Adrenal suppression and prednisolone timing

Forgot to say - but that may have appeared over time whether you were on pred or not. A new study has found that the long term pred-associated side effects, except cataracts, are not higher in patients on PMR-level doses compared with age-matched non-pred takers. You'll find the link under "Polymyalgia Rheumatica and Steroid Side Effects: New Findings" in this post:

https://patient.info/forums/discuss/pmr-gca-website-addresses-and-resources-35316

Yes, over the past fortnight, I found the New Findings along with much more, including dozens of your own posts.  The main risks I face are likely cataracts, glaucoma and osteoporosis.

My symptoms and blood tests are a perfect fit for PMR and I've no GCA symptoms.  The prednisolone works rather well 9 - 19 hours after I take the tablet.  

Taking prednisolone after evening dinner is quite attractive but I well know authorities advocate a single morning dose to avoid adrenal suppression as you, yourself, have often advocated.  My very first tablet was taken at 5 pm and I was fine until well after lunch the next day.  My tablets are plain white, not enteric.   

At 2 am tomorrow. I'll try 20 mg.  If that fails, an evening or a divided dose (say, 2/3 - 1/3) are my other options.  I'm encouraged you don't think adrenal suppression is much of an issue for me for some months, at least.

The advocacy for morning dosing is because it was found in a study in the Netherlands that taking 5mg at night suppresses adrenal function more than taking 15mg at 8am. Obviously that is very significant for the use of pred over a period less than about 2 months - you can probably get through that without noticeable adrenal suppression taking your tablets with breakfast. But when you are at above about 10mg for months and months - as we are - then there will be suppression anyway, you can't avoid it. In PMR you need to take your pred at the time that works best for you and for some it will be 2am, for others it will require a split and for others it won't make the slightest difference. By doing that, you are likely to manage on the lowest dose that is effective for you.

PS - where you have seen me advocating single morning doses it is not because I think that is best, it is rather than patients taking an equally split dose over the day (3x5mg for example) or where they have asked what is recommended. My preference would be about 4.30am and settling down for another couple of hours for it to work - but even that wouldn't work for you I suspect. But any approach doesn't work for everyone!!!

A prednisolone dose at 2:00am is based on your posts at https://patient.info/forums/discuss/pmr-prednisone-455866 and on this 2014 study at https://arthritis-research.biomedcentral.com/articles/10.1186/ar4687.  According to this study, your suggested 4:30am dose would come too late to dampen the early morning peak of proinflammatory hormones .

Incidentally, the time is now 3:30 pm and this is the best day I've had in six weeks, with only mild pain.  I even hope to play badminton tonight for the first time in a month!

I am far from disappointed that my 2am prednisolone trial, with yoghurt, was a failure with pain aplenty today.  I believe yesterday’s pain was so mild because the first 2am dose happened to be only 15 hours after the previous 10am dose.  I think now I better understand prednisolone's anti-inflammatory effect.

If my initial inflammation is mild, a single prednisolone dose will give me an 18-hour low-pain period.  However, if inflammation is moderate, the same prednisolone will give me barely a 9-hour low-pain period, 9 hours after the dose, i.e. 9-18 hours relatively pain free.  If inflammation is severe, the same dose may offer little relief.  The less the starting pain: the better the low-pain period.  For good pain control, therefore, moderate pain periods should be avoided entirely.  

Prednisolone takes 2 hours to enter my bloodstream and is exhausted inside 18 hours.  (A modest biological half-life for prednisolone is unsurprising because, being very fit, my metabolic rate is high; I exercise way more than most; I’m just 68 and in good health; and my BMI is 20.)  For me, therefore, a single dose a day is inappropriate.

I should ideally split the dose, taking the second, smaller dose no later than 14 hours after the first, before inflammation can rebuild.   If I take the morning dose at 8am, a smaller dose at 8pm should be ideal.  Finding the correct split-dose may be tricky.

Is this approach coherent?

It is less the biological halflife than the antiinflammatory effect - which lasts far longer than the pred is in the body. It ranges between 12 and 36 hours depending on the person. I have used alternate day dosing in the past - that can only work for someone where the antiinflammatory effect is long. Many people find symptoms returning in 12 to 18 hours - and while those with pain overnight at 18 hours might scrape by on once daily, if you are a 12 hour person, you will do far better with a split dose. Now whether you need to split as 2 doses 12 hours apart or perhaps in a different spacing is something you have to investigate - there are other considerations such as how it affects your sleep and so on.

I've said in the past that taking the second part needs to be an hour or two before you find the pain returning, as you say too. So yes the approach is coherent. Many people take 2/3 in the morning at some point, the rest later. But some take some immediately before bed, allowing freedom from pain in the early morning, then you have to work out where the other bit should be taken.But I would also suggest that maybe 2mg isn't quite enough - it is a very low dose so no concerns there. 

Thank you so much for your kind advice. 

Incidentally, I've read in several places: the plasma (or elimination) half-life of prednisolone is around three to four hours, but the biological half-life is 18-36 hours.

I suspect the biological half life and the antiinflammatory effect are the same thing, just different terms. But 18 is quite high for the lower end of that. I suppose though that a patient whose dose is close to the lowest effective dose will see a return of symptoms sooner than one who is still well above that dose.

Yes, the 4.30am dose is too late to avoid the inflammation starting - but it is a time that many people find acceptable as they wake to go to the bathroom around then. It is far sooner than the usual suggestion of 8-9am made by many doctors and there have been people on the forums in the past who have waited until after their breakfast at 9.30am or even later to take their pred and then have wondered why they get no relief until mid-afternoon. The earlier you take it the less inflammation it has to clear up - and it often means you can manage with a lower dose as well as having a longer day feeling well. Which is the aim after all!

My table below shows prednisolone in the blood declining over 24 hours with a divided dose of 16 and 4 mg, taken 12 hours apart.  Moderate plasma levels of Predniosolone are maintained 6 hrs longer: until 4 am the next morning rather than just 8 pm.

Time                 Prednisolone (mg)          Plasma Levels (mg)

  8 am                           16                                        0

10 am                                                                   16.0

  1 pm                                                                     8.0

  4 pm                                                                     4.0

  7 pm                                                                     2.0

  8 pm                            4                                       1.0

10 pm                                                                     4.5

  1 am                                                                     2.3

  4 am                                                                     1.1

  7 am                                                                     0.6

  8 am                          16                                       0.3

10 am                                                                   16.1

Note:  The elimination half-life of prednisolone is 3 to 4 hours. This means that it takes 3 to 4 hours for 50% of the drug to be eliminated from the system. Total elimination of the drug takes 16 to 22 hours.  A biological half-life of only 18 hours may mean inflammation reappears 18 hours after the dose. This table assumes a quicker elimination for the fit, healthy and younger.

I am rather skeptical of both the 2 am dose and the 4:30 inflammation burst.  The evidence for these on the internet is sparse and, clearly, there are vested interests pushing the 10 pm dose of enteric prednisolone.  If you look at 4:30 am in the table I've just posted, it is hardly surprising that inflammation may be rising because blood plasma prednisolone is so low on a single dose.  

Evidence in the internet may be sparse - but discussions on the 3 forums in the UK have proven the concept and it is on the basis of such experiences we suggest it, nothing else. It has little to do with the dose of pred. Personally I can feel the shedding of cytokines in the early morning - or something at least, and did so long before I was put on pred. So do others. I don't get wakened by the surge feeling when I am on the right dose of Lodotra, I do when a flare starts wna the current pred dose is too low, Many people find that they can get up to the bathroom at 3.30am and are not stiff, but at 5am they can hardly move. That was also my experience. 

Lodotra is not enteric coated, it is released in the stomach all at once, in that sense it is no different to taking plain white pred which is released for absorption immediately but it is a very convenient, if more expensive, way of not having to wake at silly o'clock to take pills. 

The study was done in Germany for RA - long before the Lodotra format was even thought of, it was as a result of the study that it was developed. I don't take the Lodotra for the 2am release per se, it is the only alternative here in Italy to Medrol which caused me all sorts of problems so I can't take it. But I do feel I benefit from the taking at night and release before 4am. So do all the other people I know who take it - and there are quite a few who either take enteric coated before bed or some who take ordinary pred who feel they get a better result for them

Be sceptical - no-one is suggesting everyone should do this or that. What we say is to try it and if it works for you - result!

I'm one who has taken pred at around 8 am simply because I can't manage an earlier time.  Until recently I've found that I felt pretty much the same all around the twenty four hours which may indicate I metabolize pred slowly?  Recently I've found more stiffness in the evenings, although I've increased my dosage, but feel better in the morning, without splitting the dose.  I think I have to assume that something not PMR is causing this, possibly a flareup of OA which has been very well controlled for decades.  If it were PMR wouldn't I feel even worse in the morning?

Taking prednisolone at 2 am, or any other time, may well be best for some.  When I was on an 9 am single dose, my pain certainly began to worsen around 4 am, 19 hours later.  When I took the single dose at 2 am, my pain again worsened 19 hours later (now around 9 pm), and persisted all the next day.  So, for me, the timing of the single-dose didn't seem to matter in the least.

I have a question.  If I happen to stop prednisolone abruptly after a month or more on 25 mg, how soon after the last dose may I expect prednisolone withdrawal symptoms - 36 hours?  What symptoms typically come first?  

I'm new to this but imagine PMR stiffness, beginning in the evening, would continue to worsen until some hours after the next 8 am pred dose.

And this morning I felt nearly normal despite having started a taper yesterday.  Maybe the flare really is over now and I can safely reduce again.  Temptation to drop quickly but as I've been at the higher dose for several weeks now I think that would be foolhardy.  

After a month at 25 mg you must not under any circumstances stop pred abruptly.  Your adrenal glands will have at least started to shut down cortisol production and it will take time for them to get back up to speed.  I don't know what the protocol is for reduction after a month on steroids, probably much faster than for those of us who've taken them long term, longer than three months for example.  But you still must exercise caution.  I think the window of being able to stop steroids abruptly is something closer to two or three weeks.  But I could be wrong.

It isn't withdrawal symptoms you need to worry about - if you have been on that high a dose for more than a month you MUST reduce slowly to avoid the risk of adrenal crisis. That could happen if you stop from 25mg to zero. You can safely reduce fairly rapidly down to 10mg and only suffer withdrawal symptoms but below 10mg you need to reduce more slowly. Please speak to your doctor.

Withdrawal symptoms themselves will appear immediately your body misses its expected dose if the step down is too big. Some people can manage relative large steps, up to 5mg at a time, at very high doses even 10mg, others can't so it is impossible to say how or when you will respond. The most common manifestation of steroid withdrawal is called "steroid withdrawal rheumatism" - so very very like PMR. You may also get other symptoms of the disorder for which you are taking the pred - and that can vary of course.

So, if a dose is accidentally missed at 25 mg, withdrawal symptom alarm bells will likely ring well before the next dose is due?

Good news! 

Single dose prednisolone, begun three weeks ago, had typically given me, at best, 9 hours relief a day.  Moreover the underlying PMR seemed to be gradually worsening - at least in the shoulders.  The 20 mg, and later 25 mg, single dose was becoming less and less effective with chronic pain almost as bad as before prednisolone. 

Last Monday, I moved from single dose to a split dose: 20 mg with breakfast and 6 mg with the evening meal. My PMR symptoms on Monday and Tuesday were dreadful - I could barely walk or move my arms - but were easing by Tuesday evening.  Wednesday, Thursday and Friday have been truly wonderful - the best I have been for six weeks! 

I am now free of all pain except when I move my arms in in unusual ways, like fetching something from a side or back pocket or removing a jumper  This mild pain has little impact on most activities including strenuous sport.

A question.  Should I stay at the 20/6 split, hoping the shoulder pain will eventually resolve, or should I cautiously begin to reduce my prednisolone dose by, say, a gram every few days?

I would give it at least 3 or 4 weeks at the 20mg - the usual is up to 6 weeks at the starting dose until the symptoms have resolved/stabilised. 

And no, you don't reduce by 1mg (I assume you mean mg not gram!) every few days. You should only reduce by 1mg every 2 weeks at the most. If you keep changing the dose that quickly you will have no idea at all where a flare started to happen if it does as it can take 2 or 3 weeks for a dose that is very slightly too low allowing leftover inflammation - like a dripping tap the bucket will eventually fill and overflow. 

There is no hurry. This a a slow job - PMR is a chronic illness, not one for which you take a dose of pred and stop. About a quarter of patients need pred for 2 years or so - but for half it takes up to 4 to 6 years and for some even longer. There is no way to know in advance which group you belong to nor what dose you will need so you start at a dose that is high enough for most people and then taper the dose VERY slowly to find "your" dose. In the first year or so of PMR that dose may be relatively high but as time goes on it does usually fall as the activity of the underlying autoimmune disorder that causes the symptoms we call PMR reduces. But it can always flare up again, especially if you try to reduce the dose too quickly or in too big steps or if you overdo things. Slow and steady is the name of the game - or you run the risk of getting into a yoyo situation which just causes trouble because for some reason that also seems to make it harder to reduce next time round. So try to avoid getting into it in the first place. When you keep changing the dose all the time your poor body never gets to settle anywhere - and it just makes things more uncomfortable.

After a months on prednisolone, I well understand that the tapering of prednisolone of 10% per month is prudent although, above the 10 mg daily dose, a taper of as much as 2.5 mg per month is often advocated.  But I have been less than a month on the drug.

I do not think of my present proposal to reduce the dose as simple PMR tapering.  After just a week on 20 mg, my last 9 days have been around 26 mg, the last week a 20/6 split dose.   Only the split dose gave more than 9 hours relief, eliminating all but the mildest symptoms of PMR.  However, I have no reason to believe that a 20 mg split dose, say 15/5, would not have been more than sufficient.  

I am hopeful that if I act at once, after barely three weeks on prednisolone, I might be able to taper relatively quickly to the lower 15/5 split dose and settle there.  With this in mind I have begun a reduction of 1 mg every few days.  This rate of reduction is entirely consistent with advice to patients withdrawing from high dose prednisolone (e.g. two weeks on 40 mg for Crohn's disease).

If moderate symptoms of PMR begin to return, I will abandon this once-off reduction at once, and all further reductions will follow PMR guidelines.  Is this unreasonable?

It is the "every few days" that is the problem. You are reducing at a speed that means that your body has to deal with a change on a constant basis and also if you DO pass the limit for you NOW, you won't know where it was. In the early stages of PMR the activity of the underlying autoimmune cause of the symptoms can be quite high, and you also need to clear out all the existing inflammation first. 

The whole point of what we say on the forums is that we have been there. We have tried the speedy reductions the doctors are so keen on and for many people they simply don't work. 

You haven't got Crohn's. You have got PMR. They are not the same. Pred is usually used in Crohns to deal with a flare - you haven't got a flare, You are in the early stages of learning to live with a chronic disorder, one for which you have to find the right dose for YOU. Not for me, not for your doctor, not for anyone else here. Once you have found that you will have a lot better understanding of how to live with it - but at present it is all an unknown. When we say go slowly it is because we want to save you from making the mistakes most of us made at the start. Reduce too fast and you risk having a flare, having to go back to a higher dose and start over again. For many people that makes it harder to reduce. OK, maybe you won't be that person and you will be lucky. Only you can find out.

Very wise advise as always Eileen. 

Thank you for the perspective on "passing the limit".  I will probably now reduce nearer 1 mg a week - still very rapid.  If PMR does worsen before I reach a 15/5 split, so be it.  I won't try this fast reduction a second time.  At worse, I will return to a 20/6 split and be there a couple of weeks longer than otherwise, and in more pain than right now. I can live with that.

Incidentally, my exercise regime is also pushing the limits, which I understand from the forum is ill-advised.  Before PMR, my exercise level was energetic and extreme: high-impact aerobics, badminton, tennis, running, skiing, in-line skating and cycling.  In the last week, feeling much better, I have returned to this level without ill-effects, other than the expected sore muscles (which I habitually have anyway).  Wish me luck.  

incidentally, I did somehow manage to retain a decent level of fitness in the past two months, despite PMR, while losing 3 kg in body weight and some muscle.

Unsurprisingly, your sage predictions proved sound.  A week later, I'm back on the high pred dose.  

So I think I've learned:

 - I'm close to the right pred dose.

 - Early-warning signs of PMR returning manifest first in my shoulders and, later, in the backs of my upper thighs.

-  Since my first symptoms showed at dawn, I should increase the evening dose much closer to 1/3.  When I next reduce, it will be the day dose.

-  The returning PMR symptoms take four days to dissipate after I revert to the high dose.

- The low-level PMR shoulder pain, on the high dose, now seems to be changing from a sharpish pain when I take something out of a rear pocket to a more dispersed ache, perhaps as inflammation recedes to even lower levels.

A learning experience. 

It's what it's all about - learning more about YOU and YOUR PMR. But some things apply to us all!