Monday, 28 July 2014

Low-dose naltrexone for treatment of multiple sclerosis Are clinical trials needed. Will they happen?

Every time I talk about complementary/alternative medicine to MSers someone tells me of a good luck story about low dose naltrexone. Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. Naltrexone should not be confused with naloxone (which is used in emergency cases of opioid overdose) nor nalorphine. Using naloxone in place of naltrexone can cause acute opioid withdrawal symptoms; conversely, using naltrexone in place of naloxone in an overdose can lead to insufficient opioid antagonism and fail to reverse the overdose. Low Dose Naltrexone or LDN as it known has been hitting the news recently. However the problem is is that there is simple not enough good data to support this use. 

Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G.A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult Scler. 2008;14(8):1076-83.

A sixth month phase II multicenter-pilot trial with a low dose of the opiate antagonist Naltrexone (LDN) has been carried out in 40 patients with primary progressive multiple sclerosis (PPMS). The primary end points were safety and tolerability. Secondary outcomes were efficacy on spasticity, pain, fatigue, depression, and quality of life. Clinical and biochemical evaluations were serially performed. Protein concentration of beta-endorphins (BE) and mRNA levels and allelic variants of the mu-opiod receptor gene (OPRM1) were analyzed. Five dropouts and two major adverse events occurred. The remaining adverse events did not interfere with daily living. Neurological disability progressed in only one patient. A significant reduction of spasticity was measured at the end of the trial. BE concentration increased during the trial, but no association was found between OPRM1 variants and improvement of spasticity. Our data clearly indicate that LDN is safe and well tolerated in patients with PPMS.

Sharafaddinzadeh N, Moghtaderi A, Kashipazha D, Majdinasab N, Shalbafan B. The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010;16(8):964-9.
BACKGROUND: Low-dose naltrexone (LDN) may promote psychological well-being as well as generalized health especially in autoimmune disorders. The objective of this study is to assess the effect of LDN on the Quality of Life (QoL) of patients with relapsing-remitting and secondary progressive multiple sclerosis (MS) using the scales and composite scores of the MSQoL-54 questionnaire.
METHODS: A 17-week randomized, double-blind, placebo-controlled, parallel-group, crossover-design clinical trial was conducted in two universities. A total of 96 adult patients aged between 15 and 65 years with relapsing-remitting (RR) or secondary progressive (SP) clinically definite MS with disease duration longer than 6 months enrolled into the study. The primary outcome of the study was comparison of the scores of physical and mental health by conducting independent t-test of the results obtained in the middle and at the end of study between the two groups.
RESULTS: Variables including presence of pain, energy, emotional well-being, social, cognitive, and sexual functions, role limitation due to physical and emotional problems, health distress, and overall QoL did not show any meaningful statistically difference between the two groups. Factor analysis revealed that health perception scores were statistically different between the groups before starting, in the middle, and at the end of the study.
CONCLUSION: The study clearly illustrates that LDN is a relatively safe therapeutic option in RRMS and SPMS but its efficacy is under question and probably a long duration trial is needed in the future.

Cree BA, Kornyeyeva E, Goodin DS Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010;68(2):145-50. doi: 10.1002/ana.22006.OBJECTIVE: To evaluate the efficacy of 4.5mg nightly naltrexone on the quality of life of multiple sclerosis (MS) patients.
METHODS: This single-center, double-masked, placebo-controlled, crossover study evaluated the efficacy of 8 weeks of treatment with 4.5mg nightlynaltrexone (low-dose naltrexone, LDN) on self-reported quality of life of MS patients.
RESULTS: Eighty subjects with clinically definite MS were enrolled, and 60 subjects completed the trial. Ten withdrew before completing the first trial period: 8 for personal reasons, 1 for a non-MS-related adverse event, and 1 for perceived benefit. Database management errors occurred in 4 other subjects, and quality of life surveys were incomplete in 6 subjects for unknown reasons. The high rate of subject dropout and data management errors substantially reduced the trial's statistical power. LDN was well tolerated, and serious adverse events did not occur. LDN was associated with significant improvement on the following mental health quality of life measures: a 3.3-point improvement on the Mental Component Summary score of the Short Form-36 General Health Survey (p = 0.04), a 6-point improvement on the Mental Health Inventory (p < 0.01), a 1.6-point improvement on the Pain Effects Scale (p =.04), and a 2.4-point improvement on the Perceived Deficits Questionnaire (p = 0.05).
INTERPRETATION: LDN significantly improved mental health quality of life indices. Further studies with LDN in MS are warranted.

So the same odd addage...Further studies are warranted. 

However, this is the perennial problem...neuros and charities tend to fund small scale trials, which are invariably too small to give definitive answers and not large enough to make a compelling case for moving things forward

Pharma aren't really interested cos they can't make any money out of this in the present climate. 

Should we be doing small trials that need another in the hope that pharma will work out how to repurpose the drug or only support stuff that gives a definitive answer. Or should we keep the Status Quo going? often with false hope peddling.

Can pharma be incentivised to do these studies? 

Is it another fad treatment? 

What are your views?

BICAMS Study Feedback

Where you a participant in the UK BICAMS study? Thank You! #MSResearch #MSBlog

Dear Participant

Re: Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS): UK Standardisation

Firstly I want to say a huge thank you for taking part in this research to validate a measure of memory and information processing speed in MS.  This project would not have been possible without you and I want you to know your time and efforts are appreciated.  This project brings us a step closer to making cognitive testing more widely available to people with MS.

I am writing to you as you requested an overview of the research findings.  As I explained I am not able to provide individual test scores.  You may recall completing a 90-minute, “gold standard” collection of cognitive assessments often used in MS research (Minimal Assessment for Cognitive Functioning for Multiple Sclerosis, MACFIMS).  BICAMS is a subset of MACFIMS tests that this research sought to validate.  BICAMS consists of three tests and takes 15 minutes to administer.  It can be administered by a nurse or neurologist and requires only pen and paper.

Main findings:
  1. BICAMS is comparable to MACFIMS in its ability to detect cognitive difficulties in MS. 
  2. BICAMS can differentiate between participants with MS and control participants.
  3. BICAMS offers a practical, short neuropsychological assessment tool that can be used in routine clinical practice.
  4. Once published, data from this study can be used by UK clinicians and researchers to interpret cognitive assessment scores.
  5. This research supports previous findings that people with MS who experience cognitive difficulties are most likely to have difficulties with information processing speed and learning new information.
If you think you may have cognitive difficulties please see the next two pages of this letter for some ideas on how to compensate for these problems.  See also  Please be aware it is normal to forget things every now and again!  This does not necessarily mean you have cognitive difficulties. 

Spreading the word:

I have already shared findings from the project with MS researchers and clinicians through poster presentations at the International MS Cognition conference in June 2013 (IMScogs) and a much larger conference in October 2013 (ECTRIMS). I also plan to publish the research in a journal so we can move towards making cognitive assessment more widely available to people with MS.  BICAMS is gaining international recognition and now has its own website

Thank you again for taking part.  Kind regards and best wishes for the future.
Dr Alex Orchard
Clinical Psychologist

Memory Tips

Remember it is normal to forget things every now and again; so don’t be too hard on yourself.  Factors such as a busy life, low mood, stress and anxiety can all decrease our ability to process and remember information, whether you have MS or not

The suggestions below are not exhaustive but give some ideas of what can be helpful both to people with MS and those without.  It is helpful to know yourself and work to your strengths so pick the bits that could work for you.

General tips:
·        Structure your day/have a routine
o   This lightens the load on your brain and means you have more space to focus on processing and remembering new information.

·        Pace yourself/slow down
o   Don’t pack your week full of activities so you become tired.
o   Doing too much will reduce your ability to process new information and remember things.

·        Friends, family and technology can be great aids to processing and remembering information.
Reduced processing speed tips:

·        Avoid “information overload”
o   Don’t be afraid to ask people to slow down during conversations.
o   Ask people to repeat or summarise what they have said.
o   Summarise/repeat back what people say to you.
o   Plan your day so you don’t do lots of new things at once.

·        Summarise/clarify new information
o   During conversations repeat back/summarise important points/instructions.
o   Minimise the amount of information you have to process:
§  Block out extraneous information:
·        Use easy read versions of websites.
·        Use pieces of blank paper to block extraneous information on a page.
§  Highlight important points in documents.
§  Write bullet points of conversations/documents you have read as you go along.

·        Minimise distractions
o   Reduce background noise whilst completing tasks.

·        Do one task at a time

Memory tips:

Our memory can only hold so much information so we have to be realistic in what we ask of ourselves.  Structure and routine can allow us to go through the day on autopilot and reduce the load on our memory freeing us up to deal with and remember novel information.

·        Repetition, repetition, repetition
o   Repeating information you hear or see by saying it or writing it down can significantly improve your chances of remembering it.

·        Pace yourself
o   Be realistic about what you can manage. The more you do the more there is to forget.

·        Use a range of senses
o   It often helps to receive information both verbally and visually
§  e.g. if someone shows you something, describe what you see.  This increases your chances of remembering information you are given.
External Strategies

·        Visual prompts
o   Post-it notes and whiteboards in an obvious place can provide invaluable reminders of tasks to do, birthdays, appointments etc.
o   Use bullet points to remember the most important points.
o   Make sure these are in places you will see them easily.
o   You may find drawing or taking pictures helps you remember better than writing or verbal cues.

·        Diaries and electronic organisers
o   Develop the habit of checking these regularly so you know what you have to do for the day/week.
o   Keep diaries/electronic organisers with you to note down reminders throughout the day.

·        Reminders on your mobile/electronic organiser
o   This can help you to be on time for appointments and remind you to check your diary.
o   It can help you take medication on time.

·        Lists
o   Write down things you have to do and what shopping you need to get.
o   Information on a list is information your brain doesn’t have to remember and frees your brain up to do other things.

·        Organisation
o   Everything in its place
§  Choose one place to put your possessions e.g. keys in the pot, coat on a hook.
o   Use a filing system
§  You can retrieve information when you need it rather than using memory space.
Internal Strategies

·        Repetition, repetition, repetition
o   Repeating information you hear or see by saying it or writing it down can significantly improve your chances of remembering it.

·        Categorisation
o   Categorise information to be learnt into different groups.
o   E.g. remembering a shopping list by grouping what needs to be bought into vegetables, tinned food, meat etc.

·        Chunking
o   Most people can only remember 5-7 pieces of information.
o   When reading or listening to something containing lots of information break it up into small units so you only have 5-7 small units or keywords.  These can act as prompts to help you recall all the information.
o   A common example of chunking is remembering telephone numbers
§  Instead of 02078977385 we remember 0207 697 7395.

·        Storytelling
o   Some people find making a story makes remembering a list of unrelated items easier.

·        Rhyming
o   This can help you create links with information you already know.
o   It works well for remembering names e.g. Jean-Bean, Tall-Paul etc.

·        First letter association
o   Make up a word using the first letters of the items you need to remember.
o   e.g. Colours of the rainbow become Richard Of York Gave Battle In Vain.

·        Visualisation
o   You can create a mental picture of what you need to remember
o   You may want to picture things you need to remember from a list in a series of locations e.g. in rooms in your house.

Knights off their horses