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The Opioid Use Hiding Behind the Alleged Superiority of “Nonopioid” Chronic Pain Treatment
The SPACE randomized clinical trial, which 234 veterans with chronic back or knee pain completed, has been touted as demonstrating that opioids are superfluous to chronic pain management. According to JAMA’s summary of the trial,
In the opioid group, the first step was immediate-release morphine, oxycodone, or hydrocodone/acetaminophen. For the nonopioid group, the first step was acetaminophen (paracetamol) or a nonsteroidal anti-inflammatory drug. Medications were changed, added, or adjusted within the assigned treatment group according to individual patient response.
and not only did those in the “nonopioid” group experience fewer side effects, but
the use of opioid vs nonopioid medication therapy did not result in significantly better pain-related function over 12 months (3.4 vs 3.3 points on an 11-point scale at 12 months, respectively).
Overall, “nonopioid” treatment appears to win. Omitted from JAMA’s summary of the SPACE trial, though, is the interesting nugget that one of the medications “changed, added, or adjusted” within the “nonopioid” group was tramadol, an opioid. The treatment regimen for the “nonopioid” group can be read off the right-hand column of this graphic helpfully provided by F Perry Wilson of MedPage Today:
Admittedly, tramadol is considered an unusually mild opioid – or was considered unusually mild until recently, when it was scheduled as just another dangerous drug. Furthermore, only 13 of the patients in the “non-opioid based” group received tramadol, meaning most did not. Wilson reports,
Now, I know what you’re thinking. Isn’t tramadol an opioid? I asked lead author Dr. Erin Krebs that very question. She reminded me that this trial started in 2010: “This was before all the concerns about opioid overdose and addiction and back then a big concern was is it ethical to deprive patients of opioids if they fail all these non-opioid medications.”
It wasn’t until August 2014 that tramadol became an “officially dangerous” schedule-IV drug, after having been completely unscheduled for nearly 20 years. So the SPACE trial began back in those halcyon days when tramadol was considered “the safe opioid,” and that, along with basic compassion, appears to be the SPACE trial’s excuse for including tramadol users in the “nonopioid” category.
Indeed, tramadol isn’t just an opioid. It’s also an SNRI, a type of antidepressant, which may help explain tramadol’s formerly-mild reputation: antidepressants also help people cope with chronic pain. As the graphic above shows, stage 2 of “non-opioid based” treatment includes nortriptyline and amitriptyline, both tricyclic antidepressants, presumably for the same reason. A patient receiving tramadol isn’t just getting his opioid receptors tickled; he also benefits from accumulating serotonin and norepinephrine, both of which can improve a chronic sufferer’s mood and function without the opioid “rush.” For someone interested in using opioids as conservatively as possible – stretching small amounts of opioid-receptor tickling into the largest-possible therapeutic benefit – tramadol might seem like a wonder drug.
For many patients, tramadol was that wonder drug, and its scheduling as a controlled substance has proved a burden. As one patient regularly prescribed tramadol back when it was unscheduled puts it,
Fortunately, feeling like a scumbag addict is a great motivator for staying away from opioids, despite the fact that they do take away 100 percent of my pain and allow me to physically function through an average day. Politicians say you’re just weak. [Prospective] employers see you as a potential pill-popping train wreck. Co-workers and subordinates look at you like you’re Dr. House. Friends and family will compare your pain to theirs and blow it off. (“Your back hurts? That’s nothing. I lost three fingers working at the guillotine factory. You don’t see me suckin’ down pain pills”) I simply have to measure the physical pain against the psychological/emotional pain and realize that the latter is greater. Problem solved.
“I simply have to measure the physical pain against the psychological/emotional pain and realize that the latter is greater.” Arguably, that’s a description of tramadol’s scheduling working exactly as it should, deterring law-abiding patients from relief unless their pain is great enough to be worse than the added social stigma and inconvenience.
JAMA must be perfectly well aware that tramadol is an opioid, one which became scheduled before the end of the SPACE trial period. There’s no excuse for JAMA’s summary describing a treatment including tramadol in its final stage as “nonopioid.” SPACE’s “nonopioid” treatment would be better described as “conservative use of a mild opioid as a last resort” treatment, which is exactly how many people supporting opioid usage for chronic pain believe opioids should be used: sparingly, as one of many treatments when less-aggressive management has failed.
Obviously, those who have access to the full text of the SPACE study can read the whole thing and discover for themselves that “nonopioid,” in context, doesn’t really mean “nonopioid.” Science journalists know, though, that many readers only read their summaries of studies, or at best, the study abstracts, rather than the studies themselves, since time and access are scarce. I don’t have access to the full text of the SPACE study, but if we assume that, of the roughly 240 veterans who completed the study, half, or about 120, were in the “nonopioid” group, and we know that of those, 13 received tramadol, then about 10% of “nonopioid” subjects received an opioid. That doesn’t, by itself, prove that roughly 10% of chronic pain patients would benefit from opioid use, but if at most 10% of the roughly 100 million chronic-pain sufferers in the US, or about 10 million people, may benefit from conservative use of opioids, then claims that the SPACE study proves opioids have no place in chronic-pain management are greatly exaggerated.Published in Healthcare
Were non-drug-based treatments evaluated.
As someone without access to the full study, you know I can’t say for sure. But from the abstract and summaries, it appears not.
Non-drug methods are quite important for chronic-pain management, and I have no idea if the study took into account the non-drug methods subjects might have been using, or whether subjects had to promise to avoid changes to their non-drug regimen during the course of the study.
I have had three surgeries in the last 5 years and each time was given opioid based drugs. I filled the prescription just to be safe. I used three total. I have been using two Alieve a day but I had some bleeding so it has been almost a month since having any. I can’t say that I don’t miss them especially at night but I am working at it. As close as I get to pain pills is an 81 aspirin at night.
I find earth breaking studies that happen to support what the political class wants that arrive in a timely manner to be suspicious. We live in an age that anybody can buy some “science” to prove whatever they wish.
Another example of “science” being shanghaied by a politically driven agenda. Reading this post, I was reminded of a conversation I had with an oncologist back in the 90’s. In California, the hot political topic of the time (well, one of them) was legalizing medical marijuana. Somehow that topic came up in the conversation, and he told me that he was strongly against it. After I picked my jaw up off the floor I managed to sputter, “But, but, but, you’re an oncologist! Don’t you have patients who tell you that marijuana is the only way to relieve their pain and counter the effects of chemotherapy?” “Yeah,” he said, “but I don’t believe them.” What can you possibly say to that kind of thinking?
I can think of dozens of ways that this SPACE study could be methodologically flawed, but one of the most obvious is that when the subject patients reported pain, the researchers’ response may well have been “I don’t believe them.” I would be very surprised if this was a truly double-blind study.
I don’t think it was designed to be fully double-blind, just “randomized trial with masked outcome assessment”, which I think means the patients were randomly assigned to a treatment group, knew what treatments they were getting, and then each patient submitted pain scores, etc, to an entity (whether human or computer) while the entity was kept ignorant of which group the patient was in. Each patient in the study worked with a doctor to adjust dosage and medication as the trial wore on, which would be difficult to do without doctor and patient knowing the medications involved.
It’s not obvious that anything other than patients’ own self-reports on various assessment scales was used as data, but then, I also can’t see the full text of the study. Perhaps one of our medicos know how these scores are typically collected.
Fortunately I don’t deal with chronic pain, but I do take a serotonin uplifter (generic Lexapro), and I can easily imagine that it helps people cope with pain. I began taking it due to a chronic cough that could only be credited to off-the-scale anxiety. Taking the medication literally changed my life, made everything easier to deal with. To mislead people about tramadol and the range of its effects is irresponsible. Thanks for this OP, Midge.
I would acknowledge a data point based on his experience and my knowledge that addictive personalities are habitual liars. But then I’m not biased to accept pro-marijuana-legalization-and-usage hype.
Why must finding some of these cancer patients’ reports plausible indicate a bias toward pro-cannabis hype?
It seems possible to me to be indifferent to legalization, or even against it, while acknowledging it may have worked as described for some patients.
As someone who spent some thirty years as an anti-pesticide activist, I have this comment to make – when decent studies were done by any independent researchers or group of researchers, utilizing a sample of less than 500 people, and they then came up with a finding antagonistic to Big Industry, guess what? Why, Big Industry was then quick to remark that the sample observed was too small a sample.
But when Big Industry wants to score with the public, by releasing data with headlines in the newspapers or TV news slots, they are totally unashamed of releasing results of studies with under 500 subjects. Sometimes as few as 29 subjects.
And the idea of an industry adding an element into the category that is not supposed to contain that element is essential to the game they play. For example, Monsanto’s scientists put Aspartame into the “made with sugar” cupcakes so they could then state, “when consumed by children, the made with sugar cupcakes did not result in any difference in noticeable side effects when compared to the cupcakes not made with sugar.”
Cynic that I am, I wonder exactly how expensive tramadol is when compared to hydrocodone. (Hydrocodone being a very cheap prescription med.) Since it seems to be on the list of prescription drugs that the industry wants to promote, I am betting tramadol has a significant cost over a much cheaper hydrocodone.
Well the other big bad red flag about the finding was the revelation that they included an opioid inside the tramadol that was sampled. Yet they left tramadol inside the “non opioid” category, none the less.
BTW, these days marijuana is not seen as a mere pain reliever and an item that encourages the appetite for the cancer patient. CBD oil is curing inoperable brain tumors, thyroid cancers and blood cancers. It seems to be a panacea for cancer.
Many doctors embrace it. While those who pay homage to the Pharmaceutical Industry have their panties in a bunch and stipulate: “We don’t know enough about this to say that it can help in the slightest.”
In many cases, people who were cured of their cancer had nowhere else to turn. They had already submitted their body to the chemo or radiation treatments (as well as emptying their pocket books.) The only thing left was to go along with their oncologists and outright die, or else to try the “whack-o” idea of using CBD oil.
In this particular case, you can’t say much. Pain is mostly a subjective experience. Unless we completely discount the subjective report and only look for physiological indicators (increased blood pressure, heart rate, facial grimace, etc), we will always have people gaming the system. What we do first is monitor how they respond. Could you imagine how many people would be willing to go inpatient or overnight observation for increased dosages of opiates to ensure both pain relief and lack of respiratory/blood pressure depression? If that was the hurdle, that would discourage people as well.
Ultimately, however, we have to trust our patients on some level, otherwise there’s no point to medicine. We might as well just do whatever we want and not bother telling the patients because we don’t believe what they say anyway.
As for marijuana: getting high (as much of medical marijuana does very well) tends to reduce anxiety and perception of pain for many people. I’m sure it works perfectly well.
Back to tramadol is only a partial opiate agonist. It really doesn’t get people “high” at all. This is one reason why a lot of chronic pain people simply will not use it at all. There’s not enough of an opiate reaction to make it “useful”. The definition of “useful” for these people is being completely out of pain (like asleep or in a coma).
We have a problem. It isn’t just an opiate problem. It’s a pain problem and it’s a modern life problem. There are many modalities for pain control and more of them should be used more often (aquatherapy, for one).
Curing? I have seen no legitimate research on this, only patient reports. The best research shows some promise with epilepsy, but not cancer.
That is because people are interested in what larger groups of researchers have to say. This is absolutely spin management.
In science, however, 500 people is a small sample. 20 people is also a small sample. In order to really look at reliable results, you need repeatable studies with larger numbers of people. If the researchers had a great publicist, they’d get their stories released as well (see the chocolate and wine studies).
Seems to me that Truth in Abstracting and Summaries should be a legal requirement for any study with Fed money in it. Chances are we paid for that study in whole or in part.
The purpose of obscuring the fact that tramadol was used as a “nonopioid” option the SPACE trial appears to be to demote tramadol, not promote it. After all, reporting on the SPACE trial focuses on the ineffectiveness of opioids as a class (including, presumably, tramadol), compared to (what the unsuspecting would assume to be) wholly “nonopioid” drugs.
What I have written may appear to promote tramadol as a better alternative to other opioids, but that is because I emphasize, rather than suppress (as the JAMA summary did) the role tramadol played in the SPACE trial’s conservative (but not completely opioid-free) “nonopioid” treatment strategy.
This price comparer lists tramadol as the cheapest opioid, but bear in mind that hydrocodone is typically sold as a mixture, hydrocodone-APAP, where the APAP serves an overdose deterrent (among other things). Additionally, in 2014, hydrocodone was rescheduled from Schedule III to Schedule II, and as a Schedule II substance, the manufacture of hydrocodone must not exceed a DEA production quota which has been decreased for two years in a row.
Tramadol has been available as a generic for a while now, meaning the original patent must have expired. Hydrocodone synthesis still depends on opium poppy production, whereas tramadol synthesis does not. The welter of regulatory and geopolitical concerns surrounding opioids as a class and poppy derivatives in particular means I can’t guess which of the two drugs would be cheaper if unfettered capitalism held sway.
This strikes me as so dishonest.
It is mind-boggling.
I also can’t believe it’s legal.
It used to be conventional psychiatric wisdom that a patient could not be given any type of psychiatric drug–that is, any mind-altering drug–without the patient’s knowledge because not knowing would cause problems for the patient in and of itself. In fact, I though it was the law. I suppose the opioids are not considered to be mind-altering drugs.
It’s just not right for the researchers to lie to patients.
This is one of the largest issues in the Opiate Crisis which I have written about previously. People do not seem to understand that this doesn’t just limit purchasing, but it limits and penalizes prescribing, manufacturing, and filling legal prescriptions.
If people want to look at the full study, I have access through work. Let me know, and I will get the PDF.
That said, it’s notable that study exclusively used high potency opiates for the opiate group.
It’s funny, we can’t seem to find a rational solution to this problem. Either we take the hardline anti-opiate stance (our own Vicryl Contessa said that every patient coming to her ER complaining of pain was looking for drugs. Sucks to be the person with a dislocated knee there.) or we had out Oxycontin like candy to everyone who asks for it. It would like alternating between a death penalty moratorium and executing people for every single felony crime, or between gun confiscation and mandatory gun ownership.
In @vicrylcontessa ‘s defense, she’s probably not wrong. Most people in pain are looking for drugs. Whether or not they have legitimate pain is beside the point…
I don’t think she’d ever begrudge someone who was in there with a severe migraine, throwing up, with a blanket over his head or someone with a bone sticking out of their leg. But someone who is laughing, texting, complaining about not having enough ice…? Maybe less likely to think that pain is really real and maybe more likely to think that the patient is drug-seeking.
I’ve said it elsewhere under different topics but a free society that removes things based on the possibility that someone might misuse those things is not actually a free society.
The study was done at the VA.
The fact that public resources were used for a paywalled study is outrageous. /soapbox
That’s common practice. Journals are paywalled pretty much everywhere. Academics hate it.
The UK a few years ago tried to put a stop to it by insisting that all government funded research was Open Access, but I’m not sure how that’s actually been going.
Midge, did you say that 30% of the US population suffers from chronic pain? 100 million would be about 30%.
Tramadol seems cheap also. I was prescribed both last year for an extremely painful infected venous ulcer and the cost was negligible. I saw two docs and each started me with tramadol, which, by the way, did not touch the pain. However I have found it useful for moderate pain which needs more than OTC drugs and it doesn’t make me dizzy and nauseous like oxy- or hydrocodone.
Also the pharmacy requirements for filling tramadol are much more lax.
Did they subdivide the pain into specific types? Some kinds of pain related to inflammation (ie arthritis) will respond to NSAIDs. But what about neuropathic pain or disc pathology or torn meniscus? Different pathologies are gonna respond differently.
Second problem is it flies in the face of reality. Opioids work for pain. They just flat out do. You can find/do a study that can prove anything if you want to. It’s like those studies that show that anabolic steroids “don’t work”. (Studies done by anti-doping authorities.) They just work and everybody knows it. Trying to prove that they don’t just calls into question the credibility and bias of the authors.
My mom was given tramadol years ago for a pain problem (can’t remember) and discovered that her mysterious cough she had quit, so the dr. kept her on it. She used to cough all day and night and they could not find out what caused it or how to treat it. This was an accidental find. There is a cough dr. somewhere that had a short post about tramadol’s effectiveness in this area.
Our dog took it for years too.
But journals cost money to produce, so they can just get out their wallets.
I was complaining to my GP about some hip pain that bothered me after doing our usual 3-mile walk or after a round of golf. He sent me to a specialist who did x-rays and confirmed I have some arthritis in the hip. He showed me the x-rays of both hips, and I couldn’t really tell the difference, but he’s the doctor, right?
He prescribed something (I don’t remember the name) that he said might affect my BP. Sure enough, it shot way up, so he prescribed another one. The first time I took one, I felt like I was floating up there above it all–it felt good! Then I looked up Tramadol and said no way, baby! Now I just take two extra strength Tylenol and grit it out.