Category Archives: pain

So much for that

You may remember that not so long ago I wrote about what looked like a drug discovery success story for pain: anti-NGF therapy for osteoarthritis. Well, it looks like that success was short-lived. Somehow I missed this over the Christmas break, but, the FDA has ended trials on anti-NGF therapies for osteoarthritis due to development of avascular necrosis in some patients. Nothing positive can come of avascular necrosis and the pulling of several trials would suggest that this is a drug class effect (or at least suspected to be). Anyway you cut it, this is bad news.

A pain drug discovery success story: anti-NGF therapy for osteoarthritis

ResearchBlogging.orgWith all the recent layoffs in Pharma, coupled with the axing of many analgesic drug development programs within these institutions, its nice to finally see a success (albeit of potentially short longevity — more on that later). The treatment is Tanezumab. Tanezumab is a humanized antibody against nerve growth factor (NGF). The biologic effectively blocks NGF interaction with its receptors, TrkA and p75. Basic researchers in the pain field have been working on the idea of blocking NGF function as a pain treatment for some time now. In fact, I’ve written about this before:

[in response to a question from Whimple] On your other question, are there examples where the clinical never would have been possible without the preclinical the answer is also yes. My example is not a good one because I likely would have been able to instigate a trial but it would have been much more difficult without the preclinical. On the other hand, the anti-NGF treatments for chronic pain are an excellent example of where it would not have been possible. We have known for a long time that NGF is involved in preclinical pain models and in human pain. We have also known that genetic mutations in humans that block NGF signaling (mostly receptor mutations) cause a terrible disease wherein people with the mutation have profound mental retardation, total lack of pain and inability to sweat. While it was the view of most researchers that this was due to a developmental issue, it was not known if blocking NGF signaling later in life would lead to similar deficits and this made any trial on anti-NGF therapies impossible due to very serious safety issues. After decades of preclinical work it is now known that anti-NGF treatments later in life do not cause similar problems and this animal work has made the safety issue a much smaller issue. So, due to literally thousands of papers on NGF signaling in animal models we have a good idea that these treatments will not cause devastating side effects in humans and these therapies are now late in clinical development. If they gain FDA approval I expect that they will become important treatments for chronic pain disorders. That is but one of several examples wherein animal work was absolutely neccessary to develop new pain treatments.

Onto the trial… (Lane et al. 2010 NEJM) The idea was to see if tanezumab would have efficacy for osteoarthritic knee pain. Rather than looking for efficacy in a currently treatable population, the investigators went for the gold and chose to study the effect of tanezumab in advanced osteoarthritis of the knee patients that did not receive pain relief from analgesics (mainly opiates) that are generally used in this patient population. They recruited about 450 patients and broke them into 6 groups: placebo and escalating doses of tanezumab. Treatment was given over 16 weeks and after that time frame they moved to open label. The results are striking: Continue reading

Compare and contrast

From the most recent International Cannabinoid Research Society Meeting Abstract Book: Continue reading

First step toward the holy grail of pain research? Molecular identity of a mechanically gated ion channel, Coste et al., 2010 Science

ResearchBlogging.orgFor as long as I have been in pain research (and long before I ever even thought about pain research) the topic of mechanically-gated ion channels has been a huge deal. The reasons are simple:
1) We obtain information about our environment through touch (among other things) but in certain conditions touch can become painful. We call this allodynia. The problem is we don’t know how this happens (but we have some good ideas — more on this later) and, ostensibly, identifying ion channels involved in mechanosensation would go a long way toward helping us understand this.
2) Certain types of mechanical inputs are painful (e.g. pinch or pin-prick) and these types of input become even more painful after injury. We call this hyperalgesia and, again, we have some good ideas of the processes that underlie this hyperalgesia but, ultimately, without knowledge of the initial transducer of mechanical inputs, it is hard to understand this fully.
3) Time for the most obvious reason, we just flat out don’t know how we feel mechanical stimulation. There are hundreds (or thousands, depending how you think about it) of papers out there on this but, to date, no one has clearly identified a mechanically-gated channel expressed by vertebrate sensory neurons.

Until now. There were all types of rumors flying around about this at IASP. This is not unusual, however, as I have heard similar rumors at SfN and IASP meetings in the past. On Sept 2, a paper was published in Science from the Patapoutian lab at Scripps, La Jolla, that may open the flood gates in terms of describing how mechanical stimulation is transduced into signals that can be transmitted to the CNS.

How’d they do it? Continue reading

And I’m off…

to Montreal! Having lived in Montreal for 3 years as a postdoc at McGill I’m about as excited as I can be to be headed back to my old stomping grounds for the International Association for the Study of Pain meeting. Mrs. JP and I will be there for a week and are both attending the conference. This will be Mrs. JP’s first time at the conference and our first time going to a conference together (the basic and clinical mix at this conference has provided the opportunity). Should be exciting!

This is the first IASP meeting on the new two year rotation (next one is in Japan 2012 and then to Argentina 2014). The schedule for this meeting is very strong (IASP is always good) but the growth in the field is readily evident from this year’s line-up of talks and posters. I may try to blog the conference but more likely I’ll be sending out tweets.

Pharm 551A class, there will be no posts this week for class content since I won’t be around.

Long standing R-series grants are not the problem

Genomic Repairman has a little rant up over at Labspaces in which he becomes exasperated at someone in his field who has had two R01 continuously for at least 26 years. Abel Pharmboy has already dealt with this in hilarious fashion (weedhopper? — haven’t heard that one before) so I won’t belabor the obvious; however, I would like to point out a few long-standing grants in my area — pain research — that have had a profound impact on our understanding of pain.

Let’s start with what, to my knowledge, is the granddaddy of them all in the pain field: Ed Perl’s 36 year old (expired in 2008) R01 entitled “SPINAL AND PROJECTION MECHANISMS RELATED TO PAIN”. If you’ve got a neuroscience or general medicine textbook handy, look up the word “nociceptor”. These are pain sensing neurons in the peripheral nervous system. Now go read what the textbook says. There should be something there about how these neurons are noxious stimulus detectors that specifically respond to stimulation in the noxious range. They also respond to many chemicals and temperature changes into the too hot and cold to handle range. What you just read is work that was funded by this R01. Similarly, if you are interested in how noxious input is processed in the dorsal horn of the spinal cord much of what you will find in the textbooks came from Ed Perl’s work funded by this R01.

How about another old one (the grant, not the person): Gerald (Jerry) Gebhart’s 28 year old R01 entitled “MECHANISMS AND MODULATION OF VISCERAL PAIN”. Of his 300+ publications, many of them were funded by this long-standing R01. Like Ed Perl’s grant, to understand the contribution that this continuously funded grant has had on our appreciation of pain processing is quite simple — pick up a textbook. Much of what we know about visceral pain has come from work done in this grant. The work spans from understanding how descending modulation systems (periaqueductal grey (PAG) and rostral ventromedial medulla (RVM)) amplify pain of a visceral origin to the receptors and molecules responsible for causing visceral pain. Pretty important stuff and, I might add, if you are working in Pharma trying to develop drugs to target visceral pain, chances are you are relying pretty heavily on Jerry’s work not only for target identification but also for the techniques that you will use to validate whether your drugs are doing what you want them to do. You may have also noted from that link above that Dr. Gebhart is also the current President of the International Association for Pain.

Let’s do one more shall we… Allan Basbaum’s 33 year old R37 (Merit Award) entitled “BRAINSTEM CONTROL OF PAIN TRANSMISSION”. Where to start with this one? Anatomical mechanism of analgesic action of opioids: check. Anatomy of bulbospinal projections to the dorsal horn of the spinal cord: check. The list could go on and on. Again, this is all standard textbook stuff now. One thing that really interests me about this grant is the remarkable transformation that the work has undergone as state-of-the-art techniques in biomedical science have changed. Perhaps more than any one else I can think of in the field, Dr. Basbaum’s lab has not only kept up but consistently led in continuing to push the edge in terms of using the latest and greatest techniques to address problems in new and exciting ways. He’s also the current Editor in Chief for Pain, the most influential journal in the field.

There are many more such examples in the field but I think you get the point. If you search for all 3 of the researchers I have highlighted above in NIH Reporter (all years, not active projects) you will note that these long-standing grants represent the bulk of the funding that each of these PIs have held over their careers. In my view this adds considerable stability to the field with very little sign of stagnation. Its interesting to check the abstracts for these grants in renewal years (generally every 5 years). You will note a remarkable change in the hypotheses being addressed and a real progression in the work from funding period to funding period. One might even argue (I would) that the titles don’t really fit the grant anymore but that’s part of the beauty of choosing a very general sounding title. I wish I would have done that for my first R01.

UPDATE:
I totally missed that DrdrA hit this up too…

Drug discovery in academia and NIH, a new type of U01

First off, WOW!!, this has easily been the busiest day ever on juniorprof. Many, many, thanks to Abelpharmboy, Zuska, Melissa McEwan and Almost Diamonds for linking here and sharing your support for the campaign and also to DM for all the support over on twitter for the #painresearchmatters campaign. I am humbled by all of your support and encouragement. Keep the tweets pouring in on twitter with the hashtag #painresearchmatters!

Now, onto our regularly scheduled program: Drug discovery in academia. To some of you this may seem like a strange thing to post about since the common perception is that there is no drug discovery (at least no REAL drug discovery) in academia. I have to admit, I tend to agree that drug discovery in academia is limited and oftentimes lacks the type of rigor that is really needed to develop a drug. For an extensive series of posts on industry vs. academic drug discovery head on over to Derek Lowe’s place. He has all his posts on the topic nicely categorized and they are a very interesting read. One of my all time favorites is this one where he points out that while the compound may be useful as an in vitro tool, it is likely less than useful as a scaffold for further drug development for very obvious reasons. This brings us to the bane of drug discovery: absorption, distribution, metabolism and excretion (ADME). This is something that industry does very well. After all, if you want to make a drug that enters the brain it damn sure better cross the blood brain barrier. ADME in academia, well, let’s just say, not so much. The reasons for this are likely pretty simple: its an important area of drug development but not the most exciting, by any stretch of the imagination (sorry you ADME specialists), and it often requires all sorts of rather expensive testing in model organisms that aren’t used often in academic labs. Its also highly compound-specific and this makes grant writing very hard (or so I hear).

On the other hand, there are very good reasons to do more drug discovery in academia. First, most of the disease models employed for drug development are created in academic labs. Ditto on the development of drug targets for diseases. Its also true that many, if not most, of the endogenous activators of receptors and enzymes have been discovered through the efforts of NIH-funded research. These endogenous ligands are usually the platforms on which additional drug scaffolds are made and academic pharmacologists are pretty darn good at generating structure activity relationships (SAR) for drug-receptor interactions. So what’s the hold-up? In my view its the nature of the academic beast. The medicinal chemists and in vivo and in vitro pharmacologists that are needed to bring a drug discovery effort to fruition just don’t have the opportunities to come together in an academic setting like they do in pharma industry. Pharma industry is built for this sort of thing. NIH grants are not. All of this adds up to major impediments to drug discovery in academia while the potential benefit is huge. Drugs developed through academic efforts have the potential to be much cheaper, target diseases were there is little, if any, potential profit margin (orphan drug programs aside) and would be a huge boon for NIH. Imagine how much easier justifying big increases in NIH funding would be if NIH funded labs were doing work that was leading directly (in the most literal sense of the word) to new therapies. I think this would be huge. Continue reading

#painresearchmatters campaign

Yes, I’m on twitter and I’m now posting in Twitterspeak. That’s the hashtag for a little campaign I am starting on twitter to highlight the importance of pain research. The idea is simple, tell the twitter world why you support pain research or why pain research matters to you and use the hashtag #painresearchmatters. I’ll be posting facts about pain and links to interesting papers on pain throughout the coming weeks. I hope you will join me.

This week has not been a good one for pain researchers. Some of our own have come under attack by a publication that is misrepresenting both the purpose and interpretation of their work. This has led to numerous stories around the web resulting in a real firestorm at McGill that has serious potential to spread. I won’t be linking to any of these stories because none of them even bother to describe the purpose of the experiments. If you want to see the story behind the recent fury, read the paper.

It has long been my opinion that us pain researchers do a pretty poor job of educating the public about what we do and why. This is one of the reasons I started the blog. If you’re new here and you want to take a look at some of what I have written about pain and pain research here are some links to start with:

1) What is hyperalgesia and what is allodynia
2) Why does pain become chronic
3) What is central sensitization
4) Why are new classes of analgesics needed
5) Can chronic pain be reversed
If you want to read more, here is an article I co-authored in the popular press. No access? Email me and I’ll send you a PDF.
A wealth of information can also be found at the IASP website

Here are some facts about pain that illustrate why pain research is so important. These are just a taste of what I will be posting on twitter
1) The World Health Organization considers relief from pain to be a universal human right
2) Migraine headache is the most common neurological disorder in the world
3) More people seek medical attention for pain than for any other reason
4) Nearly 50% of people who seek medical treatment for pain report that they do not achieve pain relief with treatment
5) Chronic pain conditions disproportionately affect women

Now that I’ve given you some basic information its time to tell you why pain research is so important to me. Continue reading

Principal Investigators Association can…

Well, I won’t be as explicit as CPP but that’s about how I feel about them right now. I got an email from them the other day (well, I get an email from them every single day but this one was special) asking me to comment on whether a mouse pain study at McGill was compliant with IACUC rules. That caught my attention just a little bit since I was a pain researcher at McGill for 3 years. I headed on over to the page and was more than a little surprised at what I saw.

I suppose that the purpose of such posts on their site is to help sell their products, whatever those are, and they think their products are going to be helpful to PIs such as myself. Safe to say that I wasn’t interested before and I’m certainly not interested now. The post is about whether the development of the mouse grimace scale, a method to measure affective components of pain in mice, was compliant with McGill’s Animal Care and Use Committee (ACUC) rules. I’m not sure exactly what they’re arguing but it appears to be a pretty one-sided affair and the comments are fairly vitriolic with some threats leveled against the McGill researchers. Great way to sell products to basic scientists doing animal research…

The thing that really gets me about the whole thing (aside from the fact that they are putting my friends and colleagues in danger) is that they completely ignore the scientific findings of the report and the rationale for doing the study in the first place. All of this is straightforward if you take even a glance at the paper. Continue reading

What causes chronic pain – or – how does pain become chronic?

Pain, as terrible as it can be when it outlasts its stay, is actually a vital protective function of our nervous system. The body detects pain through a subgroup of primary sensory neurons, called nociceptors, that innervate the entire body and which normally respond only to high-threshold stimuli such as extreme heat or strong mechanical stimulation. This nociceptive response to potentially tissue damaging stimuli is critical for reflexes and coordinated responses to the stimulus which generally result in a protective reaction (such as withdrawing your hand from a hot stove). Hence, the activation of peripheral nociceptors by pain-inducing stimulation serves a crucial teaching function insofar as it is the signal that protects us from further damage. This fact is best exemplified by studies of rare cases where individuals have a genetic mutation that makes them insensitive to pain. For instance, a family was recently discovered in Pakistan wherein mutations in a voltage-gated sodium channel (called Nav1.7) involved in generating pain signals in nociceptors led to a total lack of pain sensation. Members of this family were working as street entertainers, performing incredible feats such as placing daggers through their arms. Horrifically, one of these young men died after jumping off a roof during one such performance. As tragic as this story is, it serves as an excellent example of how we depend on pain signals to keep us safe from potentially life-threatening injuries. Continue reading