Cost-effectiveness of maribavir versus conventional antiviral therapies for post-transplant refractory cytomegalovirus infection with or without genotypic resistance: A US perspective.

This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for post-transplant refractory cytomegalovirus (CMV) infection with or without resistance. A two-stage Markov model was designed using data from the SOLSTICE trial (NCT02931539), real-world multinational observational studies, and published literature. Stage 1 (0-78 weeks) comprised clinically significant CMV (csCMV), non-clinically significant CMV (n-csCMV), and dead states; stage 2 (78 weeks-lifetime) comprised alive and dead states. Total costs (2022 USD) and quality-adjusted life years (QALYs) were estimated for the maribavir and IAT cohorts. An incremental cost-effectiveness ratio was calculated to determine cost-effectiveness against a willingness-to-pay threshold of $100 000/QALY. Compared with IAT, maribavir had lower costs ($139 751 vs $147 949) and greater QALYs (6.04 vs 5.83), making it cost-saving and more cost-effective. Maribavir had higher acquisition costs compared with IAT ($80 531 vs $65 285), but lower costs associated with administration/monitoring ($16 493 vs $27 563), adverse events (AEs) ($11 055 vs $16 114), hospitalization ($27 157 vs $33 905), and graft loss ($4516 vs $5081), thus making treatment with maribavir cost-saving. Maribavir-treated patients spent more time without CMV compared with IAT-treated patients (0.85 years vs 0.68 years), leading to lower retreatment costs for maribavir (cost savings: -$42 970.80). Compared with IAT, maribavir was more cost-effective for transplant recipients with refractory CMV, owing to better clinical efficacy and avoidance of high costs associated with administration, monitoring, AEs, and hospitalizations. These results can inform healthcare decision-makers on the most effective use of their resources for post-transplant refractory CMV treatment.

Cytomegalovirus related hospitalization costs among hematopoietic stem cell and solid organ transplant recipients treated with maribavir versus investigator-assigned therapy: A US-based study.

BACKGROUND: Cytomegalovirus (CMV) infections among hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients impose a significant health care resource utilization (HCRU)-related economic burden. Maribavir (MBV), a novel anti-viral therapy (AVT), approved by the United States Food and Drug Administration for post-transplant CMV infections refractory (with/without resistance) to conventional AVTs has demonstrated lower hospital length of stay (LOS) versus investigator-assigned therapy (IAT; valgancilovir, ganciclovir, foscarnet, or cidofovir) in a phase 3 trial (SOLSTICE). This study estimated the HCRU costs of MBV versus IAT. METHODS: An economic model was developed to estimate HCRU costs for patients treated with MBV or IAT. Mean per-patient-per-year (PPPY) HCRU costs were calculated using (i) annualized mean hospital LOS in SOLSTICE, and (ii) CMV-related direct costs from published literature. Probabilistic sensitivity analysis with Monte-Carlo simulations assessed model robustness. RESULTS: Of 352 randomized patients receiving MBV (n = 235) or IAT (n = 117) for 8 weeks in SOLSTICE, 40% had HSCT and 60% had SOT. Mean overall PPPY HCRU costs of overall hospital-LOS were $67,205 (95% confidence interval [CI]: $33,767, $231,275) versus $145,501 (95% CI: $62,064, $589,505) for MBV and IAT groups, respectively. Mean PPPY ICU and non-ICU stay costs were: $32,231 (95% CI: $5,248, $184,524) versus $45,307 (95% CI: $3,957, $481,740) for MBV and IAT groups, and $82,237 (95% CI: $40,397, $156,945) MBV versus $228,329 (95% CI: $94,442, $517,476) for MBV and IAT groups, respectively. MBV demonstrated cost savings in over 99.99% of simulations. CONCLUSIONS: This analysis suggests that Mean PPPY HCRU costs were 29%-64% lower with MBV versus other-AVTs.

Healthcare costs among hemophilia A patients in the United States treated with rurioctocog alfa pegol (FVIII-PEG) or antihemophilic factor (recombinant), FC fusion protein (rFVIIIFc) using real-world data.

AIMS: To compare healthcare costs in patients with non-inhibitor hemophilia A treated with Rurioctocog Alfa Pegol (FVIII-PEG) versus Antihemophilic Factor (Recombinant), FC Fusion Protein (rFVIIIFc). MATERIALS AND METHODS: Administrative claims data from the Merative MarketScan Commercial (Commerical) and Medicaid (Medicaid) databases were used for these analyses. Males with non-inhibitor hemophilia A treated with FVIII-PEG or rFVIIIFc from 1 January 2016 to 31 March 2021 were identified (earliest treatment = index). Patients were required to have continuous database enrollment for six months before and after the index date. Follow-up was variable in length until disenrollment or study end. All-cause and hemophilia-related healthcare costs were reported per-patient per month [PPPM] and the average weekly dose during follow-up was compared between treatment groups. Generalized linear regressions were used to estimate multivariable-adjusted differences in total costs and weekly dosage in the two treatment groups. RESULTS: A total of 131 FVIII-PEG (66 Commercial; 65 Medicaid) and 204 rFVIIIFc (111 Commercial; 93 Medicaid) patients were eligible. Mean age was 20.5 and 24.4 for FVIII-PEG and rFVIIIFc in Commercial and 14.9 and 17.5 for FVIII-PEG and rFVIIIFc in Medicaid. PPPM mean (standard deviations [SD]) total healthcare costs in Commercially insured patients were $35,868 [$21,717] for FVIII-PEG vs $40,424 [$25,882] for rFVIIIFc. Costs in Medicaid were $27,495 [$23,243] for FVIII-PEG vs $30,237 [$28,430] for rFVIIIFc. After adjusting for baseline characteristics, the costs for rFVIIIFc (vs FVIII-PEG) were higher by $5,215 in Commercial and $3,895 in Medicaid, but the differences were not statistically significant (p > 0.05). Similar findings were observed for hemophilia-specific healthcare costs. The adjusted mean weekly dose was 6,047 vs 4,892 IU, p = 0.21 for FVIII-PEG vs rFVIIIFc in Commercial and 5,549 vs 7,228 IU, p = 0.07 for FVIII-PEG vs rFVIIIFc in Medicaid. CONCLUSIONS: Healthcare costs and treatment dosing were similar (p > 0.05) for non-inhibitor hemophilia A patients treated with FVIII-PEG and rFVIIIFc.

Real-world changes in costs over time among patients in the United States with hereditary angioedema on long-term prophylaxis with lanadelumab.

AIMS: Investigate trends in paid lanadelumab costs over time in a population of patients persistent for 18 months, and to understand overall hereditary angioedema (HAE) treatment cost trends, including costs of acute medication/short-term prophylaxis and supportive care. Lastly, we sought to describe the proportion of lanadelumab patients with evidence of down titration via changes in total paid amounts for lanadelumab in a fixed time period. METHODS: Patients were identified in the Merative MarketScan Databases who had ≥1 claim for lanadelumab during 1/1/2018-6/30/2022 (index), a ≤ 60-d gap in days of supply over 18 months, and were enrolled for ≥6 months pre-index and 18 months post-index. Lanadelumab and HAE-specific costs were assessed during follow-up months 0-6, 7-12, and 13-18. Down titration was defined as a ≥ 25% decrease in lanadelumab costs from months 0-6 to months 7-12 or 13-18. Outcomes were compared between time periods using paired t-tests and McNemar's test. RESULTS: Fifty-four lanadelumab users were included; 25 (46%) had evidence of down titration. Lanadelumab costs decreased from $316,724 to $269,861 to $246,919 in months 0-6, 7-12, and 13-18, respectively (p < .01); total HAE treatment costs decreased from $377,076 to $329,855 to $286,074 in months 0-6, 7-12, and 13-18, respectively (p < .01). LIMITATIONS: Persistence was determined via days of supply on medication claims; use of the medication was not confirmed. Down titration was based on costs; the lanadelumab regimen could not be assessed. Results may not be generalizable to uninsured patients or those without commercial or Medicare insurance. CONCLUSIONS: Patients on long-term prophylaxis with lanadelumab experienced a significant reduction (24%) in HAE treatment costs over 18 months, driven by lower costs of acute medications and lanadelumab down titration. Down titration among appropriate patients with controlled HAE may lead to substantial savings in healthcare costs.

A real-world evidence analysis of the impact of switching from factor VIII to emicizumab prophylaxis in patients with hemophilia A without inhibitors.

BACKGROUND: This study retrospectively compared annualized billed bleed rates (ABRb) in people with hemophilia A (PwHA) without inhibitors who switched from factor VIII (FVIII) prophylaxis to emicizumab. RESEARCH DESIGN AND METHODS: A real-world comparison study was performed on the effect of switching from FVIII to emicizumab prophylaxis in male, non-inhibitor patients on ABRb using an all-payer claims database (APCD) dataset from 1 January 2014, to 31 March 2021. The identification period was from 1 November 2017, to 30 September 2020. RESULTS: One hundred and thirty-one patients were included with a total of 82 and 45 bleeds in the pre- and post-switch periods, respectively. The average follow-up period pre-switch was 978.37 days (SD 555.03), whereas the average follow-up period post-switch was 522.26 days (SD 191.36). No significant differences in mean ABRb were observed pre-/post-switch (0.25 and 0.20, respectively; P = 0.4456). CONCLUSIONS: The results of this study demonstrate no significant reduction in ABRb, suggesting that switching from FVIII to emicizumab may not deliver incremental benefits to PwHA receiving prophylactic care.

Impact of switching prophylaxis treatment from factor VIII to emicizumab in hemophilia A patients without inhibitors.

BACKGROUND: Factor VIII (FVIII) replacement and emicizumab are effective at preventing bleeds in patients with hemophilia A (HA). Though benefits of emicizumab among inhibitor patients with HA (PwHA) are well established, more real-world evidence among non-inhibitor patients is needed. METHODS: Using a United States healthcare claims database, we compared billed annualized bleed rates (ABRb) and the total cost of care (TCC) before and after switching from FVIII prophylaxis to emicizumab among non-inhibitor male PwHA. Bayesian inferences were used to assess the difference in ABRb and TCC per patient per year (PPPY) pre- versus post-prophylaxis switch. RESULTS: We included 101 non-inhibitor male PwHA aged between 3 and 63 years old who switched from FVIII prophylaxis to emicizumab prophylaxis in 2018 or 2019. The ABRb increased from 0.52 to 0.62 (p = 0.83) after switch. The posterior probability of the mean ABRb increasing after the switch was 75.54%. The TCC PPPY increased from $517,143 to $627,005 (p < 0.0001) after switch and the posterior probability of mean costs increasing after the switch was 99.80%. CONCLUSIONS: Personalization of care through the identification of the most appropriate therapy for each patient can optimize clinical and economic outcomes. Future real-world evidence research could help establish the value of prophylactic options in targeted populations such as the non-inhibitor male PwHA.

Evaluating the financial impact of utilizing recombinant porcine factor VIII or recombinant FVIIa for patients with acquired hemophilia A.

OBJECTIVE: To evaluate the financial impact of utilizing rpFVIII or rFVIIa during a hospital admission for the diagnosis of acquired hemophilia A (AHA) by reviewing the margin between the cost to the hospital for providing care and the amount the hospital is reimbursed by the Centers for Medicare & Medicaid Services (CMS) in the US. METHODS: Data source was the Medicare Limited Data Set, which contains claims for hospitalizations, charges, and amounts reimbursed by CMS. Study patients were hospitalized with AHA and treated with rpFVIII and/or rFVIIa between 1/1/2015 and 12/31/2019. CMS Fiscal Year 2020 Impact Files, with hospital-level cost-to-charge ratios (CCRs), were used to estimate hospital costs. Sensitivity analyses were conducted to estimate margins at different CCRs. RESULTS: Hospital margins were, on average, positive with use of either rpFVIII or rFVIIa (rpFVIII: $51,548.89; rFVIIa: $35,943.80). Sensitivity analysis results suggest that the use of rpFVIII is similiar, compared with rFVIIa for a large majority of hospitals. CONCLUSIONS: While there may be higher reimbursement for rpFVIII hospitalizations, this analysis suggests that the use of rpFVIII, compared to rFVIIa, may have no impact on hospital finances for the majority of hospitals, despite rpFVIII's higher per unit cost.

Budget impact of introducing subcutaneous vedolizumab as a maintenance therapy in biologic-naïve and biologic-experienced patients with ulcerative colitis in France.

BACKGROUND: Inflammatory bowel disease poses significant social and economic burdens. We assessed the budget impact of including the recently approved subcutaneous (SC) formulation of vedolizumab as maintenance therapy (MT) in patients with ulcerative colitis (UC) in France. METHODS: A decision-analytic model was developed from a French payer's perspective over 5 years to assess budget impact of including vedolizumab SC as MT for UC following induction therapy with vedolizumab intravenous (IV), by subtracting outcomes of a 'world without vedolizumab SC' from a 'world with vedolizumab SC.' Comparators included approved therapies: infliximab (branded/biosimilar), adalimumab (branded/biosimilar), golimumab, ustekinumab, and vedolizumab IV. The model predicts drug, medical, and total costs, including indirect costs in a scenario analysis. A one-way sensitivity analysis explored the impact of varying individual parameters. RESULTS: Including vedolizumab SC as MT following vedolizumab IV induction yielded total cost savings of €59,176,842 (biologic-naïve) and €22,004,135 (biologic-experienced) versus a world without vedolizumab SC. Including indirect costs yielded cost savings in biologic-naïve (€62,600,716) and biologic-experienced (€24,314,915) populations in a world with vedolizumab SC. CONCLUSIONS: Introducing vedolizumab SC as MT after IV induction is expected to have substantial cost savings to a health plan from a French payer's perspective versus a world without vedolizumab SC.

Evaluating cost per remission and cost of serious adverse events of advanced therapies for ulcerative colitis.

BACKGROUND: Determining the relative cost-effectiveness between advanced therapeutic options for ulcerative colitis (UC) may optimize resource utilization. We evaluated total cost per response, cost per remission, and cost of safety events for patients with moderately-to-severely active UC after 52 weeks of treatment with advanced therapies at standard dosing. METHODS: An analytic model was developed to estimate costs from the US healthcare system perspective associated with achieving efficacy outcomes and managing safety outcomes for advanced therapies approved for the treatment of UC. Numbers needed to treat (NNT) for response and remission, and numbers needed to harm (NNH) for serious adverse events (SAEs) and serious infections (SIs) were derived from a network meta-analysis of pivotal trials. NNT for induction and maintenance were combined with drug regimen costs to calculate cost per clinical remission. Cost of managing AEs was calculated using NNH for safety outcomes and published costs of treating respective AEs. RESULTS: Costs per remission were $205,240, $249,417, $267,463, $365,050, $579,622, $750,200, and $787,998 for tofacitinib 10 mg, tofacitinib 5 mg, infliximab, vedolizumab, golimumab, adalimumab, and ustekinumab, respectively. Incremental costs of SAEs and SIs collectively were $136,390, $90,333, $31,888, $31,061, $20,049, $12,059, and $0 for tofacitinib 5 mg, golimumab, adalimumab, tofacitinib 10 mg, infliximab, ustekinumab, and vedolizumab (reference), respectively. CONCLUSIONS: Tofacitinib was associated with the lowest cost per response and cost per remission, while vedolizumab had the lowest costs related to SAEs and SIs. Balancing efficacy versus safety is important when evaluating the costs associated with treatment of moderate-to-severe UC.

A real-world study comparing pre-post billed annualized bleed rates and total cost of care among non-inhibitor patients with hemophilia A switching from FVIII prophylaxis to emicizumab.

OBJECTIVE: Factor VIII (FVIII) replacement and emicizumab have demonstrated efficacy for prevention of bleeds among patients with hemophilia A (PwHA) compared to on-demand (OD) use. Evidence investigating clinical outcomes and healthcare costs of non-inhibitor PwHA switching from prophylaxis with FVIII concentrates to emicizumab has not been well-established within large real-world datasets. This study aimed to investigate billed annualized bleed rates (ABRb) and total cost of care (TCC) among non-inhibitor PwHA switching from FVIII-prophylaxis to emicizumab-prophylaxis. METHODS: This retrospective, observational study was conducted using IQVIA PharMetrics Plus, a US administrative claims database. The date of first claim for emicizumab was defined as the index date. OD patients and inhibitor patients were excluded. Bleeds were identified using a list of 535 diagnosis codes. Bayesian models were developed to estimate the probability ABRb worsens and TCC increases after switching to emicizumab. Wilcoxon rank-sum tests were used to test statistical significance of changes in ABRb and TCC after switch. RESULTS: Among the 121 identified patients, the difference in mean ABRb between FVIII-prophylaxis (0.68 [SD = 1.28]) and emicizumab (0.55 [SD = 1.48]) was insignificant (p = .142). The mean annual TCC significantly increased for patients switching from FVIII-prophylaxis ($518,151 [SD = $289,934]) to emicizumab ($652,679 [SD = $340,126]; p < .0001). The Bayesian models estimated a 21.0% probability of the ABRb worsening and a 99.9% probability of increasing TCC after switch. CONCLUSIONS: This study found that in male non-inhibitor PwHA, switching from FVIII prophylaxis to emicizumab incurs substantial cost increase with no significant benefit in ABRb. This evidence may help guide providers, payers, and patients in shared decision-making conversations around best treatment options.

Cost-effectiveness of intravenous vedolizumab vs subcutaneous adalimumab for moderately to severely active ulcerative colitis.

BACKGROUND: The efficacy of intravenous (IV) vedolizumab vs subcutaneous (SC) adalimumab for the treatment of moderately to severely active ulcerative colitis (UC) was assessed in the VARSITY clinical trial, which demonstrated for the first time in a head-to-head clinical trial setting the superiority of IV vedolizumab with respect to clinical remission and endoscopic improvement. Both therapies offer better clinical outcomes compared with immunomodulators and corticosteroids but are often more expensive than other pharmacologic treatment options. Thus, payers and decision makers face the task of leveraging finite resources for optimal health benefits, which can be aided by the use of cost-effectiveness models. OBJECTIVE: To assess the cost-effectiveness of IV vedolizumab vs SC adalimumab from a US payer perspective using head-to-head data from the VARSITY trial. METHODS: A cohort decision tree was developed to estimate the costs and clinical outcomes associated with IV vedolizumab vs SC adalimumab to treat adults with moderately to severely active UC. Simulated cohorts began the model at treatment induction and continued to maintenance treatment with vedolizumab or adalimumab unless experiencing nonresponse or serious adverse drug reaction (ADR), in which case those patients transitioned to second-line treatment with tofacitinib, infliximab, or golimumab, where they could achieve response and/or remission or not. Those who still did not achieve response or remission or who had a serious ADR transitioned to a state of nonresponse for the remainder of the model or received surgery. The process was modeled for patients who were treatment naive and treatment experienced at baseline separately. Efficacy and safety inputs for vedolizumab and adalimumab were taken from the VARSITY trial, and corresponding inputs for other biologics were derived from a network meta-analysis. All clinical inputs were extrapolated over 2 years. Direct medical costs (expressed in 2019 US dollars) included those related to drug acquisition and administration, ADRs, routine monitoring, and additional treatment procedures. Outcomes were not discounted given the short time horizon. Univariate sensitivity and scenario analysis were applied to evaluate the robustness of the model to underlying parameter and structural uncertainty. RESULTS: Initial treatment with vedolizumab was associated with a higher remission rate at 2 years (73.5% vs 71.5%) and higher persistence (22.0% vs 14.4%) compared with adalimumab. Total direct medical costs were lower for the vedolizumab cohort ($100,022 vs $151,133), primarily driven by the lower annual drug acquisition cost of vedolizumab ($85,953 vs $137,492). When endoscopic improvement was used as the outcome measure, IV vedolizumab was also associated with higher endoscopic remission and lower overall costs. CONCLUSIONS: With better clinical outcomes and lower direct medical costs over a 2-year model horizon, vedolizumab IV was the dominant treatment strategy vs adalimumab SC in adults with moderately to severely active UC. Outcomes were driven primarily by the probability of major ADRs and induction response. DISCLOSURES: This study was supported by Takeda Pharmaceuticals U.S.A., Inc. (Lexington, MA). Schultz and Turpin are employees of Takeda Pharmaceuticals U.S.A., Inc. Turpin has stock or stock options in Takeda Pharmaceuticals. Diakite, Carter, and Snedecor are employees of OPEN Health (Bethesda, MD), which received payment from Takeda for the design and execution of this study. This study was presented at the European Crohn's and Colitis Organisation (ECCO) 2020 Congress and Digestive Disease Week (DDW), 2020 Virtual Congress.

Cost-Effectiveness Analysis of a Pharmacist-Led Medication Therapy Management Program: Hypertension Management.

OBJECTIVES: Uncontrolled hypertension is a common cause of cardiovascular disease, which is the deadliest and costliest chronic disease in the United States. Pharmacists are an accessible community healthcare resource and are equipped with clinical skills to improve the management of hypertension through medication therapy management (MTM). Nevertheless, current reimbursement models do not incentivize pharmacists to provide clinical services. We aim to investigate the cost-effectiveness of a pharmacist-led comprehensive MTM clinic compared with no clinic for 10-year primary prevention of stroke and cardiovascular disease events in patients with hypertension. METHODS: We built a semi-Markov model to evaluate the clinical and economic consequences of an MTM clinic compared with no MTM clinic, from the payer perspective. The model was populated with data from a recently published controlled observational study investigating the effectiveness of an MTM clinic. Methodology was guided using recommendations from the Second Panel on Cost-Effectiveness in Health and Medicine, including appropriate sensitivity analyses. RESULTS: Compared with no MTM clinic, the MTM clinic was cost-effective with an incremental cost-effectiveness ratio of $38 798 per quality-adjusted life year (QALY) gained. The incremental net monetary benefit was $993 294 considering a willingness-to-pay threshold of $100 000 per QALY. Health-benefit benchmarks at $100 000 per QALY and $150 000 per QALY translate to a 95% and 170% increase from current reimbursement rates for MTM services. CONCLUSIONS: Our model shows current reimbursement rates for pharmacist-led MTM services may undervalue the benefit realized by US payers. New reimbursement models are needed to allow pharmacists to offer cost-effective clinical services.

The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms.

Nearly 30% of adults 40 years and older in the United States are on a statin. Their widespread use heightens the importance of careful consideration of their varied effects on the body. Although randomized controlled trials have not confirmed cognitive impairing effects with statins, continuing evidence suggests statins have the ability to cause reversible cognitive impairment in some patients. Paradoxically, statins have also been shown to decrease the risk of dementia, Alzheimer's disease, and improve cognitive impairment in some cases. However, randomized controlled trials have similarly failed to find the beneficial effect. Supporting evidence for both claims is compelling whereas known limitations of the clinical trials may explain the lack of findings. This narrative review aims to explain why there is still controversy and how both effects can, and may, be possible. The mechanisms that have been hypothesized for each effect are seemingly independent from one another and may explain the contradicting results. Being mindful of the complex effects of statins, health care providers need to be able to identify patients who are at risk for or already experiencing cognitive impairment from statin use while also identifying those who could potentially decrease their risk of dementia with statins.

The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn's Disease, and Other Chronic Pain Disorders.

Chronic inflammatory diseases are complex to treat and have an impact on a large number of patients. Due to the difficulty of treating these diseases and the great impact on quality of life, patients often seek off-label, complimentary, or alternative medicines to gain relief from symptoms. Low-dose naltrexone has been used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn's disease, fibromyalgia, and other diseases. Naltrexone is a mu-opioid receptor antagonist indicated by the U.S. Food and Drug Administration for opioid and alcohol dependence. It is hypothesized that lower than standard doses of naltrexone inhibit cellular proliferation of T and B cells and block Toll-like receptor 4, resulting in an analgesic and antiinflammatory effect. It is the purpose of this review to examine the evidence of the safety, tolerability, and efficacy of low-dose naltrexone for use in chronic pain and inflammatory conditions. Currently, evidence supports the safety and tolerability of low-dose naltrexone in multiple sclerosis, fibromyalgia, and Crohn's disease. Fewer studies support the efficacy of low-dose naltrexone, with most of these focusing on subjective measures such as quality of life or self-reported pain. These studies do demonstrate that low-dose naltrexone has subjective benefits over placebo, but evidence for more objective measures is limited. However, further randomized controlled trials are needed to determine the efficacy of low-dose naltrexone due to insufficient evidence supporting its use in these disease states. This review provides practitioners with the extent of low-dose naltrexone evidence so that they can be cognizant of situations where it may not be the most appropriate therapy.