Low dose naloxone to relieve pain

From the “who would have guessed it” category come the idea of naloxone as an analgesic.

There have been several previous studies (see below) showing that extremely low doses of naloxone appeared to have analgesic properties, but no real explanation of how this might be possible.

The most recent interesting article is this one here, recently published in the journal of pain, showing +(-) naloxone reverses multiple models of chronic neuropathic pain in rats,


Ultra low dose naloxone attenuates morphine tolerance in rats


Low dose 0.25mcg/kg/hr naloxone reduces opioid consumption, nausea and vomiting in 90 abdominal hysterectomy patients.

The first article showing this was by Gan et al in 1997. They looked at 60 patients who had a PCA along with infusions of varying doses of naloxone or saline. It was designed to look for a reduction in itch and nausea but as well as finding this found the group that got the lowest dose of naloxone also had a reduction in opioid use, with equivalent pain score


Remote Ischaemic Preconditioning

Several years ago while in Galway I first came across the concept of remote ischaemic preconditioning (RIPC). This is the concept that subjecting one part of the body to a brief period of ischaemia (eg 3 cycles of 5 minutes of an arm tourniquet above systolic pressure, followed by 5 minute deflations) can protect the rest of the body from subsequent ischaemic insults.

In the past couple of years there has been an explosion of interest in this fascinating idea and some truly exciting results from initial trials (see examples below). However, as with most new areas subsequent studies have not been quite as impressive as initial results. This seems to follow the pattern of most new findings in medicine: “It’s amazing!” followed by discovery of some setback or complication, leading to “It’s awful / useless!”, and finally “It’s OK if used in the right way for the right patients”.

The background to the discovery of ischaemic preconditioning comes from interventional cardiologists, who noted that patients who had “stuttering” myocardial infarctions seemed to do better than those who just had a single large MI.

Further work on anaesthetised dogs by Murry in the mid 1980s showed that 4 episodes of 5 minutes of coronary artery ligation before a 40 minute ligation reduced infarct size to a quarter of the size seen in the control group.


The ischaemia seems to produce 2 periods of protection, an early window out to 6 hours and a late window out to around 72 hours.

Since then studies have emerged showing that a protective effect occurs even if the organ rendered initially ischaemic is not the organ which suffers the final insult – in fact it appears that arm or leg ischaemia can protect the heart, lungs and kidneys. This is termed remote ischaemic preconditioning. What I like about this technique is that most attempts to protect the heart so far have been drug based and very one dimensional, relying on say beta blockers or statins to target a certain receptor. This technique harnesses an intrinsic protective mechanism, rather than on us trying to pick a single mediator to convey benefit, the ischaemic insult releases a range of known and unknown protective substances. It would be very difficult to replicate this complex soup with a drug. In addition  this is almost risk free and should avoid the nasty surprises such as the finding of increased stroke and mortality found in the POISE trial which has halted the enthusiasm for beta blockers.

The study which first kicked off interest in this area was from 2007 by Hausenloy et al. 57 CABG patients were randomising to RIPC via an arm tourniquet and were found to have a 43% reduction in post operative troponin release.http://www.sciencedirect.com/science/article/pii/S0140673607612963

Also in 2007 a RCT by Ziad in 82 patients having open AAA repair showed that 2 cycles of 10 minutes of common iliac artery clamping prior to aortic crossclamping reduced MI from 27% to 5% and renal impairment from 30% to 7% compared to control.


A recent meta-analysis of RIPC for CABG incorporating 10 studies and 693 patients showed a reduction in troponin release, however the studies with better blinding showed a smaller effect size, suggesting the benefit may be lower than original trials suggested.

Another meta-analysis of 17 cardiac and vascular trials showed a reduction in markers of myocardial injury, a reduction in MI (7.9% vs 13%) and (for AAA repair) a reduction in renal injury. There was no evidence of publication bias.


RIPC also appears to have some effect in preventing contrast nephropathy in 100 patients with renal impairment having coronary angiography, with renal injury rates of 40% in control vs 12% in RIPC. This has implications for ICU patients requiring contrast CT scans.


Finally, a study just out in Anesthesiology looked at 62 patients having elective infrarenal AAA repair and found an improved a/A ratio and improved markers in intestinal injury in the RIPC group compared with control


Of interest, a dose finding study is currently underway in Australia and NZ looking at defining the optimum “dose” of RIPC for best benefit.

There are some other interesting implications of RIPC. There has been a recent trend to orthopaedic surgeons doing knee replacements without tourniquets. Could this “improvement” in fact lead to worsening post-op outcomes due the loss of protection from myocardial ischaemia in the highest risk 72 hours post operatively, the “late” RIPC protection time?

In summary RIPC offers the latest hope in achieving the holy grail of anaesthesia- reducing post operative cardiovascular complications. The biggest advantage of RIPC over previous attempts, such as beta blockers, widespread preoperative revascularisation and regional techniques is simplicity and lack of harm. It’s hard to envisage anything bad coming from some brief cycles of tourniquet inflation and as the Lancet summarised it, it might mean “an arm and a leg can save the heart”.

The Toyota approach to anaesthesia- small continuous improvements: using placebo, IV cannulation, echo, blocks and compression devices

Toyota is famous for improving their cars through a process of continuous, small, incremental improvements, a technique known as Kaizen, or the Toyota way. In this way many small improvements, each inconsequential on their own, when added together produce significant results.

I think this is a great model to use when looking at anaesthesia. Anaesthesia and surgery are complicated processes, and most of the “low hanging fruit” in terms of safety improvements have already been made. It is unlikely that any single factor will make a major difference to outcomes. However that doesn’t mean we should stop trying to improve, and using a wide range of small improvements in different areas will collectively improve the patient’s experience.

An example of this is IV cannulation, something we all do every day and which we often forget can be quite painful. In addition, this is often patient’s only way of judging the ability of their anaesthetist. I recall a poster presentation where only 2 things determined a patients satisfaction with their anaesthetist- did the IV hurt, and did they visit the patient more than just in recovery. The patient has no baseline to judge postoperative pain or nausea and can awaken after all sorts of intraoperative near-catastrophes none the wiser, however if you want to make a patient happy, get the drip in first time and make sure it doesn’t hurt!

Two articles on this topic have got my attention and changed my practice. Both involve randomised trials where patients were either warned they were going to feel a “sharp sting” or used more neutral and comforting words, eg  “I am going to apply the tourniquet on the arm. As I do this many people find the arm becomes heavy, numb and tingly. This allows the drip to be placed more comfortably”. The patients not only reported lower pain scores but were also less likely to withdraw their hand in the “kind words” group compared to the “nocebo” group. This is contrary to the common practice of warning someone, with the rational that it then won’t be as bad as they expect. In fact all this achieves is heightened anxiety and more pain (read here and here).

This is an example of avoiding the “nocebo” (opposite of placebo) effect of harsh words like sharp, sting, needle and pain. There is increasing evidence that placebo plays a major part in many interventions. Recently i went to an intriguing talk about placebo where the concept of the “open/hidden” trial was discussed. This is the opposite to a placebo controlled trial. Instead of everyone getting told they were getting morphine and half getting a sugar pill, all patients get given morphine but only half are told about it. The rest had it quietly slipped into a bag of fluid without being told. There were significantly greater reductions in pain in the group that were told they were getting the “powerful painkiller”, compared to the group that had it slipped into their fluids. The presenter gave a range of slides for different analgesics showing that for virtually all of them the pain score reductions were double in the open  “powerful painkiller” group compared to the hidden ones.

Finally, three further topics for the “continuous improvement” theme, all of which i will talk about more in the future.

The first is transthoracic echo for use by anaesthetists in preoperative assessment. This is something that was big when I was doing my fellowship at the Royal Melbourne Hospital and is spreading around the world rapidly. In this month’s Anaesthesia the RMH team have provided the first (weak) evidence that preoperative echo may improve outcome, instead of simply changing management (which has been shown in previous studies). The study is observational, of poor quality, subject to the Hawthorne effect and shows an implausibly large mortality difference, but for all that makes pleasing reading for transthoracic echo exponents such as myself (reference here).

The second is the use of dexamethasone to prolong peripheral nerve blocks. This is something we have been doing recently in our hospital in Mackay in Australia, and the results can only be described as “spectacular, bordering on scary” – 24-30 hours duration from a single shot interscalene block, including complete motor block at 24 hours. This is consistent with studies showing dexamethasone effectively doubles the duration of most nerve blocks. Just remember that the phrenic nerve is also paralysed for 24 hours!

When I first read about this I had some concerns on potential neurotoxicity, but these were alleviated by 2 things.  The first of these were the words of a chronic pain physician colleague who stated that they add dexamethasone to every block they do, have been doing so for years and have had no problems. The second is a study showing that in an animal model dexamethasone was significantly less neurotoxic that ropivicaine, and the ropi/dex combination was less toxic than other common combinations such as ropi / buprenorphine and ropi/ clonidine (reference here and here and here)

The final interesting note is on SCDs- the sequential calf and thigh compressors now ubiquitous on the legs of patients having surgery in our hospitals. Two recent articles showed that they reduce intraoperative hypotension- a bonus that at first seems unexpected until you think about it, then seems quite logical.

Reduced hypotension for caesarian:  here

This study used a variation of the normal compressors with higher pressures and longer compression times: here