Poststroke CRPS and Even More Ketamine

Good evening. I just watched President Obama clench his jaw and look like his head was going to explode, as he "turned the page" from the War-That-George-Started, which prompted neglect-and-wreck of our financial, health care, and educational systems... all of which he inherited.

All together now: Thanks, yes, thanks a lot, George W.!

All together now: Please, oh please, President Obama, don't have a stroke over George W.! Turn that dang page, dang it!

Why, speaking of strokes... the first of today's CRPS installments deals with Poststroke CRPS. Feeling much like Sergeant Schultz -- "I know nothing!" -- I did a little background reading. I recommend:

Complex regional pain syndrome underdiagnosed: CRPS type 1 is an under-recognized problem in limbs recovering from fracture or immobilized post-stroke
Journal of Family Practice, June 2005

From thalamic syndrome to central poststroke pain
G D Schott
Journal of Neurology, Neurosurgery & Psychiatry 1996 61: 560-564
(You can register at jnnp.bmj.com and have free access to articles before 2006)

If you aren't already confused about terminology, one web site I scoped out informed me that CPSP (Central Post Stroke Pain) is a type of CRPS... that used to be called Thalamic Pain Syndrome (also known as Dejerine-Roussy disease, of course!).  If Wikipedia's description of Thalamic Pain Syndrome is accurate, I am not sure that it so, despite a similarity of symptoms.  If *you* can clarify this for me, please leave me an elucidating comment!

Thalamic syndrome (or thalamic pain syndrome) is a condition that can be associated with inadequate blood supply from the posterior cerebral artery. It is a rare neurological disorder in which the body becomes hypersensitive to pain as a result of damage to the thalamus, a part of the brain that affects sensation. The thalamus has been described as the brain’s sensory relay station. Primary symptoms are pain and loss of sensation, usually in the face, arms, and/or legs.

Pain or discomfort may be felt after being mildly touched or even in the absence of a stimulus. The pain associated with thalamic syndrome may be made worse by exposure to heat or cold and by emotional distress. Sometimes, this may include even such emotions as those brought on by listening to music.

In all of the hour's worth of reading about Post-stroke CRPS, there was a disturbing reiteration of things like "sympathetic blockade" -- about which I have raled before.  Progress in understanding the etiology and processes of CRPS is now directing the treatment response away from a focus on sympathetically-mediated pain.

Anyway... here is the abstract for this latest contribution to the topic:

From Topics in Stroke Rehabilitation. 2010 May-Jun;17(3):151-62.


Poststroke complex regional pain syndrome


Chae J.
Department of Physical Medicine and Rehabilitation, Case Western Reserve University, Cleveland, Ohio MetroHealth Rehabilitation Institute of Ohio, MetroHealth System, Cleveland, Ohio.


Abstract
Poststroke Complex Regional Pain Syndrome (CRPS) affects a significant number of moderate to severely impaired stroke survivors. Until recently, advances in the assessment and management of CRPS have been limited due to the lack of a consensus on diagnostic criteria; however, with the development of the International Association for the Study of Pain diagnostic criteria, the medical and scientific communities are poised to make significant strides. Biomechanical factors and microtrauma to the hemiparetic shoulder may have a significant role in the genesis of CPRS, although the exact pathophysiology that links these triggers to the observed disease manifestation remains uncertain. Sympathetic dysfunction has historical importance in the CRPS literature. However, this appears to be only one of several possible pathophysiologic mechanisms; somatic nervous system dysfunction, inflammation, hypoxia, and psychological factors are also likely contributors to the disease process. There is no definitive treatment for CRPS, and most patients are treated empirically. Nevertheless, there is consensus that the treatment approach should be interdisciplinary with the goals of edema and pain control, maintenance of joint and muscle biomechanics, and functional restoration. As more rigorous clinical trials emerge, the treatment approach will become more rational with selection of interventions based on a specific mechanism or a combination of mechanisms responsible for a given individual's disease manifestation.

The second of today's articles is exciting, in that Dr. Schwartzman and ketamine research are in play. The journal, like most things these days, is beyond me -- Chirality. These are the aims and purposes of the journal:

The main aim of the journal is to publish scientific work on the role of molecular asymmetry in both biologically active and non-biologically active molecules in respect to their pharmacological, biological, and chemical properties. Drugs, pesticides, and other xenobiotics will be a major interest.

Papers on the chemistry (physiochemical, preparative synthetic, and analytical), pharmacology, clinical pharmacology, toxicology, and other biological aspects of chiral molecules will be published.

Among the topics to be covered are stereospecific synthesis, stereoselective analysis, preparative separation of chiral molecules, the influence of chirality on pharmacokinetics (absorption, distribution, protein binding, biotransformation, etc.), the influence of chirality on pharmacodynamics (drug-receptor interactions, pharmacological and toxicological activity), and the influence of chirality on clinical pharmacology (therapeutic index and response, bioavailability, adverse drug reactions, drug-drug interactions). Papers will also be published on regulatory and legal aspects in the development, testing, and marketing of chiral compounds.

Okay, I will 'fess up. I haven't a clue what a chiral compound is, and I am not in touch with the chirality that I was born with... although I think they might worship it off the western shores of Estonia, on a small island in the Gulf of Riga.

Hmmm? What? Oh. Right!  On to the Reference Works!

It turns out that chirality is a fascinating concept/thing/compound/word, derived from the greek for hand.  Of course, yes, I got lost in the term, but just for about twenty minutes.  Have you ever wondered whether it is eye or hand chirality involved when leaning your head aside to drink water straight from the tap?

A chiral molecule is a type of molecule that lacks an internal plane of symmetry and has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom.[1][2]

The term chiral (pronounced /ˈkaɪrəl/) in general is used to describe an object that is non-superposable on its mirror image. Achiral (not chiral) objects are objects that are identical to their mirror image. Human hands are perhaps the most universally recognized example of chirality: The left hand is a non-superposable mirror image of the right hand; no matter how the two hands are oriented, it is impossible for all the major features of both hands to coincide. This difference in symmetry becomes obvious if someone attempts to shake the right hand of a person using his left hand, or if a left-handed glove is placed on a right hand. The term chirality is derived from the Greek word for hand, χειρ (cheir). It is a mathematical approach to the concept of "handedness".

In chemistry, chirality usually refers to molecules. Two mirror images of a chiral molecule are called enantiomers or optical isomers. Pairs of enantiomers are often designated as "right-" and "left-handed."

Molecular chirality is of interest because of its application to stereochemistry in inorganic chemistry, organic chemistry, physical chemistry, biochemistry, and supramolecular chemistry.

And here you were thinking that I was gonna stay on topic, regaling you with yet another surge forward in CRPS research!  Ahem...

As I said, Dr. Schwartzman is involved, so you know ketamine cannot be far behind!  (That's unfair... but I am tired.)

From the journal Chirality. 2010 Aug 27


Enantioselective pharmacokinetics of (R)- and (S)-ketamine after a 5-day infusion in patients with complex regional pain syndrome.
Goldberg ME, Torjman MC, Schwartzman RJ, Mager DE, Wainer IW.


Cooper University Hospital, Department of Anesthesiology, UMDNJ-Robert Wood Johnson Medical School, Camden, New Jersey.


Abstract
Introduction: This study determined the pharmacokinetics and pharmacodynamics of (R)- and (S)-ketamine and (R)- and (S)-norketamine following a 5-day moderate dose, as a continuous (R,S)-ketamine infusion in complex regional pain syndrome (CRPS) patients.
Materials and methods: Ketamine was titrated to 10-40 mg/h and maintained for 5 days. (R)- and (S)-Ketamine and (R)- and (S)-norketamine pharmacokinetic and pharmacodynamic studies were performed. Blood samples were obtained on Day 1 preinfusion, and at 60-90, 120-150, 180-210, and 240-300 min after the start of the infusion, on Days 2, 3, 4, 5, and on Day 5 at 60 min after the end of infusion. The plasma concentrations of (R)- and (S)-ketamine and (R)- and (S)-norketamine were determined using enantioselective liquid chromatography-mass spectrometry.
Results: Ketamine and norketamine levels stabilized 5 h after the start of the infusion. (R)-Ketamine clearance was significantly lower resulting in higher steady-state plasma concentrations than (S)-ketamine. The first-order elimination for (S)-norketamine was significantly greater than that of (R)-enantiomer. When comparing the pharmacokinetic parameters of the patients who responded to ketamine treatment with those who did not, no differences were observed in ketamine clearance and the first-order elimination of norketamine.
Conclusion: The results indicate that (R)- and (S)-ketamine and (R)- and (S)-norketamine plasma concentrations do not explain the antinociceptive* activity of the drug in patients suffering from CRPS.

*reducing sensitivity to painful stimuli.

Ah, well.  That's science, that's the way the cookie crumbles, and c'est la vie. So the antinociceptive activity of ketamine remains elusive! It is good that they are working hard to tease out the mechanisms of its effectiveness, so that, one day, we can follow the bread crumbs back home...

I have a number of posts near completion, but keep losing my energy in the penultimate paragraph.  I promise to try and do better, or to trick myself, somehow, into finishing them.

And President Obama?  Good job, and thank you. 

By the way, I don't know if you've heard -- it may not have been included in your daily briefings -- but my Pre-Existing Condition Insurance Plan kicks in at midnight and tomorrow I go for my first battery of tests since they put the left prosthesis back in last year.  Gotta feed that high deductible (because you were willing to take on my high risk)!  So... yes, from the bottom of my heart: good job!