nonetheless unpleasant. Care must be taken to regularly check the pump delivery system to titrate the lowest dose of delivered drug needed for pain relief. Care must also be exercised as to regular patient check-ups and to be on guard for the subtle development of cognitive impairment of thought, memory, and the less frequently reported possibility of hallucinations.

Given the improving but limited nature of our current chronic pain armamentarium, I think the introduction of Ziconotide is a welcome development. Bear in mind there is a need for careful referral of prospective patients to a cautious pain specialist, who will follow the patient with the utmost attentiveness.