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Ziconotide for the Management of Cancer Pain: A Budget Impact Analysis

Open AccessPublished:October 04, 2022DOI:https://doi.org/10.1016/j.neurom.2022.08.458

      Abstract

      Objectives

      Recent recommendations on starting dose, smaller dose increments, and longer intervals between dose increase have the potential to increase the safety of ziconotide administration in addition to improving its value for money. Ziconotide is not routinely commissioned in England, with one of the concerns being whether it represents the best use of resources. The aim of this project is to conduct a budget impact analysis to estimate the costs or savings associated with the changes in ziconotide dosage in addition to its use in combination with morphine for the management of cancer pain.

      Materials and Methods

      An open, Markov-like cohort decision analytic model was developed to estimate the budget impact of ziconotide in combination with morphine (ziconotide combination therapy) vs morphine monotherapy through intrathecal drug delivery (ITDD) for the management of cancer pain. The perspective adopted was that of the UK National Health Service, with a five-year time horizon. Sensitivity analyses were conducted to evaluate different scenarios.

      Results

      Ziconotide combination therapy was more expensive than treatment with morphine monotherapy. The total costs of ziconotide combination therapy and morphine monotherapy for the first year were £395,748 and £136,628 respectively. The estimated five-year cumulative budget impact of treatment with ziconotide combination therapy for the five-year time horizon was £2,487,539, whereas that of morphine monotherapy was £913,804. The additional costs in any of the first five years are below the resource impact significance level of £1 million for medical technologies in England.

      Conclusions

      The results of this budget impact analysis suggest that although a combination of intrathecal ziconotide in combination with morphine is associated with higher costs to the health care system in England, the incremental costs are not significant. Routine commissioning of ziconotide alone or in combination with morphine would provide an alternative for a population with limited ITDD treatment options.

      Keywords

      Introduction

      Cancer Research UK estimates that between 2016 and 2018, there were approximately 375,000 new cancer cases in the UK every year, approximately 1000 cases every day. Breast, prostate, lung, and bowel cancers accounted for more than half (53%) of all new cancer cases in the UK in 2016–2018.
      It has been shown that up to one-third of patients with cancer will go on to experience chronic pain.
      • Bouhassira D.
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      Prevalence and incidence of chronic pain with or without neuropathic characteristics in patients with cancer.
      With at least half of people diagnosed with cancer experiencing physical pain to an extent, many patients suffer from severe pain, especially in advanced stages of the disease.
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      Effectiveness of the World Health Organization cancer pain relief guidelines: an integrative review.
      ,
      • Fallon M.
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      Depending on stage and type of cancer, the number of patients experiencing pain differs, with 33% of patients undergoing curative treatment to 64% of patients with advanced, metastatic, or terminal disease suffering from pain.
      • van den Beuken-van Everdingen M.H.
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      Cancer pain may be neuropathic or nociceptive but is often mixed. It may result from local tumor invasion, metastases, or as a side effect of cancer treatment. As a result, the World Health Organization developed the cancer pain ladder, with other guidelines developed subsequently.
      Traitement de la douleur cancéreuse. World Health Organization, Institutional Repository for Information Sharing.
      ,
      NCCN guidelines. National Comprehensive Channel Network.
      Despite cancer pain guidelines, studies indicate that cancer pain in Europe remains undertreated in 56% to 69% of patients.
      • Breivik H.
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      Approximately 5% to 15% of patients with cancer develop refractory pain or suffer intolerable adverse effects from systemic analgesics and adjuvants.
      Clinical commissioning policy: intrathecal pumps for treatment of severe cancer pain. Specialised Commissioning Team. National Health Service England.
      Intrathecal therapy is one way to provide pain relief for these patients. Intrathecal drug delivery (ITDD) provides analgesics directly into the cerebrospinal fluid (CSF) through a catheter attached to an external or implantable pump. Infusion of drugs into the CSF allows direct delivery of medicines to their site of action in the dorsal horn, thus avoiding the need for medicines to cross the blood-brain barrier and allowing the drugs to evade first pass metabolism. Thus, the intrathecal route allows much lower doses of analgesia, reducing the occurrence of adverse effects
      • Bhatia G.
      • Lau M.E.
      • Koury K.M.
      • Gulur P.
      Intrathecal drug delivery (ITDD) systems for cancer pain.
      and enhancing the analgesic effect.
      ITDD is an advanced stage intervention used in patients with cancer. Currently, only morphine, baclofen, and ziconotide are approved for ITDD by the Food and Drug Administration.
      • Deer T.R.
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      • et al.
      The Polyanalgesic Consensus Conference (PACC): recommendations on intrathecal drug infusion systems best practices and guidelines.
      Intrathecal morphine, baclofen, and ziconotide are also authorized for use in Europe.
      List of nationally authorised medicinal products. Active substance: Baclofen. European Medicines Agency.
      , Intrathecal drug combinations are not recommended by pump manufacturers owing to the possibility of corrosion to the infusion system and device failure. However, use of off-label drugs and drug combinations is common and recommended by an international panel of experts.
      • Deer T.R.
      • Pope J.E.
      • Hayek S.M.
      • et al.
      The Polyanalgesic Consensus Conference (PACC): recommendations on intrathecal drug infusion systems best practices and guidelines.
      Survival in patients with cancer pain after ITDD has been estimated as 39%, 24%, 16%, 11%, and 5% at 0.5, 1, 2, 3, and 10 years, respectively.
      • Stearns L.M.
      • Abd-Elsayed A.
      • Perruchoud C.
      • et al.
      Intrathecal drug delivery systems for cancer pain: an analysis of a prospective, multicenter product surveillance registry.
      Ziconotide is an analgesic drug licensed only for intrathecal use. It is a synthetic peptide, derived from the venom of the marine snail Conus magus, ω-conotoxin MVIIA. It selectively blocks the N-type voltage gated calcium channels found in the dorsal horn of the spinal cord.
      • McGivern J.G.
      Ziconotide: a review of its pharmacology and use in the treatment of pain.
      The inhibition of these channels results in suppression of pronociceptive neurotransmitter release (including substance P), thus curbing pain signals. Ziconotide has been shown to provide effective pain relief in numerous studies, including cancer-related pain.
      • Staats P.S.
      • Yearwood T.
      • Charapata S.G.
      • et al.
      Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial.
      • Pope J.E.
      • Deer T.R.
      Ziconotide: a clinical update and pharmacologic review.
      • Alicino I.
      • Giglio M.
      • Manca F.
      • Bruno F.
      • Puntillo F.
      Intrathecal combination of ziconotide and morphine for refractory cancer pain: a rapidly acting and effective choice.
      In the United States, intrathecal ziconotide and morphine are considered first line options for both cancer- and non–cancer-related pain.
      • Deer T.R.
      • Pope J.E.
      • Hayek S.M.
      • et al.
      The Polyanalgesic Consensus Conference (PACC): recommendations on intrathecal drug infusion systems best practices and guidelines.
      Ziconotide has poor ability to cross the blood-brain barrier, hence intrathecal administration. Ziconotide is known to have a long-lasting analgesic effect, reportedly lasting hours to days in animal studies.
      • McGivern J.G.
      Ziconotide: a review of its pharmacology and use in the treatment of pain.
      Although intrathecal ziconotide is commonly used for the management of cancer pain in countries such as the United States and France,
      • Deer T.R.
      • Pope J.E.
      • Hanes M.C.
      • McDowell G.C.
      Intrathecal therapy for chronic pain: a review of morphine and ziconotide as Firstline options.
      • Carvajal G.
      • Dupoiron D.
      • Seegers V.
      • et al.
      Intrathecal drug delivery systems for refractory pancreatic cancer pain: observational follow-up study Over an 11-year period in a Comprehensive Cancer Center.
      • Dupoiron D.
      • Leblanc D.
      • Demelliez-Merceron S.
      • et al.
      Optimizing initial intrathecal drug ratio for refractory cancer-related pain for early pain relief. A retrospective monocentric study.
      its use is not routinely commissioned in England.
      Clinical commissioning policy: ziconotide (intrathecal drug delivery) for chronic cancer pain. Specialised Commissioning Team. National Health Service England.
      One of the considerations for not routinely commissioning ziconotide in England was uncertainty whether the use of ziconotide represented the best use of National Health Service (NHS) resources. The recommended starting dose, dose increments, and recommended intervals between dose increases in the European Medicines Agency Summary of Product Characteristics are 2.4 μg/day, ≤ 2.4 μg/day, and ≥ 48 hours, respectively. However, recommendations based on recent evidence suggest a reduced starting dose (ie, 0.5–1.2 μg/d [0.02–0.05 μg/h] or initiation with ≤ 0.5 μg/day [0.02 μg/h]), smaller dose increments (ie, ≤ 0.5 μg/d [≤ 0.02 μg/h]), and a longer recommended interval between dose increases (ie, not more than once weekly).
      • Matis G.
      • De Negri P.
      • Dupoiron D.
      • Likar R.
      • Zuidema X.
      • Rasche D.
      Intrathecal pain management with ziconotide: time for consensus?.
      These recommendations have the potential to increase the safety of ziconotide administration in addition to improving its value for money. Furthermore, the combination of ziconotide with morphine has been shown to result in statistically and clinically significant improvements in pain intensity for a population with cancer pain.
      • Carvajal G.
      • Dupoiron D.
      • Seegers V.
      • et al.
      Intrathecal drug delivery systems for refractory pancreatic cancer pain: observational follow-up study Over an 11-year period in a Comprehensive Cancer Center.
      Recent estimates suggest that at least 8000 people with cancer pain may be eligible for ITDD in England.
      • Duarte R.V.
      • Sale A.
      • Desai P.
      • Marshall T.
      • Eldabe S.
      The unmet need for intrathecal drug delivery pumps for the treatment of cancer pain in England: an assessment of the hospital episode statistics database.
      The use of ziconotide as an adjuvant in a target population with a great need and a limited life expectancy may potentially affect the cost of the drug to the NHS. The aim of this study is to conduct a budget impact analysis to estimate the costs or savings associated with the changes in ziconotide dosage in addition to its use in combination with morphine for the management of cancer pain.

      Materials and Methods

      An open, Markov-like cohort decision analytic model was developed in Microsoft Excel to estimate the budget impact of ziconotide in combination with morphine (ziconotide combination therapy) vs morphine monotherapy through ITDD for the management of chronic cancer pain. The budget impact analysis also includes a scenario considering ziconotide monotherapy. The budget impact analysis was conducted from the UK NHS perspective.

      Model Structure

      A Markov model is a mathematical framework to represent the movement of hypothetical patients across predefined health states. The health states represent relevant events that need to be captured in the evaluation of a condition. Hypothetical patients who reside within a specific health state will experience the events that are associated with that health state, for example, accrue costs, experience health improvement or deterioration, or acquire certain characteristics relevant for decision-making.
      • Briggs A.
      • Claxton K.
      • Sculpher M.
      Decision Modelling for Health Economic Evaluation.
      The model in this analysis consists of four mutually exclusive health states. The starting health state was “all-cancer” health state. The model is termed an open Markov-like model because it enables unrestricted entry into the starting health state as new patients are diagnosed with cancer and experience cancer pain. At the end of each cycle, patients who are eligible to receive ITDD progress to an “incident-ITDD” health state, which is a tunnel health state as all patients become prevalent cases at the next cycle (ie, move to the “prevalent-ITDD” health state). Death is an absorbing health state, as shown in Figure 1.
      All patients with ITDD by definition will have an implanted device. For each model cycle, new patients requiring an ITDD (ie, patients in incident-ITDD health state) were expected to incur the device cost, device implantation cost, and the drug costs, whereas patients with existing ITDD (ie, patients in prevalent-ITDD health state) will only incur treatment costs (ie, refill procedure and drug costs). Therefore, it was important to distinguish patients with incident-ITDD from those with prevalent-ITDD in the model structure.
      The time horizon, in line with published guidance for conducting budget impact analysis,
      • Trueman P.
      • Drummond M.
      • Hutton J.
      Developing guidance for budget impact analysis.
      was five years. The cycle length was set to one week to allow important events such as weekly escalation of starting treatment doses or ITDD refill intervals to be captured. Costs were presented for the 2019–2020 price year. Costs were not discounted over time as recommended in National Institute for Health and Care Excellence guidelines and best practice recommendations for budget impact analysis.

      Guide to the processes of technology appraisal. National Institute for Health and Care Excellence. Accessed January 15, 2022. https://www.nice.org.uk/Media/Default/About/what-we-do/NICE-guidance/NICE-technology-appraisals/technology-appraisal-processes-guide-apr-2018.pdf

      ,
      • Mauskopf J.A.
      • Sullivan S.D.
      • Annemans L.
      • et al.
      Principles of good practice for budget impact analysis: report of the ISPOR Task Force on good research practices--budget impact analysis.

      Study Population

      The initial model population comprised all patients with cancer, although the subpopulation that would incur the relevant treatment costs in the analysis was those receiving ITDD. This approach was taken to differentiate incident cancer cases from prevalent cancer cases, which can be obtained from large, readily available data sets containing information about all patients with cancer but not specifically for patients with cancer with an ITDD. Consequently, the distribution of incident cases and prevalent cases in the entire cancer population can be applied to patients with ITDD. For this study and for simplicity of design, we assumed that the ratio of incident-to-prevalent patients in the entire population with cancer would be the same in the population with ITDD.
      The distribution of patients with cancer into incident and prevalent cases was obtained from an assessment of the Hospital Episode Statistics (HES) data base by Duarte et al.
      • Duarte R.V.
      • Sale A.
      • Desai P.
      • Marshall T.
      • Eldabe S.
      The unmet need for intrathecal drug delivery pumps for the treatment of cancer pain in England: an assessment of the hospital episode statistics database.
      The analysis of the HES data base identified the total number of patients with cancer and the number of deaths among patients with cancer, from which the proportion of incident and prevalent cases can be estimated. Furthermore, Duarte et al present the number of patients who were potentially eligible to receive an ITDD device and the number of patients with cancer who received ITDD over a six-year period (2014–2015 to 2019–2020).
      The starting population in this model was assumed to be the 727,607 patients with cancer in the UK for the 2014–2015 year. In the base-case analysis, the number of patients with cancer who received an ITDD (Supplementary Data Table S1) based on historical data was used to derive the transition probabilities for the base-case analysis (Supplementary Data Table S2). The weekly health-state transition probabilities used in the model are presented on Table 1. Because the use of ziconotide combination therapy is expected to lead to a modest increase in the use of ITDD, it was essential to capture the projected maximum cost impact of the use of ITDD with ziconotide.
      Table 1Weekly Transition Probabilities Used in the Model.
      FromNewly diagnosedAll-cancerIncident-ITDDAll-cancer, incident ITDD, and prevalent-ITDD
      ToAll-cancerIncident-ITDDPrevalent-ITDDDeath
      Cycle 0100.00000%100.00000%0.00000000.0000000
      2014–2015 (year 1)0.02389%0.53100%100.00000%0.58176%
      2015–2016 (year 2)0.02389%0.60552%100.00000%0.58301%
      2016–2017 (year 3)0.10058%0.68300%100.00000%0.55920%
      2017–2018 (year 4)0.06118%0.62004%100.00000%0.54287%
      2018–2019 (year 5)0.04527%0.58789%100.00000%0.52500%
      Using data reported in the HES data analysis,
      • Duarte R.V.
      • Sale A.
      • Desai P.
      • Marshall T.
      • Eldabe S.
      The unmet need for intrathecal drug delivery pumps for the treatment of cancer pain in England: an assessment of the hospital episode statistics database.
      the number of incident cancer cases for a given year was estimated by considering the annual difference in the total number of patients with cancer after accounting for the number of deaths. The ratio of patients who were incident-to-prevalent in the cancer population was then applied to the population with ITDD to obtain the number of incident cases.
      The following weekly probabilities/proportions were derived from the numbers directly reported in or calculated from the HES data analysis:
      • Percentage increment in the number of patients with cancer: transitions from newly diagnosed to all-cancer health state
      • Proportion of patients with cancer requiring ITDD and proportion of patients with ITDD with a new device: transitions from all-cancer health state to incident-case health state
      • Mortality risk in patients with cancer: transition to the absorbing health state “Death” from other health states.

      Resource Use and Unit Costs

      Costs considered were for drug acquisition, implantation procedure, ITDD device, and refill procedure. The unit costs of drugs were obtained from the British National Formulary
      National Institute for Clinical Excellence, British National Formulary
      Drug details including costs.
      whereas ITDD implantation and refill procedure costs were derived from the NHS schedule of reference costs (Table 2).
      2019/20 national costs collection data publication. National Health Service England.
      Table 2Unit of Resources.
      Resource useUnit costReference
      ITDD implantation£3,118NHS ref cost: HRG code AB13Z
      Intrathecal device£11,000Medtronic
      The starting dose of ziconotide was 0.5 μg per day, which is then increased weekly by 0.5 μg until a median dose of 3.5 μg per day is reached at week 6. Thereafter, patients continued to receive the median daily dose until death. Chemical and physical in-use stability for ziconotide alone or in combination with other drugs has been demonstrated for 14 days at 37 °C in Synchromed pumps.
      Prialt solution for infusion. Electronic Medicines Compendium.
      ,
      • Dupoiron D.
      • Richard H.
      • Chabert-Desnot V.
      • Devys C.
      • Leynia P.
      • Boisdron-Celle M.
      In vitro stability of low-concentration ziconotide alone or in admixtures in intrathecal pumps.
      As such, in the base-case analysis, it was assumed that a refill takes place every two weeks. The ziconotide dose used in the base case was informed by evidence that suggested a starting dose of 0.5 to 1.2 μg per day and dose increment of ≤ 0.5 μg per day, with an interval between dose increments that is not more than once weekly.
      • Matis G.
      • De Negri P.
      • Dupoiron D.
      • Likar R.
      • Zuidema X.
      • Rasche D.
      Intrathecal pain management with ziconotide: time for consensus?.
      Clinical advice was that when ziconotide is being used in combination with morphine, ziconotide is considered the primary drug whereas the dose of morphine is titrated as required. Given the narrow therapeutic range of intrathecal ziconotide, in the absence of unified guidance on intrathecal morphine dosage in combination with ziconotide and for simplicity, morphine dosage and dose escalation were assumed to be equivalent to those of ziconotide. The dosages used in the model are shown in Table 3.
      Table 3Treatment Dosage and Unit Cost of Drugs Used in the Model.
      Drug nameDosageQuantity per unitUnits per packCost per packSource
      Ziconotide0.5 μg/d on day 1, then 0.5 μg weekly increment until 3.5 μg/d100 μg/ml1 ml vial£302.48BNF
      National Institute for Clinical Excellence, British National Formulary
      Drug details including costs.
      ZiconotidePump rinse at ITDD implantation with 3 syringes containing 2 ml25 μg/ml2 ml vial£75.62BNF
      National Institute for Clinical Excellence, British National Formulary
      Drug details including costs.
      Morphine0.5 mg/d on day 1, then 0.5 mg daily increment until 2.5 mg/d40 mg/ml1 ml vial£9.60BNF
      National Institute for Clinical Excellence, British National Formulary
      Drug details including costs.
      BNF, British National Formulary.
      Based on clinical advice considering the conservative nature of UK physicians and the lack of experience with ziconotide in the UK, it was assumed in the base-case analysis that the market share of ziconotide combination therapy and morphine monotherapy/or other combinations could be 30:70 throughout the five-year time horizon. The ITDD implantation cost (£3118) was obtained from NHS reference costs.
      2019/20 national costs collection data publication. National Health Service England.
      These costs did not cover the cost of the device, which was assumed to be £11,000.

      Results

      Base-case Result

      A total of 109 patients entered the model as prevalent cases according to the results generated by the HES analysis.
      • Duarte R.V.
      • Sale A.
      • Desai P.
      • Marshall T.
      • Eldabe S.
      The unmet need for intrathecal drug delivery pumps for the treatment of cancer pain in England: an assessment of the hospital episode statistics database.
      Using the growth rate shown in Table 1, the total number of new patients with ITDD from the first year to fifth year is 40, 55, 64, 61, and 59, respectively (Table 4). Ziconotide combination therapy was more expensive than treatment with morphine monotherapy. The total costs of ziconotide combination therapy and morphine monotherapy for the first year were £395,748 and £136,628 respectively.
      Table 4Budget Impact of Ziconitide Combination Therapy vs Morphine Monotherapy.
      TreatmentYear 1Year 2Year 3Year 4Year 5
      Mean number of patients/wk146175181189195
      Total number of new patients/y4055646159
      ITDD placement
      Ziconotide with morphine
      ITDD placement cost includes the cost of rinsing device with ziconotide in the ziconotide with morphine model arm.
      £44,906£59,922£69,564£66,083£64,671
      Morphine monotherapy£87,767£119,623£140,080£132,696£129,699
      ITDD refills
      Ziconotide with morphine£350,842£433,088£447,414£468,697£482,352
      Morphine monotherapy£48,861£60,316£62,311£65,275£67,177
      Total cost
      Ziconotide with morphine£395,748£493,009£516,978£534,780£547,023
      Morphine monotherapy£136,628£179,939£202,391£197,971£196,875
      ITDD placement cost includes the cost of rinsing device with ziconotide in the ziconotide with morphine model arm.
      The estimated five-year cumulative budget impact of treatment with ziconotide combination therapy for the five-year time horizon was £2,487,539 whereas that of morphine monotherapy was £913,804. A significant proportion of the cost difference was due to the higher drug cost of ziconotide.
      A scenario was conducted whereby ziconotide monotherapy was considered. The associated year 1 (£374,577), year 2 (£466,845), year 3 (£489,905), year 4 (£506,456), to year 5 (£517,892) costs were lower than the equivalent cost of ziconotide combination therapy but expectedly higher than the costs of morphine monotherapy.

      Deterministic Sensitivity Analysis

      The five-year cumulative deterministic results are shown in Table 5. The results show that cumulative cost was most sensitive to an increase in the refill interval from two weeks to one month, the use of a more expensive vial of ziconotide and morphine, and the possibility of vial sharing.
      Table 5Sensitivity Analysis Results.
      ScenarioZiconotide combination therapyZiconotide monotherapyMorphine monotherapy
      Base case£2,487,539£2,355,674£913,804
      Overhead cost of refilling pump (£92)
      Inflation- and currency-adjusted value obtained from a previous cost-effectiveness study.
      £2,494,685£2,362,821£930,479
      Overhead cost of refilling pump (£671)
      Value obtained from the NHS reference cost (health-resource group code DEV18).
      £2,539,657£2,407,793£1,035,414
      Refill interval (1 mo)£1,419,908£1,320,659£835,831
      Ziconotide vial size (5 ml)£7,921,044£7,789,180£913,804
      Morphine conc. (2 mg/ ml)£3,468,279£2,355,674£3,173,744
      Relative dose intensity (80%)£2,421,606£2,355,674£761,834
      Relative dose intensity (90%)£2,487,539£2,355,674£913,804
      Include vial sharing (Yes)£1,376,962£1,296,195£795,073
      Set median survival (3 y)£2,760,932£2,614,504£1,016,171
      Set median survival (5 y)£3,239,853£3,067,915£1,195,525
      Set median survival (10 y)£3,686,785£3,491,041£1,362,931
      conc., concentration.
      Inflation- and currency-adjusted value obtained from a previous cost-effectiveness study.
      ∗∗ Value obtained from the NHS reference cost (health-resource group code DEV18).
      Of note, no overhead cost for ITDD pump refill was incurred in the base-case analysis. A sensitivity analysis was conducted using alternative ITDD refill overhead costs. The first estimate was obtained from a previous cost-effectiveness study of intrathecal drug therapy in the Canadian health system.
      • Kumar K.
      • Hunter G.
      • Demeria D.D.
      Treatment of chronic pain by using intrathecal drug therapy compared with conventional pain therapies: a cost-effectiveness analysis.
      The unit cost in that study ($120 Canadian) was subsequently used in a Canadian health technology assessment of ITDD systems.
      Health Quality Ontario
      Intrathecal drug delivery systems for cancer pain: a health technology assessment.
      It was therefore considered that using the inflation-
      • Curtis L.
      Unit costs of health and social care 2010. Personal Social Services Research Unit.
      ,
      • Curtis L.A.
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      and currency-adjusted value (£91.98) was appropriate. A second estimate that reflects the current NHS refill cost (£671) as detailed in the NHS reference costs was used. These two overhead cost estimates did not significantly change the base-case results (Table 5).

      Discussion

      We provide a budget impact analysis from the NHS perspective over a five-year time horizon that reflects a patient population with cancer pain in England. The results of this study suggest that the use of ziconotide is associated with higher costs to the health care system. However, the additional costs in any of the first five years are below the resource impact significance level of £1 million for medical technologies in England.

      Assessing resource impact process manual. National Institute for Health and Care Excellence. Accessed June 22, 2022. https://www.nice.org.uk/Media/Default/About/what-we-do/Into-practice/Assessing-resource-impact-process-manual.docx

      The results were robust to sensitivity analyses, with only the use of a more expensive vial of ziconotide (5 ml vial at a unit cost of £1086.94) resulting in a budget impact superior to £1 million per year. A lighter burden on health care resources would occur if vial sharing was a possibility. Vial sharing would require several patients to be scheduled to have a refill on the same day, which may not always be feasible if a center has a small number of patients receiving ziconotide. A large center in France that provides ziconotide and averages 256 refills per month estimated savings of €68,411 during the year 2021 by sharing ziconotide vials.
      • Dupoiron D.
      A limited number of expert centers currently provide ITDD for cancer pain in England, which is largely due to a limited number of practitioners in addition to operating room access constraints. Additional reasons for limited access to this intervention include the interface required between a number of specialties, making treatment delivery complex and only possible in large centers, the patient referral system that stipulates referrals from networked secondary care pain services or other tertiary specialties, and the lack of licensed ITDD-compatible therapeutic alternatives to morphine.
      • Duarte R.V.
      • Sale A.
      • Desai P.
      • Marshall T.
      • Eldabe S.
      The unmet need for intrathecal drug delivery pumps for the treatment of cancer pain in England: an assessment of the hospital episode statistics database.
      A recent study reported on the feasibility of conducting pump refills at the patient’s home, with 95% of patients and physicians/nurses feeling safe during the procedure.
      • Goudman L.
      • De Smedt A.
      • Huygens R.
      • et al.
      Hospital at home for intrathecal pump refills: a prospective effectiveness, safety and feasibility study.
      The possibility of pump refills at the patient’s home may improve access to ITDD, particularly in a population with cancer pain who often present with advanced ill health due to cancer and other comorbidities, limiting their ability to travel to bigger centers for implantation/pump refills and subsequent care.
      Recent systematic reviews with meta-analysis have shown that ITDD is an effective and safe intervention for the management of cancer pain, with statistically and clinically significant reductions in pain intensity observed.

      Duarte R, Copley S, Nevitt S, et al. Effectiveness and safety of intrathecal drug delivery systems for the management of cancer pain: a systematic review and meta-analysis. Published online April 11, 2022. Neuromodulation. https://doi.org/10.1016/j.neurom.2022.03.003

      ,

      Perruchoud C, Dupoiron D, Papi B, Calabrese A, Brogan SE. Management of cancer-related pain with intrathecal drug delivery: a systematic review and meta-analysis of clinical studies. Published online January 21, 2022. Neuromodulation. https://doi.org/10.1016/j.neurom.2021.12.004

      Improvements in quality of life were observed in the included studies that evaluated this outcome. Several studies in the systematic reviews included patients who received a combination of ziconotide with morphine.
      • Carvajal G.
      • Dupoiron D.
      • Seegers V.
      • et al.
      Intrathecal drug delivery systems for refractory pancreatic cancer pain: observational follow-up study Over an 11-year period in a Comprehensive Cancer Center.
      ,
      • Dupoiron D.
      • Leblanc D.
      • Demelliez-Merceron S.
      • et al.
      Optimizing initial intrathecal drug ratio for refractory cancer-related pain for early pain relief. A retrospective monocentric study.
      ,
      • Dupoiron D.
      • Lefebvre-kuntz D.
      • Brenet O.
      • et al.
      Refractory cancer pain and intrathecal infusion: experience of three cancer management centers.
      • Brogan S.E.
      • Sindt J.E.
      • Jackman C.M.
      • White J.
      • Wilding V.
      • Okifuji A.
      Prospective association of serum opioid levels and clinical outcomes in patients with cancer pain treated with intrathecal opioid therapy.
      • Brogan S.E.
      • Winter N.B.
      • Okifuji A.
      Prospective observational study of patient-controlled intrathecal analgesia: impact on cancer-associated symptoms, breakthrough pain control, and patient satisfaction.
      • Sindt J.E.
      • Odell D.W.
      • Dalley A.P.
      • Brogan S.E.
      Initiation of intrathecal drug delivery dramatically reduces systemic opioid use in patients with advanced cancer.
      A meta-analysis focused solely on patients who received ziconotide with morphine was not possible because the studies only provided aggregate data and results were not available for those specific patients alone. However, all studies reported significant pain relief in patients with cancer pain after ITDD.
      Many patients with cancer pain who present for ITDD are already receiving high doses of oral and systemic opioids, rendering them refractory to intrathecal opioids alone. Candidates for ITDD and clinicians are presented with very few evidence-based therapy options. Celiac plexus neurolysis, an intervention commonly practiced in pancreatic cancer, was found to be associated with worsened survival compared with treatment with opioids (adjusted hazard ratio 1.69; 95% CI, 1.59–1.79).
      • Zylberberg H.M.
      • Nagula S.
      • Rustgi S.D.
      • et al.
      Celiac plexus neurolysis is associated with decreased survival in patients with pancreatic cancer: a propensity score analysis.
      Other drugs may be combined with opioids to improve efficacy of ITDD, such as local anesthetics and alpha-2 agonists.
      • Dupoiron D.
      • Duarte R.
      • Carvajal G.
      • Aubrun F.
      • Eldabe S.
      Rationale and recent advances in targeted drug delivery for cancer pain: is it time to change the paradigm?.
      These, however, are not approved for use in the ITDD device, and have limited evidence of efficacy and several limitations including cardiovascular side effects and the need for precise catheter tip placement. Besides morphine, ziconotide is currently the only other intrathecal analgesic drug approved for management of cancer pain with ITDD.
      • Deer T.R.
      • Pope J.E.
      • Hayek S.M.
      • et al.
      The Polyanalgesic Consensus Conference (PACC): recommendations on intrathecal drug infusion systems best practices and guidelines.
      Although ziconotide monotherapy is licensed for use in the pump, a combination of ziconotide and morphine will not be recommended by the manufacturer of the ITDD devices. However, its track record in cancer pain treatment is far superior to either drug in isolation, hence our preference for costing the unlicensed combination vs ziconotide monotherapy. Ziconotide monotherapy or in combination with morphine is recommended by an expert consensus as first- or second-line ITDD treatment options, respectively, for cancer pain.
      • Deer T.R.
      • Pope J.E.
      • Hayek S.M.
      • et al.
      The Polyanalgesic Consensus Conference (PACC): recommendations on intrathecal drug infusion systems best practices and guidelines.
      This study considered several scenario analyses to explore the robustness of the results to variations in the parameters of the model. As recommended by a task force on good practices for budget impact analysis, we used the simplest design to generate credible and transparent estimates.
      • Mauskopf J.A.
      • Sullivan S.D.
      • Annemans L.
      • et al.
      Principles of good practice for budget impact analysis: report of the ISPOR Task Force on good research practices--budget impact analysis.
      Budget impact analyses, although informative of the impact of implementation of a new treatment in terms of costs to health care systems, do not account for potential improvements in pain control on a population of patients at a critical stage of life and ways this may affect additional resource use consumption, such as cost savings obtained from avoidance of hospital and/or hospice admission near end of life.
      • Stearns L.J.
      • Narang S.
      • Albright R.E.
      • et al.
      Assessment of health care utilization and cost of targeted drug delivery and conventional medical management vs conventional medical management alone for patients with cancer-related pain.
      Furthermore, the budget impact analysis does not account for potential improvements in survival. A randomized controlled trial (RCT) observed a cumulative survival of 53.9% at six months for patients with morphine ITDD compared with 37.2% for patients receiving conventional medical management (p < 0.06).
      • Smith T.J.
      • Staats P.S.
      • Deer T.
      • et al.
      Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival.
      The results of this RCT are quite historical and may not reflect current oncologic practices or patient survival; however, they still represent the only comparative RCT evidence for this specific population. We have also not considered the potential economic impact of the adverse events resulting from the addition of ziconotide to opioids in a population with multiple comorbidities because this can only be elucidated from clinical practice within a UK setting, which is currently not feasible.

      Conclusions

      The results of this budget impact analysis suggest that although a combination of intrathecal ziconotide in combination with morphine is associated with higher costs to the health care system in England, the incremental costs are not significant. The benefits and consequences of intrathecal ziconotide in combination with morphine should be considered in a full economic evaluation to estimate the cost-effectiveness of this intervention compared with morphine alone in a population with cancer pain.

      Authorship Statements

      Rui Duarte and Sam Eldabe conceptualized the study. Tosin Lambe developed the budget impact model, with support from Rui Duarte. Tosin Lambe, Rui Duarte, and Sam Eldabe interpreted the data. Tosin Lambe, Rui Duarte, and Rosie Eldabe wrote the first draft of the manuscript. All authors contributed to and approved the final version of the manuscript.

      Acknowledgements

      The authors are grateful to Julien Robert for providing estimates of cost-savings achieved by ziconotide vial sharing at Institut de Cancerologie de l’Ouest Paul Papin, Angers, France.

      Supplementary Data

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