How has ziconotide impacted non-cancer pain management?

KEYWORDS:

• Intrathecal
• Ziconotide
• Intrathecal pump
• Chronic Pain

1. Introduction

Intrathecal drug therapy (IDT) involves the delivery of a medication to receptors in the spinal cord through a cerebrospinal fluid carrier in an effort to modify neurotransmitter transmission. The use of these therapies has been part of the chronic pain algorithm for more than three decades, which has allowed an evolution of medication use, dosing, and patient selection. One of the most important changes during that time has been the availability of ziconotide following the Food and Drug Administration’s approval in 2005 [1]. This drug has many features that make it an attractive option for those who suffer from intractable pain. And while ziconotide has side effects, when one considers the risks of intrathecal opioids, the risk-to-benefit discussion of ziconotide is very positive.

2. Ziconotide overview

2.1. History and rationale for use

The use of IDT has been a critical part of chronic pain treatment for the past four decades. This route of drug delivery was initiated in acute pain, and subsequently became an option in end of life care. In both of those settings, the drug was injected on a single shot basis or was given briefly via an indwelling temporary catheter. Over time clinicians and researchers learned there were advantages in drug equipotent dosing, avoidance of the first-pass effect, and direct delivery of drugs that did not cross the blood brain barrier as compared to other drug routes.

As opposed to the action of intrathecal opioids, ziconotide has an action site at the voltage-gated calcium channels. This has led to a unique position in the treatment algorithm for this drug. Many expert consensus groups have recommended this agent as a first-line choice in both neuropathic and nociceptive pain [2–4]. This non-opioid medication was originally isolated from the conotoxin peptide found in the marine snail, Conus magnus [1]. Currently, the drug is manufactured in a synthetic fashion based on federal drug manufacturing recommendations and is labeled for chronic intrathecal use. The impact of this drug appears to be seen by a decrease in glutamate levels resulting from binding that inhibits the N-type calcium channels [5]. This is a unique mechanism among approved and off label intrathecal agents.

2.2. Clinical advantages

While many individuals do well with more conservative pain treatments, a significant number of patients are resistant to physical medicine, non-opioid medications, injections, surgery, and other implantable devices. As we know, the use of chronic opioid therapy in persistent pain syndromes has not shown good efficacy and certainly has been wrought with devastating unintentional problems. In this setting, intrathecal therapy has been shown to be a viable, often efficacious, long-term option. Morphine was the first intrathecal drug labeled for use in the United States, and many other regions of the world, but the failure of morphine over time has led to the use of other agents to treat patients. In addition, many combined drug admixtures have been recommended [4]. Among those drugs are two non-opioid options, bupivacaine, and clonidine. Despite widespread use, neither of these drugs have been officially labeled for chronic use. The continued search for a more efficacious agent for the intrathecal space led to the eventual approval of ziconotide to fill this clinical gap.

Ziconotide is important for a number of reasons. Most notably, the level one evidence supporting its efficacy, but it must be stated that it is does not cause withdrawal with abrupt discontinuation and has not been identified as the agent responsible for any death from an accidental overdose. In addition, ziconotide is a reasonable option in the opioid naive patient, whereas intrathecal opioids by definition require failure of oral or transdermal opioids prior to initiation. In fact, research has suggested that using ziconotide as the first medication in the pump leads to improved results compared to using another drug as the first pump agent [6].

A failure of intrathecal opioids has been the development over time of granulomas within the intrathecal space at the catheter tip. This inflammatory mass has been described to cause major complications such as loss of therapeutic effect, sensory changes, increased pain, and in some cases motor dysfunction leading to paraplegia [7]. In an analysis of ziconotide, no cases of granuloma have been attributed to this drug.

2.3. Indications

Like any decision to place an intrathecal infusion device, the use of intrathecal ziconotide should be approached with careful consideration of algorithmic treatment. The use of ziconotide has been supported in the clinical literature for both cancer and noncancer pain, and for pain of both neuropathic and nociceptive origin [8–10].

In the noncancer pain realm, indications have included [8–14]:

• Failed back surgery syndrome

• Complex Regional Pain Syndrome type 1 and 2

• Nonsurgical axial neck and back pain

• Peripheral neuropathy of diabetic, HIV, and chemotherapy origin

• Trunk pain related to nerve injury

• Visceral pelvic and abdominal pain syndromes

2.4. Contraindications

The use of ziconotide should be avoided in certain circumstances. In patients with a history of severe depression, suicidal ideation, or other psychiatric issues, a careful assessment by a psychological health professional should be obtained prior to drug initiation. A history of psychosis is a contraindication to using ziconotide [5]. Patients with an allergy to ziconotide or the IDT components are not candidates for this therapy. Additionally, the use of ziconotide is not recommended for children or adolescents [5]. Intrathecal therapy, in general, should be avoided in patients with an infection at the surgical site, uncontrolled bleeding diathesis, and spinal canal obstruction with impairment of cerebrospinal fluid circulation.

2.5. Administration

2.5.1. Initiation

Ziconotide does not cross the blood brain barrier and is not available to the nervous system if dosed via mouth, epidural injection or infusion, transdermal application, or by any route other than direct intrathecal administration. Research is underway to find a method to deliver ziconotide through the blood brain barrier, but to date, this is not commercially available [15].

In clinical practice, the use of ziconotide is initiated by an intrathecal trial. The drug may be given in a single shot bolus to measure the patient’s ability to tolerate the dose and to evaluate pain relief, or it may be given via continuous intrathecal infusion [16,17]. Since it has not been shown to cause respiratory depression, unlike intrathecal opioids, the patient can be discharged the same day as the procedure. There is a risk of hypotension, so an intravenous infusion is recommended at the time of the trial to assure proper hydration and maintenance of hemodynamics. Many physicians bolus with a 2 microgram (µg) dose and observe the patient for 6 to 8 h. In the event the first bolus does not provide pain relief, but does not cause untoward events, the bolus is often increased to 4 µg at a future date and again the patient is evaluated for an acceptable response. A successful trial has been defined as a pain reduction of at least 30% with no unacceptable side effects. This percentage of pain reduction has been debated with some clinicians recommending 50% as a required level of reduction. This is further complicated by the difficulty of many patients in understanding the numerical pain scale and defining pain reduction by a percentage. Currently, despite this difficulty, these standards remain in place.

2.5.2. Maintenance

Once the trial has been deemed a success, the patient is often implanted with a permanent device for chronic infusion. The pump is carefully filled with ziconotide and an infusion is initiated. Recommended starting dosages are found below. The pump will require occasional medication refills with timing dependent on reservoir size and infusion rate. This is performed as a sterile, percutaneous procedure in the office setting.

Unlike other intrathecal drugs, the initial use of the drug in a pump requires additional steps be taken by the care team. This involves rinsing the device with ziconotide at 25 µg per ml concentration on three occasions. This properly coats the titanium in the device and stabilizes the dosing.

2.6. Dosing and management

Once the device is implanted the physician must work closely with the patient to determine the proper individualized dose. In most settings, the authors recommend starting at a microdosing level of 0.5 to 1.0 µg per day (0.02 to 0.04 µg per hour), but many physicians choose a more aggressive dose of 2.4 µg per day, which is acceptable [18]. If the lower dose is chosen, a compliant compounding pharmacist would need to dilute the drug. If starting at 2.4 µg per day dilution is not required. The Food and Drug Administration has labeled the drug to have a maximum dose of 19.2 µg per day.

In chronic treatment, the patient will require further dosing adjustments. In non-cancer pain, we would recommend increasing the dose by no more than 0.5 µg per week, with reassessment for response. In the event of side effects, the recommendation would be to reduce the dose to the previously tolerated level that provided some appreciable pain relief. More aggressive dosing may be indicated for end of life care.

The strategy of dosing is evolving for ziconotide. The use of patient-controlled analgesia has been described with success although no prospective-randomized studies exist to give guidance [19,20]. Nocturnal dosing has been suggested with the aim of decreasing intolerable side effects. Intermittent bolusing has also been described and may be a good strategy for long-term management [21]. But again, definitive studies are missing at present to suggest any one single dosing method is superior to another. Additional work is needed to explore dosing strategies and their potential benefits.

2.7. Side effects

A significant advantage of this drug is that side effects are often dose-dependent so in the event a side effect occurs the drug can be reduced and in some clinical settings the side effects will dissipate without the need for drug discontinuation. In more severe reactions, the drug can be abruptly removed without fear of withdrawal. The most common side effects are hallucinations, psychotic thoughts, nightmares, mental status changes including confusion and temporary memory loss, dizziness, and nausea [22]. Data analysis has shown that these side effects will dissipate within a few hours of ceasing the drug, which, as alluded to above, can be done abruptly [5]. This lends a significant safety profile with this drug, not seen with intrathecal opioids. Importantly, respiratory depression and death are not known side effects of this drug [5].

The use of ziconotide has been associated with rare occurrences of muscle breakdown and in some cases elevation of serum creatine kinase (CK) [23]. This can cause renal damage if left untreated. In most of these cases the symptoms most commonly expressed include new onset of muscle pain and weakness. The diagnosis is made by a blood test, and the treatment is drug cessation and proper consultation to appropriately treat the potential renal effects. Many physicians will order a CK level early in the care of a newly implanted patient and then intermittently if symptoms are concerning. No predictive patient characteristics have been identified that would be helpful in avoiding this complication. The presence of an elevation of serum CK should be seen as a reason to avoid the drug in the future.

In the event of a ziconotide overdose, which could occur by missing a refill port, a pump malfunction, or pharmacy or programming error, immediate patient assessment is required. There is no known reversal agent or drug to balance the side effects. Recommended treatment would be admission to the hospital, hemodynamic support, and immediate cessation of pump infusion. If the overdose was secondary to pocket fill of drug, the use of ultrasound to identify drug within the pocket and subsequent aspiration is a viable option.

3. Level 1 evidence for the use of ziconotide monotherapy

Ziconotide is the most evidence-supported drug currently used in the intrathecal space for the treatment of pain. To date, there have been three double-blind, randomized, placebo-controlled studies performed involving ziconotide for the treatment of chronic pain (Table 1).

Table 1. Brief overview of ziconotide randomized controlled trials.

Author/ Year	Indication	Sample Size	Patient Ages	Study Group (n)	Control Group (n)	Starting Dose (µg/h)	Max Dose (µg/h)	Time Periods	VAS Outcomes
Staats, 2004	Cancer and AIDS related pain	108	24-85 years	68	40	0.4 modified to 0.1	No max modified to 2.4	5 day titration, 5 day maintenance, 5–6 days for crossover patients	VAS decreased 53.1% for study group versus 18.1% for placebo.
Wallace, 2006	Chronic nonmalignant pain	255	18+ years	169	86	0.4 modified to 0.1	7.0 modified to 2.4	6 day titration, 5 day maintenance, 5 days for crossover patients	VAS decreased 31.2% for study group versus 6.0% for placebo.
Rauck, 2006	Severe chronic pain	220	No ages included	112	108	0.1	0.9	21 day treatment period with titration throughout	VAS decreased 14.7% for study group versus 7.2% for placebo.

Legend: µg = microgram; hr = hour; AIDS = acquired immunodeficiency syndrome.

The landmark study by Staats and colleagues was published in the Journal of the American Medical Association (JAMA) in 2004 [8]. This pivotal study provided level one evidence of efficacy in both neuropathic and nociceptive pain for a wide range of cancer- and AIDS-related pain conditions. The study involved 108 enrolled patients (68 ziconotide and 40 placebo) with the primary endpoint being a greater than 30% reduction in pain without any increase or change in opioids. Mean VAS scores improved 53.1% for the ziconotide group versus 18.1% in the placebo group (p < 0.001). Pain relief was moderate to complete in 52.9% of ziconotide patients versus 17.5% in the placebo group (p < 0.001). Five patients had complete pain relief with ziconotide compared to no patients in the placebo group. This led to the approval of the drug by the FDA in the United States. Despite showing good efficacy, there was a significant number of adverse events (AEs), particularly vestibular in nature, in this patient cohort and this led to a lowering in the recommended starting and maximum dosages compared to study initiation. At the lower dosages, confusion was the only AE that continued to occur at a significantly higher percentage of patients between the ziconotide and placebo groups [8].

Two years later, Wallace et al. published further evidence for the use of ziconotide [9]. This study was performed in a similar manner to the Staats et al. study, but involved 257 treated patients (170 ziconotide and 87 placebo) with follow-up scores reported for 255 patients (169 ziconotide and 86 placebo). Pain was classified as both neuropathic and nociceptive of a chronic nonmalignant etiology. Mean percent VAS improvement was 31.2% for ziconotide versus 6.0% for placebo (p ≤ 0.001) with 33.7% of ziconotide patients reported as responders versus 12.8% for placebo (p < 0.001). Lastly, 43.8% of ziconotide patients had moderate or better pain relief with 8.9% of patients reporting complete pain relief versus only 17.4% of placebo reporting moderate or greater pain relief without any patients reporting complete pain relief. Again, due to early AE rates, the starting and maximum infusion dosages were decreased from study initiation to study end. Most of the AEs were related to the nervous system, including dizziness, confusion, urinary retention, nausea, vomiting, and amblyopia [9].

Also in 2006, Rauck et al. further strengthened the argument for ziconotide use [10]. In their study, they enrolled 220 patients (112 ziconotide and 108 placebo) with severe chronic pain that was inadequately controlled with systemic or intrathecal analgesics. Using lessons learned in the prior two studies, Rauck et al. initiated ziconotide at lower dosages and had lower maximum dosages. Visual analog score improved 14.7% in the ziconotide group versus 7.2% for placebo (p = 0.036). The percentage of treatment responders did not differ significantly between groups (p = 0.39). However, 11.9% of ziconotide patients reported ‘excellent’ or ‘very good’ pain control compared with 0.9% of placebo. Adverse events were reported in 92.9% of ziconotide patients versus 82.4% of placebo with the majority of patients reporting mild or moderate AEs in both groups. Similar to the prior studies, AEs related to the central nervous system were most common and more common in the ziconotide-treated patients [10].

4. Conclusion

Intrathecal ziconotide, a conopeptide molecule that does not cross the blood brain barrier, is an attractive option for patients in the pain algorithm who have failed other more conservative options. It has been rigorously studied in three double-blind, randomized, placebo-controlled trials that showed its effectiveness in providing pain relief in a wide variety of painful conditions. The low-risk profile as compared to other agents in this treatment category should make this the first choice for all patients who do not have a contraindication.

5. Expert opinion

Ziconotide should be the first drug used in the intrathecal space when considering this delivery option barring an allergy to the drug or its components, or a history of psychosis.

There are several main reasons for this opinion:

• Ziconotide does not cause respiratory depression.

• Ziconotide has not been shown to cause death, even in cases of extreme overdose.

• Ziconotide has not been shown to cause granuloma or inflammatory mass.

• Ziconotide can be abruptly discontinued without side effects or withdrawal.

• Ziconotide can be tested by either single shot or continuous infusion and in the absence of side effects, the patient can be discharged.

• Ziconotide can be used in the pain treatment algorithm without the need to be first trialed on oral opioids, which can be addictive, abused, and may cause overdose or death.

The use of ziconotide can be effectively trialed, started at a low dose, and slowly and judiciously increased to a point of pain relief while carefully monitoring for side effects. The presence of intolerable side effects will lead to discontinuation of the drug in some patients and to date no study has shown a successful strategy to reintroduce the drug at a later time.

In considering intrathecal drug delivery with morphine, which is labeled for chronic pain, or alternative opioids that are supported by the literature such as hydromorphone or fentanyl, the risk of respiratory depression, hormonal disturbances, inflammatory mass, and death are all very important variables to consider. Considering the risk of long-term high dose oral opioids, intrathecal delivery of opioids should still have a favorable risk-to-benefit ratio in most cases. Regardless, with these considerations, ziconotide is a much more attractive option in the majority of patients. It is our opinion that additional conopeptide molecules with a broader therapeutic window should be considered in the future. But until the needs of our field and patients are met by new research and development, ziconotide is our current best option.

Declaration of interest

TR Deer is a consultant for Flowonix and a former consultant for Jazz Pharmaceuticals. He is also the President & CEO of the Center for Pain Relief, Charleston. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.