Intrathecal pain management with ziconotide: Time for consensus?

Abstract This article summarizes recommendations made by six pain specialists who discussed the rationale for ziconotide intrathecal analgesia (ITA) and the requirement for evidence‐based guidance on its use, from a European perspective. Riemser Pharma GmbH (Greifswald, Germany), which holds the European marketing authorization for ziconotide, hosted the meeting. The group agreed that ITA is under‐used in Europe, adding that ziconotide ITA has potential to be a first‐line alternative to morphine; both are already first‐line options in the USA. Ziconotide ITA (initiated using a low‐dose, slow‐titration approach) is suitable for many patients with noncancer‐ or cancer‐related chronic refractory pain and no history of psychosis. Adopting ziconotide as first‐line ITA could reduce opioid usage in these patient populations. The group advocated a risk‐reduction strategy for all candidate patients, including compulsory prescreening for neuropsychosis, and requested US–European alignment of the licensed starting dose for ziconotide: the low‐and‐slow approach practiced in the USA has a better tolerability profile than the fixed high starting dose licensed in Europe. Of note, an update to the European Summary of Product Characteristics is anticipated in early 2021. The group acknowledged that the Polyanalgesic Consensus Conference (PACC) treatment algorithms for ziconotide ITA provide useful guidance, but recommendations tailored specifically for European settings are required. Before a consensus process can formally begin, the group called for additional European prospective studies to investigate ziconotide in low‐and‐slow dosing strategies, in different patient settings. Such data would enable European guidance to have the most appropriate evidence at its core.


| INTRODUC TI ON
Chronic pain remains a common and complex condition that is often challenging and burdensome at individual, clinical, and societal levels (Breivik et al., 2013). Choice of pharmacological agent and its route of administration are two of many components in a patient's individualized pain-management strategy, but they are important aspects of care that have far-reaching implications. Consequently, the development of new analgesics remains a focus of clinical research, a key aim of which is to reduce opioid use for severe and refractory pain (Jain et al., 2019).
However, given the short-term absence of novel, efficacious agents, it may be helpful to consider whether any licensed nonopioids could be better utilized; reflection on experience and evidence might identify practice adjustments that improve their clinical application.
One such approach is intrathecal analgesia (ITA) with the nonopioid, ziconotide, which has been widely used in the USA for treating refrac- This article summarizes knowledge of ITA (and of ziconotide as a compound), explores differences between United States and European acceptance of ITA, and suggests proposals for initiating development of a European-specific Consensus Statement on ziconotide use.

| INTR ATHEC AL ANALG E S IA : BACKG ROUND AND PRIN CIPLE S
Intrathecal analgesia is licensed in morphine-or ziconotide-based monotherapy regimens and is effective for many forms of chronic cancer-or noncancer-related pain of neuropathic or nociceptive etiology Deer, Pope, Hayek, Bux, et al., 2017;Deer, Pope, Hayek, Lamer, Veizi, et al., 2017;Deer et al., 2019;Hayek & Hanes, 2014). Emerging data also indicate that multidrug ITA regimens can effectively treat refractory cancer-related pain (Caravajal et al., 2018;Dupoiron, 2019;EMA SmPC, 2019). ITA offers specific advantages for patients intolerant of (or refractory to) oral or systemic analgesia. For example, by delivering the agent directly into the cerebrospinal fluid, firstpass metabolism, and the blood-brain barrier are bypassed (Smith & Deer, 2009). ITA therefore facilitates pain reduction using much smaller doses of active compound than are required with other administration routes (Smith & Deer, 2009;Webster, 2015) (Figure 1). F I G U R E 1 Intrathecal (IT) analgesia (ITA): central and peripheral sites related to the mechanisms of action of morphine and ziconotide ITA formulations, and common adverse effects. (a) Intrathecally administered drugs spread out of the IT space through the spinal cord into the epidural space, then enter systemic circulation, which might produce systemic adverse events. (b) ITA travels with the pulsatile motion of the cerebrospinal fluid (CSF) into the brain. (c) At high concentrations, ziconotide ITA might enter cortical regions, possibly leading to the development of neuropsychiatric events (e.g., cognitive impairment, psychosis). (d) Because morphine and ziconotide ITA travel with the pulsatile motion of the CSF, brainstem activity may be affected, causing systemic events (e.g., nausea, somnolence, headache); morphine ITA can also suppress respiratory centers in the brainstem, causing respiratory depression. (e) Morphine ITA spreads from the IT space into gastrointestinal and urinary systems and can act on opioid receptors involved with voiding urine and feces, leading to urinary retention and constipation. Reproduced from (Webster, 2015) with permission from Wiley Periodicals Inc In addition, compared with systemic or oral analgesia, ITA is associated with a lower incidence of long-term systemic adverse effects, such as nausea or constipation (Hayek & Hanes, 2014;Pope & Deer, 2015a, 2015bWebster, 2015).
However, in Europe, ITA is practiced in few specialist centers, and most regimens involve morphine rather than ziconotide, although where ziconotide is used the experiences are positive (McDowell et al., 2020). The low adoption of ziconotide ITA in Europe can be traced to key, inter-related differences between the United States and European practices, in particular: • European concerns regarding ziconotide dose selection and tolerability (high starting dose; poor tolerability): these concerns relate to the ziconotide dosing regimen listed in the EU Summary of Product Characteristics (SmPC) ( Table 1) • Limited recent European-specific clinical data and formal guidance on ziconotide ITA (Alicino et al., 2012;Dupoiron et al., 2012;Dupoiron et al., 2019;Raffaeli et al., 2011): this clinical literature does not align with the dosing regimen in the EU SmPC Concerns regarding the high starting dose and consequent poor tolerability of ziconotide do not apply in the USA because since ziconotide became available, much work has been undertaken by PACC to refine its dosing and administration regimens.
Consequently, the PACC pain-management algorithms particularly suit the needs of US healthcare providers (Deer et al., 2007;Deer et al., 2012;Deer, Pope, Hayek, Bux, et al., 2017;Deer, Pope, Hayek, Lamer, Veizi, et al., 2017). For example, ziconotide dose and titration recommendations in these algorithms are lower, slower, and more detailed than information included in either the FDA or EMA SmPC literature EMA SmPC, 2019;FDA, 2019;McDowell & Pope, 2016) (Table 1); of note, an update to the EMA SmPC, which will more closely align the European with the US dosing information is anticipated in early 2021.
The PACC algorithms therefore provide useful guidance on ziconotide administration but cannot be applied in European settings without considerable adaptation, given the differences between guidance and labeling information. The issue is not merely about dosing, however. Historically, there have also been differences in the provision of pain-management services between Europe and the  Deer, Pope, Hayek, Bux, et al., 2017;Deer, Pope, Hayek, Lamer, Veizi, et al., 2017 Instead, pain control in Europe has often been managed by primarycare or other nonspecialist physicians (O'Brien et al., 2017), with very few specialist pain clinics.
Local levels of experience with ITA may be limited in European health settings, not only because of the lack of specialist pain clinics but also because of reluctance to administer ITA, particularly for noncancer-related pain, other than spasticity. This reluctance has stemmed from lack of compelling data on efficacy, safety, and costeffectiveness of ITA systems for noncancer pain, or evidence relating to nonopioid ITA use across diverse patient populations (Bottros & Christo, 2014;Deer et al., 2019).

| ZICONOTIDE: PHARMACOLOG IC AL SUMMARY
Before discussing clinical aspects, it is helpful to summarize the attributes of ziconotide that make it an attractive candidate for chronic, refractory pain management. Ziconotide is a synthetic, water-soluble cone snail venom-derived peptide with a molecular weight of 2,639 Daltons. In the systemic circulation, it is rapidly degraded by Phase I hydrolytic enzymes that are ubiquitous in the body, but it does not interact with cytochrome P450 enzymes (Pope & Deer, 2013). Ziconotide does not easily cross the blood-brain barrier, instead revealing its highly potent antinociceptive effect only after intrathecal administration (Smith & Deer, 2009).
Ziconotide is a nonopioid analgesic that selectively binds to Ntype voltage-sensitive calcium channels on primary nociceptive afferent nerves in the dorsal horn of the spinal cord .
This mechanism releases analgesic neurotransmitters into the synaptic gap and subsequently blocks pain signal transmission ( Figure 2) (Klotz, 2006;Pope et al., 2017). Because it has a narrow therapeutic window, careful dose titration, and a lag time to allow for onset (and offset) of analgesia and adverse effects are required Deer, Pope, Hayek, Bux, et al., 2017;Deer, Pope, Hayek, Lamer, Veizi, et al., 2017;Pope et al., 2017;Schmidtko et al., 2010). These aspects-in part-influenced the low-and-slow dose and titration strategies developed by PACC Deer, Pope, Hayek, Lamer, Veizi, et al., 2017), but given that they do not concur with the current EMA SmPC, may have driven the cautious approach and slow uptake of ziconotide across Europe.
It is important to consider why the EMA SmPC includes such a high, fixed starting dose for ziconotide ITA. The answer lies in the pivotal clinical studies of ziconotide, which used aggressive titration schedules involving an initiation dose of 2.4 μg/day (Rauck et al., 2006;Staats et al., 2004;Wallace, 2006). Ziconotide was licensed on the basis of these data because of the good efficacy and overall safety findings reported, although the high-fixed initiation dose was associated with a high rate of adverse effects including neuropsychotic episodes, confusion, and nausea (Rauck et al., 2006;Staats et al., 2004;Wallace, 2006). With the benefit of hindsight, it is therefore understandable why European clinicians have been reluctant to use ziconotide as a first-line ITA, if they align their practice with the current EMA SmPC. Implanted pumps must be refilled every 3-4 weeks when ziconotide is diluted with preservative-free sodium chloride 9 mg/ml (0.9%) solution for injection. Dilution is essential during the trialing phase, but degradation of ziconotide takes place over time due to the decrease of L-methionine in the pump (EMA SmPC, 2019).

| EUROPE AN CON S EN SUS S TATEMENT ON ZICONOTIDE: PRELIMINARY CONS IDER ATIONS
Key requirements of any European Consensus Statement specific to ziconotide ITA will likely involve patient selection, drug-trialing, pump choice, device implantation, ongoing administration, patient management, and outcomes assessment. This list is not limited; points listed below, and briefly illustrated in Figure 3, merely form the basis for future discussions.

| Patient selection for ziconotide ITA
It is wise for European guidelines on ITA to reflect on PACC recommendations, which list ziconotide and morphine as first-line options for active cancer-and noncancer-related pain, regardless of whether pain is localized or diffuse (Deer, Pope, Hayek, Bux, et al., 2017;Deer et al., 2019). However, PACC guidelines emphasize that, unless contraindicated, ziconotide should be the first drug selected for noncancer patients (Deer, Pope, Hayek, Bux, et al., 2017): In contrast to opioids, it does not cause tolerance, dependence, or respiratory depression (Smith & Deer, 2009). PACC guidelines consider ziconotide to be particularly suitable for patients who cannot receive morphine (due to underlying conditions or opioid intolerance, for example) (Deer, Pope, Hayek, Bux, et al., 2017;McDowell & Pope, 2016).
The following points regarding patient selection should be con-

| Rationale for Ziconotide as first-line ITA
Morphine ITA was the gold standard for several years but ziconotide ITA has been far more widely investigated (reviewed

| Neuropsychiatric evaluation
There can be little argument that all patients with noncancer-related pain require thorough neuropsychiatric assessment before commencing ziconotide ITA Deer, Pope, Hayek, Bux, et al., 2017

| Confirmation of pain diagnosis
Before starting ziconotide, the patient's pain diagnosis should be confirmed, to ensure that the pain is of nociceptive or neuropathic origin; ziconotide has been shown to be beneficial when other drugs have failed (Lux & Rasche, 2011). Although ziconotide ITA is effective for many types of cancer-and noncancer-associated pain, it is not effective for global pain, headache, or facial pain and should not be trialed in patients presenting with these symptoms (EMA SmPC, 2019).

| Ziconotide administration during the trial
There are three main approaches to trialing ziconotide, all of which are undertaken in in-patient settings, to monitor safety and efficacy responses: • Bolus administration (using syringe devices rather than pumps): • Flexible-dose administration (e.g., bolus night-time dosing in addition to pump administration) • Initiation with low-dose, slow-titration therapy (continuous intrathecal infusion using internal or external pumps). pump before trialing has a high cost and morbidity burden, at a stage when its therapeutic benefits are unknown. Trialing ziconotide in noncancer patients therefore usually requires temporary delivery methods to establish the initial efficacy and safety response.

| Catheter tip placement
In addition to the choice of pump, catheter tip positioning is extremely important, and any European Consensus statement should include drug-specific guidance on this aspect of administration.
For ziconotide ITA, the catheter tip should be placed at the spinal level closest to the dermatomal region of pain. With lumbar pain, for example, the catheter tip should be at T8-T10 (Bäckryd, 2018;Deer, Pope, Hayek, Bux, et al., 2017;Deer, Pope, Hayek, Lamer, Veizi, et al., 2017; tip placement higher than T8 is associated with emergence of side effects including hallucinations. N-Type voltagedependent calcium channels in the ventricle might be affected by ziconotide concentrations that do not cause such side effects when the catheter is placed at a lower position. Requirements for catheter tip placement vary for other ITA agents and cannot be made without evaluating the pharmacodynamic profile and stability of the specific regimen concerned. CSF dynamics should be taken into account (Prager et al., 2014).
In all cases, catheter tip positioning must be an X-ray guided procedure, with details of placement appropriately documented in the patient's notes.

| Trialing ziconotide ITA in cancer-related pain
The PACC algorithms state that full trialing of ziconotide ITA is unnecessary for patients with cancer-related pain (although this has a low evidence level in PACC). This approach also applies in European settings, but risk of adverse events should be minimized by adopting one of the following strategies: • Immediate surgical implantation of an internal pump in patients with life expectancy of >3 months, then commencing ziconotide ITA using a low-and-slow dose titration process ○ For patients with shorter life expectancy, a subcutaneous port should be used • Administering ziconotide via intrathecal catheter port, to assess the patient's response prior to internal pump implantation ○ There is emerging evidence that ziconotide administration via intrathecal catheter may be an efficacious long-term option for patients with cancer-related pain (Dupoiron et al., 2020).

| Trialing ziconotide in noncancer-related pain
The PACC algorithms recommend that full trialing of first-line ziconotide ITA is necessary for patients with noncancer-related pain, to minimize the risk of complications Deer, Pope, Hayek, Bux, et al., 2017;Deer, Pope, Hayek, Lamer, Veizi, et al., 2017); however, trialing is not universally performed in specialist pain centers. Discussion of the following points, from European perspectives, is required: • How closely should titration follow the PACC recommendations rather than the FDA and EMA SmPCs for ziconotide?
• How long should the in-patient phase typically take?
• What are the thresholds for therapeutic failure (e.g., emergence of specific adverse events; lack of meaningful pain response over likely to be specific to the US health sector (Deer, Pope, Hayek, Bux, et al., 2017). As a foundation for discussions, and in the absence of any local protocols, a trial period could be a minimum of ~1 week in-patient stay (a maximum 4 weeks with an external pump), followed by implantation of the permanent pump, with the correct dose being found over the next few months, in outpatient consultations. Given different healthcare settings across Europe, it is likely that any recommendations on trial duration would have to include variability.

| Ziconotide dosing and tolerance
The low-dose range for ziconotide initiation in the PACC algorithms (0.5-1.2 μg/day for cancer-and noncancer-related pain; Table 1) (Deer, Pope, Hayek, Bux, et al., 2017) should form the basis of discussions in relation to the European Consensus guidelines for treatment initiation.
Certainly, the dose should be titrated upwards very slowly every 2-3 days until an efficacy response is observed. Although it is helpful to have a standard protocol, this acts as the foundation for individualized therapy: time taken to reach a target (efficacious) dose is not important. Broadly, in the patient with noncancerrelated pain, if no pain relief is observed when the total ziconotide dose is 10 μg/day and the patient has received ITA for 3 weeks, this would be a reasonable point to review the individual case as being a likely nonresponder. However, some patients may not experience a reduction in pain until higher doses are administered. Notably, the PACC guidelines include an upper threshold of 19.2 μg/day for achieving the initial response. Before classifying a case as a treatment failure, it is important to establish whether any technical or human factors may have resulted in the lack of response. If nothing can be identified, ziconotide ITA should be stopped.
There is no maximum daily dose of ziconotide for patients with cancer-related pain, if the patient tolerates ziconotide and it continues to provide pain relief. There is no evidence that patients with chronic pain conditions develop tolerance to ziconotide even with long-term use (Smith & Deer, 2009). On the contrary, dosages can often be reduced over time, with efficacy maintained (Deer et al., 2018;Deer et al., 2019;Schmidtko et al., 2010;Webster, 2015 Elevations in creatine kinase were reported in some patients receiving ziconotide in clinical trial settings (Rauck et al., 2006;Staats et al., 2004;Wallace, 2006 Indeed, it may be advisable that recommendations for outcomes assessment are made by an independent third party, such as an interdisciplinary working group of pain experts, rather than falling solely within the remit of any Consensus group.

| ARE A S FOR ADD ITI ONAL FO CUS
Ziconotide ITA has the potential to be a cost-effective painmanagement strategy for many forms of chronic, severe cancer-or noncancer-related pain . Of utmost importance is that this therapy is administered by physicians who are comfortable initiating and managing ITA, who are supported by a healthcare infrastructure that provides all aspects relevant to ITA (implantation, maintenance, programming, reservoir refills, and troubleshooting).
Before consensus guidelines for ziconotide ITA are drafted, further research and peer discussion is required, including (but not limited to) the following points, many of which are beyond the scope of the present paper: Pan-European guidelines would need to allow flexibility, to suit different healthcare models across the continent. Before any guidelines can be prepared, further research investigating dosing and administration of ziconotide ITA in European patients with cancer-or noncancer-associated chronic pain is required. Research priorities include evaluation of low-and-slow dose titration protocols, internal and external pumps (and catheter ports) for trialing ITA, multidrug ITA regimens, and switch protocols with opioid-based ITA.
If ziconotide ITA is shown to be a practical, efficacious and welltolerated option, research and discussion should also consider its position in the pain-management pathway (to ensure that patients who might benefit most from ziconotide receive it at the appropriate time for their health and well-being).
Pre-existing concerns relating to ziconotide use in Europe must be properly investigated through sharing clinical experience, and evaluating data, during the consensus process. There is already good evidence from the USA that, following appropriate screening and low-and-slow dosing protocols, ziconotide ITA is an effective alternative to morphine-based ITA with good long-term safety and tolerability. If similar strategies can be devised and adopted in Europe, wider implementation of ziconotide ITA might follow. Ultimately, this could help to fulfill unmet needs for management of chronic, refractory pain by extending analgesic choice in this time of the global opioid epidemic.

ACK N OWLED G M ENT
Medical writing assistance was provided by Linda Edmondson, independent medical writer.

AUTH O R CO NTR I B UTI O N S
All authors participated actively in the meeting and contributed to the development of the consensus manuscript, including approval of the final draft.

PEER R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1002/brb3.2055.