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Low dose naltrexone (LDN) in MS: Effects on medication use. A quasi-experimental study































Abstract
Low dose naltrexone (LDN) has become a popular off-label therapy for multiple sclerosis (MS). A few small, randomized studies indicate that LDN may have beneficial effects in MS and other autoimmune diseases. If proven efficacious, it would be a cheap and safe alternative to the expensive treatments currently recommended for MS. We investigated whether a sudden increase in LDN use in Norway in 2013 was followed by changes in dispensing of other medications used to treat MS. We performed a quasi-experimental before–and–after study based on population data from the Norwegian Prescription Database (NorPD). We included all patients that collected at least one LDN prescription in 2013, and had collected at least two medications with a reimbursement code for MS, or collected a medication with MS as the only indication in 2009 or 2010.
Outcomes were differences in cumulative dispensed doses and incidence of users of disease modifying MS therapies, and medications used to treat MS symptoms two years before and two years after dispensing the initial LDN prescription. The eligible 341 patients collected 20 921 prescriptions in the observation period. Apart from changes in line with general trends in MS therapy in Norway, there was no difference in neither dispensed cumulative doses or number of prevalent users of MS specific medication. Initiation of LDN was not followed by reductions of other medications used to treat symptoms associated with MS.

Introduction
Naltrexone is an opioid antagonist originally used to treat opioid and alcohol addiction [1,2]. In the past two decades, naltrexone in low doses (<5 mg/day, Low Dose Naltrexone, LDN) has gained popularity among some patients and doctors as off-label treatment of multiple sclerosis (MS) and other autoimmune diseases like Crohn’s disease, psoriasis, and rheumatoid arthritis [3]. Few studies have investigated the efficacy of LDN in MS, hence LDN should be considered an experimental, alternative therapy.

The suggested mechanisms of action for LDN in autoimmune diseases are mainly related to endogenous opioid activity [4]. In MS, one hypothesis is that LDN results in reduced apoptosis in oligodendrocytes [5]. The safety profile of naltrexone is well known when used for approved indications at the standard dose of 50 mg/day. The FDA issued a black box warning concerning hepatotoxicity in high doses (>300 mg/day), but this has not been considered a clinical problem at standard doses [6]. The risk of hepatotoxicity is probably lower for LDN compared to higher doses of naltrexone. Recently, Norwegian neurologists described a case of treatment-resistant immune thrombocytopenic purpura (ITP) that was probably linked to LDN use by a MS patient [7]. However, ITP is also a known adverse reaction of interferon beta, a standard treatment of MS [8].

In Internet forums, a number of MS patients report beneficial effects of LDN including reduced relapse rate and slowed disease progression. They also report fewer side effects than most other established therapies. In August 2017, LDN was rated better than baclofen, glatiramer acetate, intravenous glucocorticoids, and interferons beta as MS therapy on CureTogether, an online social patient network [9].

High quality clinical and pharmacoepidemiological studies evaluating the effect of LDN in MS are lacking, possibly because naltrexone is a low cost generic drug with limited commercial potential. If efficacy is proven comparable to or better than standard treatment options, it could be a cheap alternative to many expensive medicines.

The effects on quality of life (QoL) of LDN in MS have been examined in two placebo-controlled, double-blinded crossover studies. One study funded by American LDN supporters, found significant effects on some QoL measures. A similar study from Iran found no effect in patients receiving 4.5 mg naltrexone/day [10,11]. In a retrospective study on long-term treatment in MS, the authors found that LDN monotherapy did not result in an exacerbation of disease symptoms, adverse effects or deterioration of general health [12].

On February 28 2013, the biggest commercial television station in Norway (TV2) aired a documentary on the alleged beneficial effects of LDN in MS. Patients with severe MS explained how the use of LDN had almost normalized their functioning [13]. This resulted in a substantial increase in the awareness of LDN among patients with a wide range of chronic diseases. According to data from the Norwegian Prescription Database (NorPD), the yearly periodic prevalence of LDN users increased from < 100 to more than 11 000 during 2013 [14]. This sudden increase provided an unprecedented opportunity for quasi-experimental studies to assess the effect of LDN on prescribing of other medicines in MS and other chronic conditions. Using NorPD data, we have already observed that the sudden increase in the use of LDN in Norway in 2013 was followed by a significant reduction in opioid dispensing among persistent LDN users [15].

It is reasonable to assume some correlation between severity of MS symptoms and the type and amount of drugs dispensed to MS patients. If LDN has a clinical effect in MS, it is plausible that initiation of LDN therapy could be followed by detectable changes in the dispensing of disease modifying substances, or changes in dispensing of drugs used to treat MS symptoms (e.g. glucocorticoids and baclofen). However, there is insufficient evidence to conclude any direct association between dispensing of drugs and severity of the disease. Regardless whether LDN has an effect or not in MS, it is interesting to investigate potential changes in prescription patterns of relevant medication following initiation of this controversial treatment. Such changes would affect costs, side effects and drug interactions in this patient group where polypharmacy is common, and should be of interest to both prescribers, patients and those who pay for health services.

Objective
The aim of this study was to evaluate whether initiation of LDN therapy was followed by a change in the dispensing of medication used in MS. If so, were there any differences between MS patients that collected LDN once, and MS patients that collected LDN twice or more?

Methods
Study design/Setting/Resources for the study
We performed a quasi-experimental study based on data from NorPD, which contains individual data on all prescriptions dispensed since 2004 to the entire Norwegian population excluding hospital and nursing home patients. Details on NorPD are published elsewhere [16]. In short, each prescription in NorPD contains a unique pseudonym for the personal identifier and demographic data of both the patient and the prescriber, the medical specialty of the prescriber, the Anatomical Therapeutic Chemical classification (ATC) code and the amount of drug in defined daily dose (DDD), date of dispensing, and location of the dispensing pharmacy. The Norwegian Institute of Public Health is the host of the database [17]. It is possible to follow individual patients’ dispensing over time as NorPD contains information about reimbursed as well as non-reimbursed prescriptions. Only dispensed products that have a product identifying number are recorded, and consequently, products produced in the pharmacy such as reformulated naltrexone tablets are not included. The database contains no information on the indication for therapy, but has disease codes (ICD-10 or ICPC-2) for reimbursement. We applied to NorPD and paid a fee to obtain a data file containing information from January 1 2009 to December 31 2015 for all Norwegian patients that had collected at least one LDN prescription (product identification code 361181) in 2013 [18].

Study subjects
MS patients who had collected at least one LDN prescription in 2013 were included in the study, and we defined the first LDN dispensing date as “Index date”.

Patients who in 2009 and 2010 had collected medication that is only approved for MS or with a reimbursement code for MS (ICD-10 G35 or ICPC-2 N86) were considered MS patients. Patients who collected naltrexone before 2013 and patients who died before 2013 were excluded.

We stratified all MS patients into three groups based on the number of LDN prescriptions dispensed during 2013 and 2014:


We have previously shown that median naltrexone daily dose among Norwegian persistent LDN users in 2013 and 2014 was 3.7 mg [14]. A majority of patients in the LDN x 4+ group collected LDN sufficient for at least one whole year’s continuous use, and they were classified as persistent users. The patients in the LDN x 1 group presumably only had LDN available for a short period, and could be considered a control group.

Variables
We used the following variables in this study: person identifier for patient, patient age and sex, reimbursement code, ATC code, product identifying number, date of dispensing, and dispensed volume in DDDs.

Outcome variables
The primary outcome measure was a change in the dispensing of disease modifying agents as well as baclofen and systemic glucocorticoids in each group (LDN x 1, LDN x 2–3, LDN x 4+). We analyzed all disease modifying agents separately and aggregated in drug classes. In order to account for new treatment options during the study period, we performed pooled analyses on agents that had a secular reduction in dispensing in the Norwegian population (interferon beta and glatiramer acetate), and on disease modifying MS agents (dimethyl fumarate, fampridin, fingolimod, teriflunomide) that were introduced on the Norwegian market during the observation period. Secondary outcomes were changes in medications indirectly associated with disease activity or quality of life for MS patients. MS patients frequently report pain, and we therefore focused on analgesics [18]. We also considered drugs used for urinary frequency and incontinence, constipation and erectile dysfunction in addition to antidepressants, hypnotics, and benzodiazepines. A detailed description of outcomes is given in S1 Table. All outcomes were expressed as differences in average cumulative DDD in each group, and as a change in number of users as percentage of all patients in each group between the two years (730 days) preceding and the two years following the Index date.

Measurement
For each group, we added up the number of average DDDs collected and the number of users for each drug in the two years (730 days) before and two years after the Index date (Index date + 729 days). This means that the total observation time was four years, and the first potential outcome observation date before Index date was January 1 2011, and the last potential observation date after Index date was December 31 2015.

Bias
To increase the specificity of the MS diagnosis, patients had to have collected at least two prescriptions that met inclusion criteria (see S1 Text for complete inclusion criteria). We assumed that newly diagnosed MS patients would have a larger increase in MS-specific drugs than patients that were observed over the entire period. Inclusion was therefore based on NorPD data from the two (2009 and 2010) years preceding the observation period (2011–2015).

Study size
The number of patients fulfilling our inclusion criteria in NorPD determined study size.

Statistical methods
Data were prepared for analyses in SPSS 23 and Excel 2013. Pairwise two-sided t-test was used to test significance of mean changes in DDD in each group for all examined drugs. Confidence intervals (95%) for difference of means were calculated. Change of number of users was expressed as proportion (%) of each group with confidence interval (95%) calculated in accordance with method for non-independent proportions [19]. A significance level of 0.05 was used to assess whether there were changes in prescribing before and after LDN different from zero, or difference-in-difference between groups.

Ethics
The project protocol was submitted to the Regional Committee for Medical and Health Research Ethics of Northern Norway. The committee concluded that disclosure was not mandatory, since the data were pseudonymized. The local privacy ombudsman for research at the University Hospital of North Norway approved the project. For Norwegian central health registers like NorPD, consent from individual patients is by law not required. A significance level of 0.05 was used to assess whether there were changes in prescribing before and after LDN different from zero, or difference-in-difference between groups.

Results
Participants
The inclusion of patients and the number of dispensed medications of interest are presented in Fig 1. All prescriptions collected by the included patients in the entire observation period (two years before and two years after the Index date) were available for analyses, in total 16 368 patient months. Baseline characteristics are presented in Table 1. The proportion of females was highest in the LDN x 2–3 group.

The included patients collected 1 744 LDN prescriptions in the study period, and the median was 5 dispensed LDN prescriptions. There were 10 261 dispensed prescriptions of outcome drugs two years before Index date, and 8 916 two years after.

Changes in the dispensing of disease modifying MS drugs, systemic glucocorticoids, and baclofen are presented in Fig 2, Table 2 (DDDs), and in S2 Table and S1 Fig (number of users). Changes in the other drugs included in the analysis are shown in Table 3 (DDDs) and in S3 Table (number of users). There was no significant difference between the groups of LDN users. There was a significant reduction in the dispensing of interferons and glatiramer acetate in all groups, both in terms of total cumulative DDDs and number of prevalent users.

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