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Why Can’t We Make Better Painkillers?
I asked this question on Fred’s post about the problems his family’s had filling his mom’s prescriptions for painkillers — medication she needs to treat the pain of advanced lung cancer. Moments after asking it, I began thinking, “Hey, wait — that’s a good question.”
Or maybe it isn’t, but I figured there could be no harm asking, because I bet I’m not the only one to wonder.
Why is it that the only really effective painkillers we seem to have are highly addictive and dangerous drugs that addicts love? The point of a painkiller is to make the pain go away, not to get you high, so why do we not yet have a class of drugs that only do the former? Or, to wit: We already do have many of them, such as aspirin, acetaminophen, and ibuprofen. And those are great, effective drugs, as anyone who’s had a headache or a sprained ankle knows. But apparently, they’re not effective enough to treat more serious pain.
So for those of you who know more about medicine, pain management, and drug development than I do: What’s the problem?
It seems to me that the long-term solution to the problem Fred and his family are confronting — one my family has also confronted, and I’ll vouch for the horror of trying to secure effective painkillers for a terminally ill relative and being treated like a common drug addict for doing so — is to create a better class of painkillers. We clearly need painkillers that treat pain but are of no special interest to people who want to get high.
In other words, isn’t this a medical research problem?
Can anyone here shed any light on the obstacles to creating that kind of drug? Is anyone close to doing it? Are any such drugs in testing? If not, who’s doing the most interesting research into the problem?
It seems to me the market for such drugs must be absolutely massive — if we consider “pain” a disease, it’s one we will all, almost certainly, face sooner or later. And short of dementia, I’d guess it’s also the one most of us most fear. Most of us would pay almost any amount of money not to experience terrible pain, or worse still, see a loved one in excruciating pain. So I can’t imagine there are no financial incentives to drug development: an orphan disease, this is not.
An effective painkiller that posed no risk of mental impairment or addiction would be (I would think) one of the most profitable drugs ever manufactured. It would leave Viagra in the dust. It would inherently be an obvious social boon, with a very significant secondary social benefit: There would be no reason strictly to control or limit its prescription.
Why is this problem so difficult, medically? Is the obstacle a known and thus-far insoluble medical one? Or is it a political, regulatory, or economic problem? Is it somehow related to the drug development process?
Does anyone here know?
As I was writing this, another question occurred to me. What would be the obstacle to creating drugs that get people as high as the opiate painkillers do — if that’s what they want to be — but that don’t impair mental functioning and judgment, and aren’t as likely to kill them if they overdose? Why, in other words, aren’t we fighting a war for drugs — much better ones?
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As a practical aside, there are some less-used methods of pain control, especially for patients with terminal cancer pain. Ketamine can be quite useful and has found a place in hospice care (it is also being found to help serious depression, very rapidly!). It binds to kappa opioid receptors (rather than mu) and can provide good relief. It can be used parenterally or orally, the latter requiring higher doses. The main side effect is altered perception, which can be vivid (rather like marijuana). These are easily overcome with small doses of benzodiazepines, administered at the same time. Since it is not an opioid, it is not a respiratory depressant and far less habit-forming.
Speaking of combinations, addition of stimulants, IMHO, is an underused strategy. For example, opioids plus stimulants like dextro-amphetamine provide very good pain relief with much less drowsiness. The latter potentiates the analgesic effect of the former. In England, the Brompton mixture has been in use for many years. It consisted originally as heroin, cocaine and alcohol, with thorazine added for nausea (the bane of all opioid therapy) when needed.
BTW, an enormous amount of research has gone into finding opioids which don’t cause nausea – as there has been searching for those which are not addictive. This leads to my suspicion that pain relief via opioid receptors may not be separable from these undesired effects. Perhaps other receptors can be found and manipulated, but I don’t know of any.
All of this is fascinating. I wonder if you have any insight, or can help me understand, why certain signals along the nerves are understood as “pain.” Does that have to do with the nature of the signal or with the place in the brain to which they’re directed? (Does that question even make sense?)
From introspection, I note that if I bite my own finger gently, I experience it as “pressure.” If I bite it harder, I experience it as “pain.” I’m assuming that the signal is traveling up exactly the same path. What happens — and where in the body does it happen — when it becomes “pain?”
That sounds like a very good thing to know if the goal is to ameliorate pain. Does it help at all with my final question, though, which is whether it might be possible to design drugs that get people high but at less risk? Because that combination sounds rather like a speedball — the kind of thing that leaves bands like Def Leppard minus a guitarist, right? That just can’t be the path to go down if we’re trying to figure out how to get the high without the impairment of judgment, risk of death, and destruction of everything in the addict’s path, right?
Claire – re #62 & 63, I will answer as best I can later, as I am in Zurich visiting my son (whom you met we me last fall in Paris) and heading out the door just now.
Briefly, as to 62, pain signals originate in specific pain receptors and the signals from these receptors travel along specific nerve fibers, which are “wired” to specific neurons in the spinal cord, the dorsal root ganglia (reflexes, like sudden withdrawal from e.g. touching a hot object occur at spinal level before conscious perception of pain); these sensory neurons in the spinal cord send signals along specific pathways (tracts) up to specific areas of the brain, in which the conscious perception of pain is formed. So, it is not the nature of the signal (all nerve impulses are action potentials (no time to link); it is the route of the specific nerve fiber and its destination in the central nervous system which results in reflexes (withdrawal) and conscious perception of pain, as opposed to touch, pressure, position, etc. To be continued…
If I got pain on reading about pain I’d be in big trouble, since I have to deal with people’s pain every day as a massage therapist, but the psyche is definitely connected to the soma, and if someone comes in with pain that has no clear cause, I always ask them to think about what was happening in their life right before the pain began. I’m not sure we need to understand the exact mechanism, how precisely thoughts cause the asymmetric muscle tension that results in pain, but we do need to accept that mind and body are not separate. Certainly we should not be surprised that many drugs intended to treat a purely physical problem also affect the mind.
When I worked in a cancer center, the psychiatrist and palliative care were the only MDs I could get to consider this combination. Eventally, they trained the hospitalists, but it was shocking to me that oncology and the pain service wouldn’t even consider it.
As the chief of hospitalists said, “you shouldn’t have to be crazy or dying to get good pain relief.”
I’m sure there is lots of research going on. We have had much stronger synthetic opiates, some semi narcotic pain meds like tramadol, and other non narcotic methods of pain control attacking non opiate receptors like gabapentin. It’s a hugely complex problem and takes years and billions of dollars. For just a taste of the complexity, here’s an anesthesia introduction to pain physiology .
But here’s the thing about Fred’s mom and similar cancer patients. Opiates work wonderfully for pain, they are literally God’s gift to us. The idiocy of worrying about “addicting” people who have advanced cancer makes me crazy. When I see cancer patients in the ER, and they are being treated with Vicodin or Percocet I want to scream. Those patients need whatever dose of opiate required for comfort. If we treated them properly, and keep them comfortable, there would not be the pressure for “death with dignity” laws we are seeing. People fear pain and suffering more then they fear death when they have a terminal disease.
That’s the truth Kozak, people don’t want to suffer. Main concern for most. I too have been infuriated at terminally ill patients deliberately under medicated. People remember when their loved ones suffer and it stays with them forever.
That’s a fascinating reference, Kozak, and answers so many of my questions, thank you. It seems as if there are thousands of promising avenues to explore and many reasons to be hopeful, doesn’t it?
People have been making variants of this argument sotto voce, but someone should make it explicit. The reason we can take extreme pain relieving actions for dying patients is because they’re dying anyway. This is the entire point of the doctrine of double effect. Giving a dying man a lethal dose of morphine to ease his pain is entirely justifiable because he’s dying anyway. Giving a non-dying man the same dose is murder. Giving a dying man who is not actually in pain such a dose is a gray area on which I will not pass judgment in public.
And by similar logic we can say the same of the crazy -if not lethal doses, doses that have mind-altering effects are acceptable on the crazy because they are crazy anyway.
As to the particular cocktail, I have no idea which side of the lines it falls on.
Kozak,
As the iconoclastic voice on this post I think I need to explain myself a little more. First, I couldn’t agree with you more about the absurdity of denying advanced pain medication to those who absolutely need it. People who have chronic conditions need an express pass to get the meds they need. People who would abuse that kind of drug deserve to be in jail like Michael Jackson’s physician who was using anesthesia drugs on him. I really don’t think it is that hard to tell the difference and it is disgusting that we can’t do better at this.
Cont.
Cont. from # 71
I read your pain physiology link. This is what I was really driving at. Our hardware based pain apparatus is totally integrated into us at the simplest and most complex levels. Whether you want to ask the question ‘why did that happen from an evolutionary standpoint?’ or if no one minds ‘why did Gd build us that way?’ it really doesn’t matter. From either perspective we realize that pain is an integral part of being human. I think if we had more respect for our pain system we wouldn’t accept so many addicts. Turning off safety systems is a behavior that doesn’t exactly generate sympathy (remember Three Mile Island). For some reason addiction generates sympathy and it shouldn’t. On the other hand, realizing that in the situation of a chronic condition our own safety system, our pain system, isn’t protecting us but just making life impossible allows us to confidently use whatever medication is necessary to switch it off.
Regards,
Jim
Claire, lots of pain. Daily excruciating headaches for over 20 years. Horrible back pain that completely dominated my life. No pain med ever touched my headaches. Sometimes, a decongestant (and later, combined with Mucinex) helped if primarily sinus. But after 20 years of nothing helping, and shrugs from doctors, I found the power of Amazon with a search for books on chronic headaches. Got the book, kept the headache diary and bookmarked the page that discussed preventatives. I started on an SSRI and after three weeks- poof, headaches down to maybe one a month.
My back pain does not stem from any disc or structural problems. I was a regular chiropractic patient. Again, anything I took for pain didn’t help ( mostly OTC stuff, but occasionally I might try a prescription if I had one left over from dental fun). I have always been a regular exerciser – walking, spin class, aerobics when people did that, weights, yoga, Pilates, etc. Several years ago it got to the point where everything I did injured something. It was very disheartening. My office looks like a physical therapy office. Fortunately, I can close the door for a few minutes and do my exercises. Over the past few years I have learned that most of this is posture related. It is very difficult to change your posture after a lifetime of it. Sitting at a desk hunched over a computer makes things so much worse, and indeed things started getting much worse when that took up 40-60 hours of my week. About six months ago my massage therapist told me to check out Eric Goodman (Foundation Trainings) on the inter web. I did, and these exercises have helped my back more than anything. It’s been kind of a miracle.
Have you ever tried a standing desk? I have a few friends that have made the switch and they say there’s a huge difference.
As usual with drugs that make you feel real good it seems to come down to dopamine…
Drugs like cocaine and amphetamines also can permanently alter dopamine neurochemistry. Opiates seem to have the same effect, and patients who have been addicted or heavy users seem to have some permanent issues with perception of pain.
I’ve been following Derek Lowe’s In The Pipeline for a couple of years now:
While he’s not specifically addressed your question, the overall answer to your question is: it’s really really hard to discover any drug that works positively in the human body.
The failure rates for new drugs are astronomical, and the body is so complex that at our current level of understanding, it’s essentially a chaotic system.
For instance, one of the side effects of morphine is that it shuts down the intestinal tract. Why? We don’t really know, but there’s probably an evolutionary advantage.
Most chemicals in the body have effects on multiple systems, and almost never just on the one thing that you’re trying to affect.
All attempts to systematize drug discovery have failed. The majority of academic research in the field is useless. Flying to the moon is a far easier task than discovering a pain killer that meets your criteria.
Contessa, have not tried a standing desk, although my son has. Without proper posture I don’t know how much it would help. What has really helped me sit up properly is a Back Joy. I first saw it in the hospital uniform shop, but got it on Amazon. Another source for fabulous posture help is Ester Gokhale, hailed as the posture guru of Silicon Valley. She also has several videos on YouTube, and I have her book. of course, both she and Eric Goodman are in California, or I would be tempted to do some individual training. Thank goodness for the Internet. After 3 weeks of doing the foundation training my massage therapist asked me what I was doing because I was so much straighter and less tight. I do have to keep up with it; if I miss a week I start hurting again. Ice is a great help as well.
You are exactly the kind of person I was writing about @#49. Not everyone will succeed as well as you have, but in my experience people who take charge of their own health tend to find solutions. It ain’t easy, and you have my admiration.
I had terrible side effects on it. It would put me in a great mood when I took it. (Not in a high seeking sort of way.) But a week later I was emotionally deadened. Like I couldn’t feel loving feelings for my then girlfriend (now wife), and I would feel ambiguous about our relationship in general. It was scary.
There is new information (some referenced in Kozak’s reference, which answers several of your questions) regarding genetic variations in opioid receptors and modulation of gene expression with acute and chronic pain. There may be a population of individuals who make insufficient endorphins (or who have insufficient or defective receptors) and suffer chronically depressed mood. Opioids were the first drugs used to treat depression. There seems to be a group of addicts who – given opioids ad lib – plateau their doses and live normal lives. (continued..)
(con’t.)
Anesthesia pain management of post-op pain is now multimodal. We give NSAIDs and gabapentin or pregabalin in an attempt to reduce nociception peripherally and modulate it centrally. We also use continuous nerve blocks with local anesthetic, by inserting thin catheters percutaneously, placing the tip next to a nerve. Beginning in recovery room, a dilute solution of local anesthetic is infused for two to three days so that it bathes the nerve supplying the surgical site (e.g. femoral nerve for total knee replacement). In addition, the patient has a PCA (patient controlled analgesia) whereby they receive IV doses of opioids. Use of dilute local preferentially blocks pain fibers and leaves partially intact motor and proprioception function so the patient can participate in physical therapy, which begins on the day of surgery. Synergy.
As to a drug which would give a “high” without the adverse effects – it might be done with existing drugs, but would be, obligatorily, a “team sport.” Administration of IV anesthetics is empirical. IV anesthetics are all rapid onset and short acting. So, we give a dose of a drug and observe its peak effect. If it is judged sufficient, wait for evidence that more is needed. The same principle applies with combinations, which are given alternately. So, a “safe” high could be achieved in one individual were (s)he to to have the drugs administered and the effects monitored by another – a designated-driver, so to speak. This is the principle of IV sedation.
I had a colon resection a few years back. The surgeon explained to me that morphine would impair healing time. I don’t like being in hospitals, so I was pretty motivated to get out ASAP. I also didn’t like the morphine—I thought the one upside to this experience was going to be trying morphine: not so.
The nurse was horrified when she came in 12 hours after surgery and realized I hadn’t had any painkillers. Well, it didn’t really start hurting until day 2. Then I only used morphine so I could sleep, since all it did for me was knock me out.
I was out in 2.5 days, a record, the surgeon was pleased to inform me.
The negative side effects of painkillers even on the healing process can be significant.
Effects on motility which are well-known, are not necessarily related to “healing time.” The latter term usually refers to wound closure and complete healing of the anastomosis (the reconnection of ends of the bowel). Opioids do slow motility and return of gut function (moving contents along) is a major milestone in recovery from abdominal surgery. The mere handling, cutting and sewing (or stapling) the gut also causes some degree of ilius. My own view is that it is within the realm of informed patient consent that this decision should fall – given accurate facts about ilius, the impact of opioids and the trade-off between pain relief and the likely speed of return to bowel function. The nurse’s response was understandable. It is rare for abdominal surgery patients to no receive opioids post-op.
I have so many more questions — with everything I read about this, another one occurs to me — but I’m wary of taxing your patience, so do feel free to say, “I usually charge for this expertise by the hour, so enough.” But if you feel moved to answer: Is there such a thing as a class of people who don’t respond to opiate painkillers? I’m thinking of that supposedly magical PCA I was given after I had surgery. I pressed the button over and over — I was in a lot of pain — but it didn’t seem to do a thing.
I know that if I take drugs like Vicoden or Percoset I’ll get high as a kite and twice as friendly — they’re very enjoyable — but they don’t actually seem to kill pain. If I’m in actual pain (the kind of pain associated with quadricep contusions, torn ligaments, sprained ankles, getting your nose bitten off by a dog, etc., and yes, I’m a bit accident-prone), forget the Percoset and pass me the tylenol. It works a lot better.
Am I a medical anomaly?
Anomaly? Maybe not. It’s pretty common for some people to respond much better to some kinds of pain relief than others, seemingly for no very obvious reason.
A friend of mine with early-stage rheumatoid arthritis is responding best to Tylenol, while, for many other people I know, Tylenol doesn’t do much at all. Oh, maybe enough to warrant taking it if it’s the only painkiller you’re allowed – but it’s not killing the pain, more like taking just… barely… enough… edge off the pain to permit marginally improved functioning. Personally, I hate when I’m restricted to Tylenol, and consider those who get the most pain relief from Tylenol lucky ducks indeed!
I can’t think of anyone I know who takes Tylenol as their primary pain reliever. It worked for me as a child. I only take it when I’m trying to aggressively reduce a fever now. Taking 600 mg NAC with each dose is good protection against liver stress. (They give people who overdose an IV of the stuff.)
FYI: ” Taken together, our findings indicate that morphine treatment results in a delay in the recruitment of cellular events following wounding, resulting in a lack of bacterial clearance and delayed wound closure.”
And: “Return of bowel sounds, reflecting small-intestine motility after colectomy, correlated strongly with the amount of morphine used. Similarly, total morphine use adversely affects colonic motility. …efforts to optimize the care of patients with colectomies should be directed … toward diminishing use of postoperative narcotics.”
They told me to ask for it when I needed it. Which I did. I didn’t fault her at all.
No, I’ve never found any of the painkillers actually reduce pain. Morphine knocked me out, and the other ones you mention have other neuro effects, but pain reduction hasn’t been one of them.
Maybe we’re both anomalies, but you’re not alone. ;)
Which is generally not a good idea. The advice given by the medical profession regarding fever reduction is not supported by either the scientific or medical literature.
You get better faster with a fever. That’s what it’s for.
I’ve got to stop reading this thread. I’m just too suggestible. Every time I return to it, some new part of my body starts to hurt.