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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?
Published in General
Claire:
I spoke to my wife (an Internist) and here are her thoughts on chronic pain management, especially for cancer patients:
To Claire (continued)
I hope the above has been helpful.
I believe that, and it’s a hugely interesting point with many implications. But there are aspects of the body’s functioning that are relevantly similar to some machines, as least as far as we understand them, right?
That’s for sure. But how does aspirin work? Why does that drug kill mild pain — quite well — but not extreme pain?
The more I think about this, the more I realize I don’t know and don’t understand.
This should help explain some of it.
It is helpful, and completely consistent with everything I’ve been told about pain management. I have a feeling that to even begin to really understand this, I’d have to go back and crack an organic chemistry textbook and try to remember things I haven’t studied in about three decades. I just realize that as I look at all of these statements, they kind of don’t make sense. And they prompt in me more very basic questions: Are the opiates in fact killing the pain, or do they change peoples’ relationship to the sensation of pain, if that makes sense? That is, do people feel the same sensation, but not feel bad about it — in a sort of Buddhist “Pain is inevitable, but suffering is optional” way?
(I don’t know if that last question makes any sense at all. I’m confused, obviously.)
Claire:
I had a kidney removed for because of cancer 15 years ago (next week actually). When I work up from the surgery I was hooked up to self administered morphine. From my experience, I did not feel the pain. When I went off of the morphine, I definitely felt the pain. So from my experience the sensation was gone. My wife cautioned me not to stop the morphine too early because the pain would feel worse and it would be harder to get ‘back on top of it’.
My wife has helped her best friend and two close friends die from cancer. Managing their pain at the end was always the most challenging part for her. She strove to keep the pain at bay but to ensure that her friends we still engaged in the reality around them and were lucid enough to say their final good bye’s to their loved ones.
Assorted answers from the wrong type of doctor:
Of Theology: “Cursed is the ground because of you, in pain you shall eat of it all the days of your life.”
Of Chemistry: “Let’s assume that they do… making DooDah a possible cancer target… What they will not do is try to provide a drug lead… This is where the drug industry comes in… We’ll have to figure out how to produce active enzyme in a reasonably pure form… …” It continues at length. In another place he talks about the difficulty of targeting drug leads. Admittedly, he’s not talking about pain killers, but I imagine the process is the same.
I wouldn’t get in a car being driven by someone who had just run a marathon.
First: congratulations. These days I’ve become so used to thinking of cancer as “automatic death sentence” that I tend to forget that many people do indeed survive it. Fifteen years is great.
When I had surgery in roughly the same area (c.f. my earlier post about my ovarian cysts, which I’m sure no one wants to read twice), I was hooked up to the same thing. I was in a lot of pain afterward. A lot. (Although maybe they did your surgery through laparoscopy? I had to have a full-on laparotomy, which I recommend to no one. It’s no fun.) The morphine seemed pretty useless. I assume it would have been worse without it, but it was really bad even with it. I kept pressing the “medicate me” button, but it didn’t seem to have much effect. That permanently discouraged me from believing that morphine was a wonder painkiller.
What torments me is that we just can’t know if we’re medicating terminally ill patients in a way that manages their pain. After all, they can’t come back to tell us.
Fine. How about a brisk three-mile walk, then.
My own spotty recollections of organic chemistry is that we have 4 basic ways to stop pain: stop the production of the enzymes that trigger pain receptors (Aspirin, NSAIDS), reduce the inflammation at the site (NSAIDS, Aspirin, ice-packs), block the transmission of the pain to the central nervous system (Tylenol), or jam the pain receptors in the brain with another neurotransmitter (Opioids).
The further up the chain you go, the more effective the relief, but also the more damaging the side effects. Stopping the triggering of pain at the source is relatively safe -it won’t much adjust your biochemistry and the major dangers are in the metabolizing of the drug (hence, damage to kidneys and liver). However, if the pain is widespread and really big, your body will kick in redundant pain transmitters in the CNS, which is what Tylenol and cannabis block. Blocking transmissions to the CNS stops the pain, but also mucks up your body’s self-regulation -presumably why marijuana users get the munchies, but I’ve never seen it specifically noted -and can cause cardiovascular, digestive, and respiratory problems.
In really bad cases, your body will continue sending even more redundant signals, so we have to jam them at the source -the brain. We flush the brain with neurotransmitters so that there is nothing to receive the pain signals. But this blocks everything else, too, so you become high. Too much jamming and your brain can’t adjust back to normal afterwards.
Despite the similar names, the relationship between a runner’s high and a drug high appears to be rather tenuous.
The experience of somatic pain has survival value. It leads to behaviors which cause us to avoid it when possible. It differs from visceral (protopathic) -e.g. cancer pain – and neurologic pain. Pain results from stimulation of specific pain receptors found in most tissues of the body (interestingly, the brain has none). Specific pain receptors transmit information to the brain via peripheral nerves to the spinal cord along specific pathways. Peripheral nerves can be though of of bundles of wires of differing types. Among these wires are several types of fibers which transmit pain information centrally. Others transmit touch, proprioception, and impulses which cause muscle contraction. Pain is not simply overstimulation of peripheral sensors.
Opioids diminish the perception of painfulness in the face of a given painful sensory input. They do not modulate the sensory input. It may be that the sense of “wellbeing” (or “satiety”) resulting from opioids binding to mu and kappa opioid receptors cannot be separated from the pain relief. Given the amount of effort in finding a molecule which relieves pain without altering sensorium (and being addictive) I suspect this is the case. Heroin was named, in part, for this purported heroic accomplishment.
Blocking pain impulse transmission via peripheral nerves is also problematic, since local anesthetics block – to varying degrees – transmission in all peripheral nerve fibers. Although pain fibers are most sensitive (least myelinated), some degree of numbness and weakness inevitably accompanies any attempt to block pain by injection of local. Local also suffers from tachyphylaxis.
I used to tell post-surgical (non-cancer) patients in the hospital who were going home on pain medicine a couple of things:
1. Pain-free is not the goal. So, let go of that dream (I was much more tactful).
2. While everyone responds to pain medicine differently, with opioids, I could bet on there being subsequent constipation and mild depression/irritability.
However, advanced cancer is a whole different animal, and my opinion and ALL the research says, they should get whatever meds they need to manage their symptoms and side effects and get them to their maximum level of functioning and/or quality of life.
From the premier scientific journal USAToday, a brief story on non-addictive opiods.
Also, Claire for the purposes of our discussion here, we can set aside the mind-body connection, but for distribution to the population, it’s a real challenge.
I often told patients that tolerance (the physicological need for more drug for the same response) was tolerance, but addiction was tolerance plus some mental health component resulting in a set of behaviors plus physical responses known as addiction.
I can’t quite say we should end the war on drugs (probably for emotional reasons, not good solid philosophical or research based ones). But our current regulation scheme certainly causes a host of problems.
Oh my gosh, you are singing my song, sister! If I had a dollar for every time a patient asked for two Percocet then proceeded to rate their pain a 4 out of 10….really!? Or if I had a dollar for every time a patient said “Therapy told me to take my pain medicine as much and as often as I could.” Again…really!? The whole thing about patient’s right to have their pain addressed has morphed into many patients thinking they have the right to be free from pain, not just have their pain managed. Someone just cut into you and removed or replaced a part of your body- you’re going to hurt. Let go of that dream. But I’m totally in agreement that with terminal cancer patients, have whatever it takes to be comfortable.
Civil Westman is an anesthesiologist and that specialty knows more about pain in the surgical setting and afterword than anyone. Often that specialty does chronic outpatient pain management as an additional specialty. He has the advantage of seeing anesthetics advance as well as pain management become a science and an art.
Way back in the 90’s when I was doing hospice work, I took a number of classes of chronic pain management. I’ve treated hundreds of terminally ill patients and thousands of chronic pain patients. There are hundreds of tricks depending on the type of pain and the area of pain. Chronic pain in a functional person is far different than managing acute temporary pain or the pain in someone who is terminal. Alcoholics and drug addicts need to be addressed differently.
Claire, the terminally ill patients who do OK have family members that hug and thank you. That’s one way you know but most of them are verbally proficient nearly until the end. I’ve done many things I won’t discuss here.
There is no safe way to treat pain except perhaps topical meds ( I have a great cocktail for complex regional pain syndrome Klaatu but you’ll need to disparage the GOPe and insult Boehner/McConnell or I won’t tell you).
Contessa, the man with the Internal Med wife and Civil have given plenty of info to answer you.
I’ve called the cops on about 20 abusers who were selling or doctor shopping. I usually give people the benefit of the doubt and just give them a warning or let them go.
Rite Aid still carries Oxycontin but I suspect all the big opiods are going to be in a central locked and guarded location. This is what my buddy the pharmacist thinks since he’s sick of losers putting a gun in his ribs for oxy, hydro, and methadone. Pharmacy robberies are a huge issue now and getting worse.
Whatever people can curse the docs/NPs who are stingy with meds or deny them have zero clue what it’s like to be called by the cops or coroner when a dead kid has your name on the pill bottle next to them.
I take a much more radical approach. I do not believe that orthodox medicine will do much better given the way in which it understands the human body. Drugs are antagonistic to the body, so why would they not have a big downside? Do we have drugs today that are very much better than aspirin and morphine, which have been around for awhile? The need for pain relief is the main reason people seek help outside standard medicine, and some of it even works. Until there is more serious interest in alternative methods by the medical industry, there is not likely to be a lot of improvement. I do not see that happening, which is another story.
In my massage therapy clinic, we see quite a few people who have figured out how to take care of themselves without standard drugs. I saw someone yesterday who has a painful auto-immune disease but who lives a very athletically active life without drugs. She has had to do her own research, with lots of trial and error, and that’s pretty much what it takes.
There are plenty of non-medication pain control modalities and techniques Sandy. Many docs utilize them but many ignore them as well.
Physical Therapy, biofeedback, counseling, chiropractic therapy, massage therapy, various herbs, placebos(homeopathy), topical relief, acupuncture, Chinese medicine, exercise, and many others are what can be used. I’ve referred to all except homeopaths but sometimes my patients see them.
DocJay: Whatever people can curse the docs/NPs who are stingy with meds or deny them have zero clue what it’s like to be called by the cops or coroner when a dead kid has your name on the pill bottle next to them.
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To this point, I had a sweet little 78 YO lady come into the clinic on Wednesday asking for a refill on her Norco, not something we do a lot of in hepatology. She said that her PCP refused to give her a refill and was very upset that she asked for one. Come to find out, his DEA number was revoked for over prescribing. Unfortunately, the few ruin things for the many.
Thanks for this. You are right, and we work with a lot of docs and see them in our practice.
This is fascinating discussion. I would be interested in learning what we are learning in neuroplasticity that has potential. Here in our county ( and I don’t think we are unique), deaths from poisoning have quadrupled in the last 15 years. Approximately 3/4 of poisoning deaths are due to overdose. Our state is working hard to crack down on over-prescribing, doctor shopping, and pill mills. A side effect is that addicts are turning to heroin – treatment admissions for heroin in our county have doubled in two years.
I see a chiropractor whose office is in between two suspect doctors. There is a line in the morning, cash, in- house pharmacy, etc. the drug task force guys have them on their radar but haven’t been able to nail them yet. There are always cars full of people ( and I mean no available seats, so not a patient’s ride) in the parking lot, presumably waiting for a hand off. They will get these guys eventually; unfortunately, both have purchased their office space, so the space will be tied up in court for years after they are busted. (My husband a real estate lender and I do health stats, so2 perspectives.)
Meanwhile, people who truly need these meds have to face way too many obstacles. It’s all so frustrating.
It really is, and I’ve got yet another question. How many of you, on reading this, experienced some kind of pain?
Just reading this thread and thinking about it caused me to feel (or at least, “was very suspiciously correlated with my feeling”) pain in my back, neck, head, and forearm. Minor pain, and obviously totally psychosomatic. But I definitely felt it.
The power of suggestion and the placebo effect have been shown again and again to be real. And we clearly so poorly understand why that should be so.
Claire,
First of all how come you start these really interesting discussions when I’m off line? No need to answer that.
I have a very different attitude to this entire discussion. First, I think we are all talking about pain as the problem. We are failing to ask what pain’s function is. Pain is our bodies way of telling us something is physically wrong. If we are unable to experience pain we will not know something is wrong. If we are unable to experience intense pain then we will not know that something is severely wrong.
If we experience severe pain for extended periods it can tax our ability to cope. Thus anything that relieves the severe pain will be addictive in the sense that if stopping its use involves the severe pain coming back we will do almost anything to get the pain stopped again.
Thus almost all pain modification regimes will be addictive to some degree. If the sensations that are side effects are especially pleasant then there is a doubled incentive for addictive behavior. I would remind you that just having an intense pain stop is a very pleasant sensation for the person who was just having the pain.
Now I will recount my own most recent experience with intense pain. In 2005 I was driving back from a short shopping trip on a weekend. There was a malfunction in my cars cooling system. Part of the cooling system exploding just as I was parking the car. (I was very lucky because if the cooling system had exploded a few minutes earlier when I was doing 65 mph on I-95 I think I would be dead and I might have taken others with me) The explosion sprayed my ankles with hot radiator fluid. I immediately had 3rd degree burns on both ankles. The skin on my ankles was falling off like cooked cabbage.
They took me to the burn unit. I was given some strong drugs for the pain and a one week prescription for the pain pills. The severe burn had to be washed daily and special cream anti-biotic applied and special non-stick bandaging applied. Do to my circumstances I was doing this myself. I think I am correct in stating that burn pain is one of the worst. For the first week I got by with some major discomfort. I would take my drugs 45 min before I would wash the wounds. Still the pain would be intense and would take 15 minutes or so to subside.
Cont.
Cont. from #55
However, they would not renew my prescription for the strong drugs at the end of the week. The horrific burn wounds would take well over a month to heal. I was told to take Tylenol at high doses. I tried my same procedure of taking the pain medication 45 minutes before washing time. The pain was through the roof. I got through washing my ankles somehow. I applied the cream and special bandaging between low screams. However, now was the worst part. The pain was not going away. It was fabulously intense if I rested my feet on the floor. It was fabulously intense if I rested my feet on a pillow in bed. Finally, after half an hour of agony I discovered that I could sit in bed and wrap my arms around my knees holding my feet in mid-air. I would rock gently on my curved spine and make a low sound. This rhythmic method seemed to distract my insanely firing nerves enough to endure it. After about 90 minutes of this the nerves seemed to wear out and the pain dulled enough for me to put my feet on the pillow.
This went on for three more weeks. The worst part was anticipating washing time. It was like waiting to be tortured. After the first month the pain very slowly lessened and lessened. I was not fully healed for two and half months. What is odd is that almost immediately after being taken off the drugs and experiencing the horrible pain, I began to think of the poor people especially children who had burns on large parts of their bodies and what they must be going through. It helped me stay calm and recognize that I was indeed lucky.
Pain is not the enemy. Out false attitude to life is the enemy. Gd (or if you insist evolution) has not created a world that is easy for us. We are expected to find our own way. If we try then Gd will help us. We must help ourselves then we can help each other too.
Regards,
Jim
The papers linked at Sharyl Atkisson’s site will help you with that.
The reason is that pain is biologically very important and is complex.
As with all very old systems, many other functions are interwoven with nociception.
For example, the opioid receptors have a significant immune connection. Low dose naltrexone (the opiate antagonist used to treat opiate overdoses) affects the regulatory T cells in interesting ways.
http://chriskresser.com/low-dose-naltrexone-ldn-as-a-treatment-for-autoimmune-disease/
Not until someone you love is in pain. Then it’s the worst enemy you’ve ever had.
It’s virtuous to be stoic for oneself. It’s neither virtuous nor even possible to be stoic for someone you love.
Claire,
Nowhere in my post did I suggest that we simply accept pain or ignore suffering. My suggestion is that pain is intimately part of being human. The assumption that one can eliminate it completely is a very dangerous one that can lead us astray.
I think that dealing with one’s own pain is the only thing that sensitizes you enough to truly deal with and help others. Often the ones most close to you are the ones it is most difficult to help. Your emotions are so intense you lose perspective.
Sorry if I sound harsh but I think we are lost in an illusion of scientific perfectionism. If we can’t solve every problem immediately we become all too willing to dispense with ethics as if cutting corners will make the difference. It rarely does.
To really solve problems in a big way you must think outside the box. For instance Cancer is not a pathogenic disease like the normal disease model. It isn’t about killing some external pathogenic vector. It is an information based disease of DNA itself. A subroutine on your DNA that exists in every cell of your body but is normally inactive has been activated in a Cancer cell. To stop Cancer we must find a way to turn the subroutine off. The normal treatments are usually misapplied pathogenic treatments. They are only partially effective and have huge side effects. We are looking for William Tell to shoot the apple off of our loved one’s head and instead we get carpet bombing of their whole body. There are people who think outside the box this way. They hope to find the off switch for the Cancer subroutine.
Best I can do.
Regards,
Jim