Why are new classes of analgesics needed?

I’ve written a few posts here lately about cannabinoids as new classes of analgesics. At some point I think I also wrote a post about how I am a chronic pain sufferer. I am one of millions of Americans that suffer from chronic low back pain. Over the past week I’ve been having a flare-up of epic proportions. Although the present situation basically sucks-ass for me, it does provide a nice opportunity to explore why the development of new analgesics is so important. There is a great clinical need and this stems largely from intolerable side effects of available analgesics.

Let’s start with a simple fact. Opiates and NSAIDs are effective analgesics. If you have an acute injury, chances are that you can take these compounds and have your pain effectively relieved. The problem is that if you need to take these compounds over the long term you are going to experience some side effects and in most people those side effects are going to make you stop taking your analgesics. Let’s look at the case of Juniorprof to understand how this happens.

I have had low back pain on and off since I was 18. I have a degenerative disc (L4) that was discovered after a football injury when I was still in high school. That same disc herniated about 2 years ago causing me to need surgery. I have taken just about every drug that you can imagine to alleviate the pain. More or less all of them have worked but they have all caused side-effects that I could not tolerate. Let’s look at the classes of compounds I have tried:

1) Opiates. When the pain becomes intolerable I generally turn to opiates. They work quite well; however, I cannot work and take opiates. I also really like taking them, which is a bit scary because these are highly addictive compounds and there is clearly a strong potential there to transform Juniorprof into Juniorjunky. So, opiates, I like you guys but I know what you can do to me over the long-term so you aren’t really an option for managing my pain over the long-term. Finally, my pain episodes can last for weeks on end. I need to work and I simply cannot think clearly when I’m on opiates. Hence, opiates are not really a viable option.

2) NSAIDs. These are those compounds that inhibit what we call COX enzymes. COX enzymes make compounds that cause inflammation like prostaglandins. In addition to causing inflammation these compounds also cause pain. Hence, NSAIDs can relieve inflammation and also cause analgesia. I have taken a variety of NSAIDs (but mostly advil) for more than a decade. For the most part I have not had side-effects from these compounds — until now. NSAIDs work fairly well for pain. They take the edge-off but they aren’t nearly as effective as opiates. They also decrease inflammation which can help the problem that is causing the pain resolve. The problem is that they cause gastrointestinal irritation. For the past week I was taking some really high doses of an NSAID (a high dose because the low dose didn’t do squat). It was working well enough to let me sit and work in a relatively comfortable state. I was happy (on a relative scale) but then the stomach pain came on in a major way. Tell-tale sign of NSAID side-effects. So, now I’ve got to take some anti-acid meds to make the stomach pain go away but those take a few days to get going and in the mean time new doses of NSAIDs make the stomach pain worse. Not a good situation!

There is a potential solution here. There are COX2-selective drugs now (like Celebrex) that don’t cause these stomach problems. On the other hand, they aren’t always effective for pain (they seem to work best for arthritis). I took a few of these more than a year ago and they didn’t help the low back pain at all so I’m not going to get very far with these.

3) Anticonvulsants. Anticonvulsants, like gabapentin (or neurontin), work well for neuropathic pain and there is generally a neuropathic component to low back pain. I have tried gabapentin at a variety of doses and while it works for pain it gave me some rather severe and disturbing side effects: massive confusion. Quite literally. Gabapentin just about made me forget my name. Like opiates, if I was really desperate I would take it but I simply cannot take off from work during every pain episode because the pain meds turn my brain to mush. There are some other anticonvulsants out there that I have not tried that have been shown to be effective for low back pain. Topiramate (topomax) is a good example but I haven’t tried it. Maybe I should.

4) Mixed compounds. When I say mixed compounds I mean drugs that have many mechanisms of action but no one really knows exactly how they work. My favorite examples here are tylenol and tramadol. We discussed tylenol earlier. Tylenol helps with the achy type pain but it doesn’t do a thing for radiating pain (which is what really gets me) so this isn’t much of an option. Tramadol actually works very well; however, tramadol has some opiate activity and is an addictive compound (this is a tad controversial — but see the next sentence). Once upon a blue moon I got pretty close to heading toward juniorjunky status with tramadol so I’m reluctant to go back to that one.

So, that is by no means an exhaustive list but it covers the basics. Again, my case is far from unique, there are millions of people suffering from a variety of chronic pain conditions experiencing the same frustrations with analgesics on the market today. I suppose that the only thing that make my case unique is that I happen to be one of the thousands of researchers around the world working to discover new and better analgesics. This fact raises an interesting question: are there any investigational drugs in my lab that I would consider taking to help my pain? You bet! But alas, I know next to nothing about their safety or the side effects that the compounds may have so I suppose the more appropriate answer is I wish. You see, the vast majority of the compounds that people like me investigate have never been taken by humans and most of them never will. This is because most of them will prove to do some nasty thing in some model that we never would have anticipated. These are the frustrations of drug discovery.

Let’s end on a high note here. Hope is not lost!! The truth is that we know more about what causes chronic pain than ever before and we have a long list of quality targets to develop drugs against. It will take time but new and better analgesics will come. On that note, time to get back to work…


14 responses to “Why are new classes of analgesics needed?

  1. I had an R21 application for lead identification of novel analgesics that went through A2 status and never got funded. The fucking asshole study section complained that there was no need for novel analgesics, because we have plenty that work well. Fucking ridiculous douchecornets!

  2. I had one of those new innovator awards rejected with reviews that said something along the lines of: fucking brilliant idea but novel analgesics are not a pressing medical need. So yes, fucking douchecornets!!

    Seriously though:
    1) More people seek medical attention for pain than any other thing in the US and NIH doesn’t even have a pain-specific study section for preclinical work!! This represents a complete and utter failure on the part of my research community. I’m doing everything I can to get into a position (largely through professional organizations) to do something about this.
    2) Every biomedical researcher/clinician who discounts the need for novel analgesics should have to spend a day in a pain medicine clinic. I’ve spent time volunteering/working in a variety of clinics in my day. Pain clinics are consistently full of the most desperate and depressed people you will find anywhere. And for one reason, there fucking analgesics don’t work!!

  3. I think we should keep on working hard trying to find good analgesics. However, a major contributor to chronic pain disability is depression and anxiety. The way I see it, by the time the pain sufferer finally gets to the pain clinic, the pain has probably already “chronified” and the sufferer’s quality of life has already taken a serious nosedive. The trick would be to catch it as early as possible to prevent the whole situation from spiralling down too far. So I think more emphasis must be put on better training med students on pain so they can recognize it and treat it sooner. Also, many pain clinics aren’t really clinics, but places where patients go to get their scrips renewed. A true pain clinic is multidisciplinary and puts as much if not more emphasis on the psychological repercussions of the pain (loss of social status, income, etc).

    My wife has had severe low back pain for about 15 years and had many a surgery (fusion of L4-L5-S1, etc…) and doesn’t get much help from any drugs. She trained as an MD, so she knows exactly what’s going on with the meds. She is not working now, which is also very hard on her. On the other hand, we’re trying to start a family, so she’s been completely off the meds for over a year and is doing fine (relatively speaking, of course). The reasons? Exercise and stretching as well as a happy home life. She’s not cured, but through a lot of hard work, she’s found a balance that has very little to do with meds.

  4. How do you get the little smily winky face to stop appearing!!

  5. FN, Fine points as usual. It is worth pointing out to the audience that antidepressants (mainly tricyclics but some SSRIs also seem to work) not only can help fight depression in chronic pain patients but they also appear to have some analgesic effect that is separate from the antidepressant effect.

    I should also point out that, like your wife, I rely heavily on physical therapy (mainly pilates and stretching) to manage my back problems. However, during spells like I am having now I need an analgesic to be able to do my physiotherapy. Too bad none of the analgesics are working for me right now.

    Finally, no idea how to get rid of those smiley faces. Sorry.

  6. Analgesics are not a pressing medical need?! Yep, those people should be forced to spend some time at a Pain Clinic asap!!

    I had the distinct pleasure of choosing between Stupimax or Morontin (as the pain docs and nurses call them). The only thing that is generally better about topiramate compared with gabapentin is that you lose weight instead of gaining (which is the better for most people). Yeah I was too dumb to work but I was super skinny so, Yay! right?

    After a few weeks side effects got milder, as in I could remember most words, but I was seriously dumb and had no working memory for the 2 years that I took it. And it was noticable, I mean I could not enter people’s numbers in my phone and had to ask people to write it down for me or do it themselves. (Somehow I managed to get a PhD in there which makes me wonder…)

    One of my favourite pain clinic moments was when I raised the same concerns you mentioned about regular opiate use and refused a prescription for Oxycontin, asking for an alternative please. The nurse went and consulted the big shot pain doctor and came back with a Methadone prescription…

    If the patient is to actually function/work and not be simply zonked out of existence, the existing therapies leave a lot to be desired… It’s really sad for me to hear funding agencies are not aware of this serious problem.

    Hope that flare-up doesn’t last too long!

  7. It’s really sad for me to hear funding agencies are not aware of this serious problem

    I honestly cannot believe that study section members (or program for that matter) do not understand just how bad the problem is. I think that the lack of an NIH pain institute (there was one back in the 80s) and the lack of a pain-specific study section is the real problem. When the funding is tight, as it is now, there is a tendency to protect your turf. If your grant ends up in the wrong place you might get this stock critique as a defensive measure. In other words, they don’t want to fund it because it can subtract from what they think their section is supposed to fund. Not sure what happened to PP but this could be a possibility.

    The primary pain study section is somatosensory and chemosensory systems (SCS) at least for preclinical work, in case anyone is interested.

  8. Wow. Your back and drug story is unbelievably similar to my own. It’s good of you to write about this. You’ve clearly pretty well to overcome, overall. Hope the pain clears up soon.

  9. …done pretty well…

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  11. I recently woke up from surgery experiencing such intense pain that I was starting to convulse. Narcotic analgesics saved my life. Narcotics are like antibiotics, misuse and over use can quickly make them ineffective, correctly applied and they are a godsend.

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  14. Hey that you just very much for the article, it absolutely was quite and educational go through! I will be back later on for confident.

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