The Myth of "Rescue" Medications

First off a clarification.  I am talking about the specific case where a short acting medication is added to a long acting form of the same medication and not "as needed" medication in order to determine the correct daily dosage.   In my line of work it occurs in two situations, long acting stimulants and their immediate release versions and long acting opioids and their immediate release versions.  I will illustrate that these practices are driven by myths about the medication rather than pharmacokinetics.  There is always the additional consideration about addiction lurking in the background, but the conscious and unconscious determinants of addiction frequently depend on the myths that I will be discussing about medication effects.

The example that I will use here is Concerta (long acting methylphenidate) compared with immediate release methylphenidate.  The graph from the package insert above shows the plasma concentration from a single 18 mg dose of Concerta and three successive 5 mg doses of immediate release methylphenidate.  As noted in the comparison of the curves and additional pharmacokinetic parameters the curve associated with three successive doses of immediate release methylphenidate is nearly identically replicated by a single dose of Concerta.

What is happening when additional doses of a immediate release methylphenidate are prescribed to a person who is already taking Concerta?  I  have seen this happen with sustained release stimulants and sustained release opioids.  I have seen it happen as a single dose of the immediate release preparation or multiple doses over the course of the day.  The patient is usually advised that this is a "rescue" medication that they should take if needed.  The first possibility is that the dose of sustained release medication has not been optimized and a higher dose of the sustained release medication needs to be given.  That is usually not the case.  The most frequent reason for taking the rescue medication is that the patient believes they are experiencing breakthrough symptoms and for a moment they need a higher dose of a medication.  There are serious problems with that concept.  As can be seen from the curves comparing Concerta and methylphenidate it does not make pharmacokinetic sense.  Any additional dose of immediate release methylphenidate on top of Concerta would greatly increase the expected plasma concentration at that point.

The main problem is that both ADHD and non-cancer pain are chronic conditions.  By definition they do not respond well to medications and they will not resolve typically with any amount of the medication.  Many people who take stimulants for ADHD assume that the human brain can be fine tuned with a medication.  There is also a widespread myth that they are cognitive performance enhancing drugs.  The real effects of stimulants are modest at best and there is no good research evidence to support a cognitive enhancing effect.  A similar bias exists for the use of opioids for chronic non-cancer pain.  The person believes that "If I take enough of this medication - my pain will be gone."  Study after study of opioids for chronic non-cancer pain shows that pain relief with opioids is modest at best, with results very similar to what would be expected with non-opioid medications like gabapentin and antidepressants.

There are secondary problems with believing a medication will produce perfect cognition or perfect pain relief.  The first is a tendency to see any medication with such powerful abilities as being able to solve a number of problems that are not the primary indication for the medication.  As an example, with a stimulant - if this medication has such a profound effect on my cognition maybe it can help with with other difficult problems like excessive appetite and weight problems or feeling like I don't have enough energy at certain times during the day.  With the opioid the  thought typically is that it can be used for mental pain as well as physical pain and it is used to treat anxiety, depression, and insomnia.  Whenever a medication is not used strictly for the prescribed indication there is a risk that it will be used for "what ails you."  The danger is dose escalation and addiction.  There is also the risk of attributing too much of an effect to the medication when it does not appear to be doing much.  A person may start to believe that they can't function without the medication but a detailed review of their target symptoms and ability to function shows that there has been a negligible effect.  And finally there is the danger of taking a medication that may produce euphoria, increased energy, and create a sense of well being and not realizing that at some point that is the only reason the medication is being taken.  I have had many people tell me that the medicine did nothing for their pain or cognition but that they kept getting refills because they "liked taking it."

There is what I call the Talisman effect, but probably to a lesser extent than with benzodiazepines.  Many people develop the idea that they are taking a medication that is much more effective than it really is and therefore they have to take it with them wherever they go.  They are conferring what are essentially magical properties to the medication and at some level thinking that they are unable to function in life without it.  They get anxious if they think about not having it or running out.  This not only causes a lot of unnecessary anxiety, but it also prevents the person from using other psychological or conditioning techniques that may work as well or much better than the medication.

These are some of the problems with the idea of taking a rescue medication if you are already on a long-acting form of the medicine.  Physicians in general do not do a good job of explaining these potential problems or even the basic problem of taking a medication that causes euphoria or reinforces its own use.  A more widespread recognition of these problems would go a long way toward curbing overprescription, overuse, and addiction to these medications.    

        

George Dawson, MD, DFAPA

References:

1.  Graph of plasma concentrations of Concerta and methylphenidate is from the package insert on FDA web site at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021121s014lbl.pdf

Johnny Cash On Doctors And Chronic Pain

Driving home on a Friday night, as usual I am listening to public radio.  This time I happened to catch an interview with the late Johnny Cash.  Many people are not familiar with how much pain he endured over the course of his life, especially toward the end.  His problems with drug addiction are better known and that combination of chronic pain and drug addiction is a dangerous one.   I found a photo of Cash on Flickr that was taken by a photographer who encountered him when he had significant pain and I am currently trying to get permission to post that photo at the top of this essay.  The years of pain and illness appear to have taken a toll in this portrait and he looks weary.  I heard him commenting in a radio interview on the PBS series Blank on Blank.  After and introduction that describes him as having severe constant pain in his left jaw and the statement that he cannot take pain medications, the interviewer Barney Hoskins suggests that he is brave and Cash replies (1):

Johnny Cash: "No. I’m not very brave because for five years I didn’t try to take the pain.  I fought it.  I had a total of 34 surgical procedures on my left jaw.  Every doctor I’ve been to knows what to do next, too.  To relieve me of pain, I don’t believe any of them.  I’m handling it.  It’s my pain.  I’m not being brave either.  I’m not brave at all after what I’ve been through, I just know how to handle it."

That is hard fought wisdom when it comes to dealing with chronic pain.  In the previous few lines Cash had explained why he could not take pain medications.  He described it being like an alcoholic not being able to drink alcohol.  His pain started when his jaw fractured during a dental procedure and never healed appropriately.  In Hilburn's biography (2), Merle Haggard is quoted as saying that Cash was at a chronic 8/10 level, using the typical 10 point pain scale for the last 8 years of his life.  It is difficult to imagine how hard it might be to try to sing with chronic jaw pain.

Managing chronic pain in a person with a significant addiction problem is one of the most challenging areas of medicine.   For the past 15 years, the USA has been in the midst of an epidemic of opioid painkiller use and accidental overdose deaths.  This has been largely due to the effects of the politicalization of pain and pain medications starting with initiatives to prescribe more opioid pain medications for chronic pain and for acute indications that previously may not have resulted in that kind of a prescription.  From what I can tell, the liberalization of opioid prescribing came about initially as the result of initiatives from the Joint Commission (JCAHO), the Veteran's Administration, and the American Pain Society.  The initiatives can be viewed on this timeline. 

The treatment of chronic pain is also viewed as a treatment that involves multiple modalities.  It can certainly involve the use of various forms of pain medication, but physical therapy and psychological therapies are also mainstays of treatment.  I have consulted in many situations where patients have had multiple surgical interventions for pain that have not been effective.  I have never seen a person with 34 surgical procedures for the same pain.   From a purely medical perspective, the treatment can involve opioid medications, but also gabapentin, pregabalin, and various antidepressants.  Chronic pain is frequently associated with insomnia, anxiety, and depression and additional medical or psychological interventions for these problems is useful.  Many people have strong biases about opioid medications and consider them to be the ultimate treatment for pain.  Double blind, placebo controlled studies show that for neuropathic pain, the relief is moderate and generally equivalent to non-opioids.  Unfortunately for many, that fact is not known until after the person has become addicted to the opioid.

The surgical approach to pain is gradually changing over time.  I did a lot of neurosurgery during medical school rotations and in those days, there was a definite prosurgical approach to back and neck pain.  Imaging studies were more primitive with a predominance of CT versus MRI imaging of the spine.  I observed a lot of laminectomies and posterolateral fusions, using bone graft from a rib or iliac crest.  I was also in the clinic and saw large numbers of patients coming back over time for chronic opioid prescriptions for continued pain that failed to clear up with the operative procedure.  Our standard prescription in those days was Darvocet N-100s,  a fairly low potency opioid analgesic that also contained acetaminophen.  It was voluntarily withdrawn from the market by the manufacturer in 2010 after this labeling revision by the FDA in 2009 highlighting the risk of overdose, cardiac conduction abnormalities and fatal arrhythmias.  In the course of psychiatric practice, I pay close attention to spinal problems.  Spinal injuries are surprisingly common.  Degenerative disease of the spine is also common and there is very little focus on spinal health and the prevention of these problems.  In the people I have seen over the years, good prognosis spinal surgery in terms of pain relief generally involves a well defined lesion and neurological deficit in addition to the acute pain.  Chronic unchanged pain is still an outcome after repeated surgery.  At that point the question becomes, is there any medication that will reduce the level of pain.   Some people will do well with chronic opioids, but the problem is that patients with addiction generally do worse and exposing more and more people to opioids is increasing the number of people with addictions.  SAMHSA suggests the algorithmic approach in Exhibit 3-1 (3) above.  The problem is that there is no good data for relapse, failure, or success rates after trying an opioid for chronic pain in a person with an addiction.  My experience suggests that relapse rates are very high and success rates are very low, but I am seeing a population with a very high rate of addictions
         

In the absence of any markers of opioid addiction liability or reliable interview approaches a conservative approach is required and an extremely cautious approach is required if the patient has a known addiction problem.  The comment on doctors by Johnny Cash is one that is best not forgotten.  One of the reasons that opioids are prescribed in the first place is that pain is chronic and refractory to usual treatments.  In some cases, years of trying multiple opioids and going through residential drug treatment centers has resulted in the perpetuation of chronic addiction and chronic pain.  The algorithm above suggests the appropriate course of action for patients with that problem.  They need to be tapered off the pain medication and typically maintain the medication is necessary.  In many cases there is a significant amount of pain relief and improved function by tapering and discontinuing the opioids.  In some cases, the ability to function improves because the addiction fades away even though the pain is no better.

Johnny Cash got to the point where he could be tapered off the opioids and make it on his own.   That is a tough goal, but one that more people should strive for at least until there is a better solution to chronic pain and addiction.  He also reminds us of the role of physicians in this process.  My overall impression is that there are more physicians willing to draw the line and say: "I really don't think that another operation or medication is going to add much to what you have already tried." ..... but I don't think there is a lot of evidence to back up my opinion.      

George Dawson, MD, DFAPA

References:

1:  Barney Hoskins.  Johnny Cash on the Gospel.  Blank On Blank.  October 1996. 

2:  Robert Hilburn.  Johnny Cash - The Life.  Little, Brown, and Company.  New York. 2013. 

3:  Substance Abuse and Mental Health Services Administration.  Managing Chronic Pain in Adults With or in Recovery From Substance Use Disorders.  Treatment Improvement Protocol (TIP) Series 54.  HHS Publication No. (SMA) 12-4671.  Rockville, MD: Substance Abuse and Mental Health Services Administration, 2011. (Figure 3-1 above is from page 34 of this manual).

Abuse Deterrent Opioids - Are They The Solution?

I have a significant interest in opioids, specifically opioid use disorders or addiction to opioids.  We have seen an opioid epidemic in this country largely due to a naïve approach to chronic pain and exposing people unnecessarily to the risk of addiction.  At one level this is a failure of regulators who adopted the idea that chronic noncancer pain is best treated on a mass basis with opioids.  At another level it is a failure of American culture.  Americans are focused on abusable medications and they always have been.  This is not a recent phenomenon.  The reason that addictive drugs are regulated in the first place is that they were widely abused when they could be purchased over the counter from any pharmacy.  Advocates of legalizing drugs almost universally ignore that fact.  It is common to find people hoarding opioid prescriptions, giving them to their neighbors, and taking them for indications other than pain like insomnia, depression, or anxiety.  At the cultural level, opioids are generally regarded as magical pills that will cure whatever ails you.  But there is no such pill.

Physicians are not blameless in this process.  Around the turn of the 19th century, some physicians were maintaining large numbers of people in addiction as part of their medical practice.  At the turn of the 20th century, some physicians advocated “pain as the fifth vital sign” and the widespread practice of recording a patient’s pain rating in routine clinic visits with their vital signs.  In some cases this rating was mischaracterized as an “objective” measure like the other vital signs.  Any physician who is told that the pain rating is a “14” on a scale of 1-10, knows that little objectivity is involved.  The opioid epidemic is often viewed as a problem in physician education or a cognitive deficiency. I doubt that is the problem.  Every physician knows the basics about prescribing opioids by the time they leave medical school.  I can recall working in a clinic of chronic pain patients while I was a medical student in the 1980s.   In that clinic we prescribed hundreds of opioid prescriptions per month.  I also recall that none of those patients was ever asked about addiction or why they still wanted to take the medications even though their pain never seemed to improve.

This problem has also led to significant insights into the real function of the US Food and Drug Administration (FDA).  The FDA web site has three paragraphs on “What we do.”  The first paragraph highlights what I always thought was the main function of the agency:

“FDA is responsible for protecting the public health by assuring the safety, efficacy and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation.”

That seems like a straightforward definition.  In practice it is more complicated.  The best example I can think of to illustrate that is the FDA approval of the sustained release, high-dose hydrocodone product Norco.  The FDA’s own scientific committee overwhelmingly recommended against approving this product in the midst of an opioid epidemic.  They were overruled and the product was approved based solely on the manufacturer meeting regulatory requirements.  Despite concern about getting medications to market fast enough it seems like there are few obstacle to opioid preparations that are basically old medications repacked in a new form.

The financial considerations in this field are significant.  Several years ago speculation was that any successful abuse-deterrent opioid formulation would be a billion dollar a year drug for that manufacturer.  That is highlighted by the number of recent approvals for these drugs noted in the table below.

The current market for abuse-deterrent opioids is estimated to be about $7 billion.  The global pain market is estimated to be worth about $50 billion growing at a rate of 10% annually.  From the table above it is apparent that this is basically a patent extension market.  All of the main ingredients in these medications are generic opioids that are very inexpensive on their own.  By putting them in a special formulation or combining them with opioid antagonists (naltrexone or naloxone) the manufacturers claim they are producing a medication that is less likely to be abused. Whether or not that ultimately happens is anybody’s guess.  I tried to pull up one of the more notable prodrug use web sites and have not seen those compounds and so far no suggestion on how to defeat the abuse deterrence.  There are historical precedents.   Abusable drugs generally follow a predictable course of oral use to smoking or insufflation (snorting) to intravenous use.  Breaking up that chain of events is one strategy that may lead to less severe drug use, but the fact remains that the original oral formulation is still a potent medication that can lead to addiction.  The original case in point was the reformulation of Oxycontin in 2013.  The original capsule could be breached and the contents snorted, smoked, or injected.  The reformulation put the oxycodone in a hydrogel making it less available for snorting, smoking or injecting.  The detailed package insert still says that this formulation and the original formulation place the user at risk for addiction.

What can be learned about the proliferation of abuse deterrent formulations?  There is a strong incentive both in terms of market size and low production costs.  All of the medications in the table are very inexpensive generics that are reformulated with an inexpensive antagonist or a different pill matrix.  The main safeguard is the FDA in terms of the total number of these medications on the market.  The FDA has the potential to decrease the incidence of opioid use disorders.  There is no evidence that is their strategy because they are approving medications over the objections of their own Scientific Committee.  In some cases they discuss post marketing surveillance as being a measure of whether the abuse deterrent medication is working.  Neither of those strategies would seem to be very likely to me.  It is well known that reports of signifiant medication related events are probably very low relative to the actual incidence of these events.  I have previously advocated for a pharmacosurveillance/data-mining solution that would produce results before the expected complications of opioid dependence and unintentional overdoses.  The FDA’s current approach seems to be that further education of physicians will solve the problem.  This is not a problem of physician education.

As the formulations of opioids continue to propagate, there needs to be an awareness that the FDA is not attempting to contain the number of new opioid products released and that a preventive approach is necessary and is more likely to save lives than waiting for people to report complications or waiting for the Drug Enforcement Agency to make arrests.  It is also time to consider what can be done at the level of American culture and focusing on some basic misperceptions that result in the overvaluation of opioids.  The idea that opioids can alleviate chronic pain, that they are the best treatment for chronic pain and that everyone can take them safely are primary among them.

There also needs to be a better understanding of opioid use disorders.  Recent stories in the popular press make it seem like addictions are easy problems to get over.  Just make a decision to stop and most people are able to.  Tell the old story about returning Vietnam vets and how easy it was for most of them to stop using heroin.  These are not the people who are seen in acute care settings or who are treated for drug overdoses.  Many of those people will say that they knew they were using a lot of the drug, that they were not thinking about suicide but they did not care if they lived or died because: "All I wanted to do was get high."

That is a powerful incentive for defeating abuse deterrent pills.



George Dawson, MD, DFAPA   


Supplementary 1: What is an New Drug Application (NDA)? This is the formal application to the FDA where the sponsor (usually a pharmaceutical company) proposes that a new drug be approved for sale and marketing in the United States. For detailed information from the FDA web site follow this link.   

  

Lessons From Physical Therapy

I remember the first time I experienced any significant knee pain.  My wife and I had just purchased an old house and as part of the sweat equity that young homeowners do we were going to refinish all of the hardwood floors ourselves.  If you have ever tried that, the most imposing part of the task is sanding all of the floors.  Hardwood floor sanders are very heavy pieces of equipment with cast iron bodies.  My first task was to carry this machine that I guess easily weighed over a hundred pounds up to a high second floor in our old house.  That was about 25 steps and a landing.  By the time I got to the top, it felt like both knees had bottomed out and were starting to creak.  At the time I was a competitive cyclist and training by putting in 200-250 miles on the roads and hills of Duluth, Minnesota.  I had never encountered this type of pain before during cycling, speedskating or weight lifting.   I compensated the best I could by taking the sander down just one step at a time and bringing it up and down again after we ruined the first staining attempt.  Eventually the pain went away, but I had learned several valuable lessons.  Cycling for example, did not cause any knee pain even after this acute injury.  I developed a strong preference for cycling and skating and decided to forget about running.

A couple of years went by and I developed some pain in my lateral knee.  I had already been diagnosed with gout in medical school and compared to gout pain most other musculoskeletal pain is minor.   My experience with physicians diagnosing gout was very mixed and I did not want to get a recommendation for medication if something else would work better.  Instead of seeing a primary care physician, I went in to see a physiatrist who happened to be a sports medicine doc.  He jerked my knee around and was satisfied it was stable and showed me some basic iliotibial band stretching exercises.   Within a week the pain was was gone.

My most foolhardy adventure in knee injuries was trying to extend my usual 40-50 miles training rides to 100 miles with no buildup.  I was out riding the roads in Washington County and remembered a theoretical 100 mile loop that I always wanted to ride.  It was a hot summer day, I felt very fast, and I had plenty of daylight so I took off.  At the 3/4 mark I was coming up a long steep grade and felt some left knee soreness that persisted the rest of the way.  My knee was burning when I stopped and I ignored it and did not ice it that night.  By morning I had developed a significant effusion and could not bend it.   I saw an orthopedic surgeon the next day who jerked my knee around, told me it was an overuse injury, and put my leg in a knee immobilizer.  Within two weeks I was out cycling again.

At other times I have allowed my body to get seriously out of whack.  After years of cycling I started to realize that I ended each session with severe neck and shoulder pain.  After numerous adjustments to the stem length on my bike, a physical therapist figured out I was was extending my neck too far to look up from my riding position and fixed the problem by modifications to my riding position and neck exercises.  At one point, I was almost exclusively cycling and got to the point it was painful to walk around the block.   The solution was again exercise modification and exercises to improve hip flexibility.  

All of this experience has led me to be very conscious of knees and other joints and keeping them in good working order as I age.  Not just my joints but the joints of my wife, family and friends.   It is kind of amazing to hear the emphasis on physical activity at all ages and yet there is no information out there on joint preservation or how to preserve your back.  Many people are surprised to learn that the circulation to intervertebral disks in the spinal column is gone at some point in the late 20s.  That makes biomechanics and muscle conditioning some of the most important aspects of joint and back function as you age.  It also makes physical therapy and exercise some of the most important tools to maintain musculoskeletal function with aging.   When I develop some kind of musculoskeletal pain, the first thing I do is call my physical therapist and schedule an appointment to see her.   She does an examination and an analysis of the biomechanics of the problem and tells me how to solve it.  I have been through the process many times with a physician and the main difference is that there is no biomechanical assessment, no actual manipulation at the time that may be useful, and no specific exercise program to make it go away and stay away.

The results of a medical evaluation are as predictable.  You have a diagnosis of muscle or joint strain.  Use ice or heat whichever one makes you feel better.  I have been told by rheumatologists that there is really no scientific basis for the heat versus ice recommendation only the subjective response.  And of course the recommendation for NSAIDs (non-steroidal anti-inflammatory drugs like ibuprofen) or acetaminophen.  I ignore the NSAID recommendations and take as few tablets of naproxen every year as I can.  I consider NSAIDs to be highly toxic drugs and avoid them even though they are effective.  I had a rheumatologist at a famous clinic tell me that the best evidence that NSAIDs were effective was the negligible amount of joint cartilage that was left when patients came in for joint replacement therapy.   Strong evidence that NSAIDs could knock out the pain as the joint deteriorated.   The only time that I was ever offered an opioid was when I had my first gout attack.  I was seen in an emergency department for severe ankle pain and discharged with a bottle of acetaminophen with codeine - a medication that is totally useless for gout pain.

In clinical practice I see a lot of people with chronic pain.   I notice that many of them are taking NSAIDs on a chronic basis and experiencing complications of that therapy like renal insufficiency.   I notice that practically nobody sees a physical therapist.  I notice that many people are now started on oxycodone or hydrocodone for mild sprains and injuries involving much less tissue injury than many of the injuries I have sustained during sports.   There are also many people who do not receive adequate advice on modifying their activities once an injury or series of injuries has been sustained.   For example, should a person keep running if they have sore knees, are 30% overweight, and have radiographic and physical exam evidence of degenerative joint disease?  Many people seem to have the idea that they can just wear out joints and have them replaced and the replacements will be as good as new.   Some will decide that it is just time to hang it up and start to sit on the couch and watch television.  They are surprised that their pain worsens with months of inactivity.   Some of the patients with back pain decide: "This pain is so bad that physical therapy is not going to do anything.  I am going to get surgery as soon as I can."  The widespread ignorance and neglect of musculoskeletal health is mind boggling to me.

I got into an exchange with an orthopedic surgeon in our doctor's lounge one day - over lunch.  He wanted to talk about narcissistic personality disorder and I wanted to talk about the biomechanics of the knee and hip joints.  It was a lively exchange and in the end he agreed with me about the huge importance of biomechanics during physical activity and as a way to prevent injury and degenerative disease.  It turned out he just wanted to hear about the personality disorder and did not have an opinion on it one way or the other.

I teach a lot about central nervous system plasticity in a neurobiology course that I give several times a year to different audiences.  Widely defined, plasticity is experience dependent changes in the nervous system.  There are a number of mechanisms that can lead to these changes.  Kandel and others have pointed out that these are the mechanisms of animal learning.  Two examples jump out of those lectures.  The first is a physical therapy example of knee extension exercises in the treatment of knee injuries.  It has been known for some time that quadriceps strength and balance through the knee are critical factors in knee rehabilitation and the prevention of future injuries.  Research in this area shows that increased quadriceps strength can occur in the same session.  The other example I use is a guy who wants to go to the gym to increase the size of his biceps.  He starts doing curls and within 6 weeks his strength has increased by 25% but there is no muscle hypertrophy.  His biceps diameter is unchanged.  What do these two examples have in common?

The common thread here is CNS plasticity and everything it allows us to do.  Plasticity will allow your to keep your joints healthy and relatively pain free if you allow it to.  You have to be willing to accept the idea that pain can come from deconditioning and biomechanical problems that are reversible by plastic mechanisms.  The only additional information needed is if it is safe to exercise and that can be provided by a physician and a physical therapist.

And the lesson for psychiatry?  Chronic pain patients certainly need to hear this information especially if they are deconditioned.   People addicted to opioid pain medications who are not getting any relief need to hear this information.  Patients in general with exercise modifiable conditions who see psychiatrists need to hear this message.  There is also a lesson for psychotherapy no matter how it is delivered.  Kandel's original example of plasticity was a psychotherapy session.  If your brain is modified by exercise there is no reason to think it can't be modified by anything from straightforward advice to more complicated therapies.   Success in that area can lead to the limited or no use of medications and a conscious focus on what is needed to maintain health like I discuss from my own experience.  I certainly don't take any medication for pain that physical therapy or exercise adequately treats.  The same argument can be applied to anxiety and depression that can be adequately addressed by psychotherapy or other psychological interventions.  On the other hand if most people don't know that physical therapy, exercise and activity modification successfully treats musculoskeletal pain and other problems they are unlikely to try.    


George Dawson, MD, DFAPA

Supplementary 1:  There are currently only 4 Medline references on biomechanics plasticity sports.  This seems like a promising area for sports medicine, physical therapy, and rehab medicine.

Supplementary 2:   The photo at the top of the page is an exercise I do to alleviate knee pain that I learned from the book The Knee Crisis Handbook by Brian Halpern, MD with Laura Tucker.  The exercise is called the quad set (p. 238) and although the author suggests a towel under the knee, I am doing it on a styrofoam roller.  This book contains a wealth of information on knee health.  I do not recommend doing what you see in the picture without reading the book.  I have no conflict of interests related to this book and purchased it online entirely for my education.

Supplementary 3:  I could not figure out where to fit it in above but after 25 years riding with 175 mm crankarms on my bike, I dropped them back to 172.5 mm.  The bike fit expert for my new bike was convinced it was a good thing to do.  My new bike rides so much differently it is difficult to know what to attribute to crankarm length.  

Some Arguments on Drug Tolerance and Prohibition

I have extensive experience treating people with alcohol and drug use problems.  I am always amazed at the lack of knowledge about addiction and alcoholism in the general public and how that impacts public policy.  As a result I occasionally get involved in public forums to argue a few points.  As a matter of disclosure I am thoroughly independent and vowed not to vote for any major party candidates a long time ago.  That doesn't prevent people from sending me heated e-mails accusing me of either being a Democrat or a Republican.  Of course you can also be attacked for being a independent and being too much of an elitist to not accept the fact that only major party candidates can be elected.  I have never found that to be a compelling argument.  My latest post to the quoted excerpt follows.  You can read the entire sequence of posts by clicking the link at the bottom.  There are obvious limitations to engaging in this exercise and that should be evident by reading the exchange right up to the last post where I get the expected shot for being a psychiatrist.  Tiresome isn't it?

“Come again...Politicians are pushing for legalization?  Politicians have been spewing the “war on drugs” “tough on crime” protecting the “fabric of society” bullshit for the last 40-plus years.”

Sorry – I try just to stay to the facts.  If you read the actual history of drug use in this country we swing from periods of prohibition to drug tolerance.  We are currently swinging into a period of drug tolerance and I fully expect to see drugs legalized in some way or another in most states.  So I really don’t have a stake in this fight either way.  So you can lighten up.  I am not “on your side” but I can predict with certainty that it will happen.  You can Google “politicians who support drug legalization” as well as I can.  As more of them get on board you will hear an escalation in rhetoric on how they will tax and control it.

You can put any type of spin on it you want – more freedom, freedom from the war on drugs, ability to generate more taxes, ability to treat any problem you might have with medical marijuana, you name it – history shows the outcome will be the same.  If you are still serious about legalizing heroin and coca like you previously stated that experiment has already been done and the outcome will be the same.  That experiment is being done right now with diverted legal opioids (the source of synthetic heroin) and according to the CDC we are in about year ten of an opioid epidemic that is killing more people in many states than motor vehicle accidents – about 15,000 people a year.  If you consider that the drugs typically called synthetic heroin on the street are usually pharmaceuticals with known safe doses, that also illustrates the nature of the problem.  If you think that nobody will be looking for synthetic marijuana if marijuana is legalized – I know that is false per my previous post.  No matter how free you are to smoke marijuana, there are very few employers I know of that will tolerate it at work and none if you are in a job where your decision making can lead to substantial liability. 

The problem with the “war on drugs” and excessive incarceration of people with drug charges in many ways parallels the excessive incarceration of the mentally ill because we have a health care system that is politically managed.  The politicians realized a long time ago that you can save health care costs by incarcerating the mentally ill instead of treating them in medical settings.  It may not have been a conscious decision up front but they have done little to stop it after it was clearly underway.  The three largest mental hospitals in the US right now are county jails.  Addicts in many cases are treated even more poorly if they are incarcerated because they do not get medically supervised detoxification and go through acute withdrawal.

In any “war” somebody has to be blamed and denied resources.  I prefer Musto’s analysis of the US tending to blame other countries for our drug problems:  “That analysis avoids the painful and awkward realization that the use of dangerous drugs may be an integral part of American society.”  That is reminiscent of Mexico’s Past President Vincente Fox pointing out that Mexico’s problem with cartel violence is fueled by America’s massive appetite for drugs supplying the money.  On that basis he was a proponent of the legalization and control of marijuana argument.  That doesn’t address the massive appetite for drugs problem.

The problem with the politics of addictive drugs is that people generally don’t know much about addiction.  There is a significant portion of the population that is vulnerable and the only thing it takes in increased availability for them to start having significant problems.

So good luck with the new temporary American dream of increased access to intoxicants and enjoy it while you can.  Depending on exactly what gets legalized – I would predict that would be the next 20 – 40 years.  That is the usual time it takes to complete a cycle.

Minnesota Politics and Issues Forum

George Dawson, MD, DFAPA

David F. Musto.  The American Disease: Origins of Narcotic Control.  Third Edition.  New York, Oxford University Press, 1999: p 298.  

Additional Clinical Note 1: A couple of graphs from my other blog that show alcohol use patterns over time are available on my other blog for the United States and the United Kingdom.  Graphs of opioid consumption over the past decade by the UN drug control agency shows a linear increase in consumption and production.

Additional Clinical Note 2:  If you had the patience to follow the political thread you probably notice the marijuana advocate trying to tell me that I was saying there was an epidemic of synthetic marijuana abuse that occurred with the legalization of marijuana.  My argument was simply that marijuana users if they are screened for THC at work will switch to synthetic marijuana in order to avoid positive toxicology screens and job loss.  Now in the February 5, 2014 edition of JAMA a report from the CDC it turns out that there was an "outbreak" of synthetic marijuana use in Colorado in August and September that involved about 200 people.  There was a similar outbreak in Georgia in August of 2013.  In addition  to the medical characteristics I would encourage the CDC to collect data on how many people were smoking marijuana to avoid toxicology testing and how many people were unable to stop smoking marijuana in order to achieve that same goal. I sent the CDC a note on how to refine their methodology. 

Supplementary Material Note 1:  My response from the CDC.

The Great Unconscious - Why REMS Are Bound To Fail

REMS is an acronym for Risk Evaluation and Mitigation Strategy.  It is an FDA initiative to deal with the risks associated with certain medications.  I first encountered this new concept because one of my lectures is on the current opioid epidemic and looking at the potential risks of opioids.  The FDA has an REMS section on their web site including a list of all currently approved REMS.  For the purpose of this post I am going to focus on the REMS for Extended Release and Long Acting Opioids.  The actual document is 42 pages long.  I read it twice and really cannot see anything in the document that would detect the major problems with opioids or potentially prevent those problems.  It suggests a thorough evaluation of the type than many primary care physicians no longer have the time to do.  The basic elements of a complete history and physical exam, pain diagnosis and examination for addiction and psychiatric comorbidity needs to be taken in the context that substantial numbers of patients with psychiatric diagnoses are now diagnosed by a symptom checklist that is checked off in about 2 minutes.  If there is any take home message from this REMs it should be that chronic pain requiring opioid therapy should be referred to a specialty center where they have the time and staff to do the required assessment.

The biggest misconception here seems to be that patients are accurate reporters and they have no unconscious agenda.  It leads me to question whether the FDA employs any psychiatrists.  It also highlights a naive approach to medicine that suggests physicians and patients are automatons who are basically reading and completing checklists.  The complete checklist suggests the diagnosis.  On what planet does this happen?  With regard to the population of patients with an addiction seeking treatment of chronic pain with opioids, the following graphic may apply.

The data represented in the above diagram are from the National Survey on Drug Use and Health.  The sample size is 70,000 persons, but the conclusions in the diagram are all drawn from the survey and have the usual limitations.  What the diagram shows is that most people who believe they need treatment for an addiction do not make an effort to get it.  The NSDUH looks at detailed information across a number of treatment settings and reasons for not accessing treatment.

I use the above diagram when I am taking with primary care physicians or residents about the situation where they are trying to determine whether or not it is safe to prescribed opioids for chronic pain.  I point out that the people they are seeing in their office probably resemble the sample participants from the NSDUH.  How would those evaluations of themselves affect their response to questions about addiction during their assessment?  By the  time people see me and they have an entirely different frame of reference.  They may have had one (or several) near death experiences from overdosing on opioids.  They may have become homeless and lost the support of their friends and family.  They may have encountered a number of situations making the drug use problem very difficult to deny.  The people receiving the REMS evaluation from their physicians will almost always be similar to the NSDUH sample.  The implication is that these folks won't be "honest" with their physician, but the problem is much more than an honesty problem.  Anyone with an addiction has lost their capacity to fully recognize the nature and severity of the problem.  Their responses are based on a number of biased decision-making processes that continue the addiction.  The primary care physician is in the impossible position of needing to be a lie detector with a person who may not feel like they are lying.  It is another operation of the great unconscious but in this case one that is unrecognizably biased by addiction.

The response to opioids is the first clue that there may be a problem.  People disposed to addiction have a striking response to opioids.  The described an intense euphorigenic effect.  In contrast to the usual ideas that opioids are sedating many will feel much more energetic and productive.  A distinct feeling that a hoped for potential has finally been realized with the expected boost in confidence is often a third feature that is extremely reinforcing.  These are generally the opioid response features that place a person at high risk for opioid addiction.  

The unconscious aspects of drug addiction are described in a number of ways.  Sellman describes it as compulsive drug seeking being initiated outside of consciousness.  Koob talks about the process going from an initial process of an impulse control disorder involving positive reinforcement to compulsive activity that is driven by the negative reinforcement of avoiding withdrawal phenomena.  Most people are not conscious of that process unless it it reviewed with them in detail.  Another unconscious aspect of addiction is cravings.  Cravings can vary from a spontaneous intense urge to use a drug to an urge associated with sensory phenomena that occurs after exposure to a drug cue like seeing people use the  drug on television.  Whether the craving is cue-induced or spontaneous they represent a drug induced change in a person's conscious state that can be present long after there has been exposure to a drug.

A risk management strategy to identify problems with opioid prescriptions needs to incorporate a strategy that takes these features into account.  Information about limiting access to prescription opioids and destroying unused opioids is certainly a useful public health strategy but it does nothing for a person who has a strongly reinforcing reaction to the drug.  At the minimum there needs to be education that the response to the drug is a key feature to identify addiction risk.  Patients need to be educated about that as well as addictive behaviors and those anchor points need to be revisited at every physician visit where response to pain, addictive behavior, psychiatric comorbidity and functional capacity needs to be assessed.  These are also the areas where the bulk of physician education needs to occur.  There is also the issue of whether teaching primary care physicians is the best strategy to limit opioid overprescription.  It may ultimately be the best strategy because the lessons learned could be applied to the overprescription of many drugs with similar dynamics like antibiotics, benzodiazepines, and stimulants.  There is also the model of specialty referral to reduce the burden on primary care clinic.  This model was popular in many states prior to the more widespread practice of prescribing opioids for chronic noncancer pain and it is the basis of the guideline for treating chronic neuropathic pain by the National Institute for Health and Care Excellence (NICE).

George Dawson, MD, DFAPA          

The FDA and Opiate Regulation

Does the FDA have a clue about the safe prescribing of opioids?  Based on their September 10 press release we are about to find out.  If you go to the FDA web page this appears to be the most relevant document.  It contains the following warnings:

BOXED WARNING

In the boxed warning in Highlights, include the following text:

• Tradename exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1)

• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow Tradename (formulation) whole to avoid exposure to a potentially fatal dose of (active opioid). (5.2)

• Accidental consumption of Tradename, especially in children, can result in fatal overdose of (active opioid). (5.2)

• For patients who require opioid therapy while pregnant, be aware that infants may require treatment for neonatal opioid withdrawal syndrome. Prolonged use during pregnancy can result in life-threatening neonatal opioid withdrawal syndrome. (5.3)

For products with an interaction with alcohol, also include the following:

• Instruct patients not to consume alcohol or any products containing alcohol while taking Tradename because co-ingestion can result in fatal plasma (active opioid) levels.  (5.4)

As I read through these warnings I have several associations.  First off, physicians were told 12 years ago in JAMA that they were undertreating pain, misunderstood pain, and that pain treatment needed to change.  That was a naive document that depended on an assumption that pain could be "quantitated" on a 10 point scale.   Over a decade and 100,000 opioid overdose deaths later we are not told that providing this information on drug labels will make a difference.  That leads me to my second association, there is nothing in the above warning that I didn't learn in medical school 30 years ago, including the risk of neonatal withdrawal.  The third association is that this definition and intervention is almost completely naive about addiction.  A person with an addiction does not care about dire warnings.  They don't care about their pain ratings.  They care about acquiring and using addictive drugs.  It is the nature of addiction.  Their entire conscious state has changed. The tendency toward opiate addiction or not is probably biologically determined and a doctor cannot predict who is at risk.  If you take an initial dose of opiate and experience intense euphoria, high energy and productivity, and intense sense of well being or feel like you finally have become the person you always wanted to be - you may be a person at high risk for opiate addiction. It doesn't really matter if they have a chronic pain disorder.

What needs to be done?  What should the FDA being doing immediately.  The four most important misconceptions driving both the epidemic of opioid dependence and the accidental overdose trend are:

1.  Opioids are a silver bullet and will eliminate chronic pain if the dose is high enough.

2.  Once a maintenance dose is achieved the level of pain relief should be constant.

3.  Opioids are only taken for primary gain - the analgesic effect or the elimination of pain.

4.  Opiates - prescribed by a doctor will not lead to reactivation of a previous addiction.

What do people need to know now?  Probably not the new package insert for opioids.  Most physicians don't read it.  Every person taking an opioid need to know that it can affect their subjective state in such a way that it will place them at risk for addiction.  They need to know at that time that they need to contact their physician and discuss it and the possibility of alternate or more closely monitored treatment.  They need to know that there is no medicine that will treat chronic pain into remission.  Physicians need to know a number of things including the fact that there is no medication that will eliminate chronic pain.  They also need to know that it takes time and detailed evaluations (calls to pharmacy, tox screens, limited prescriptions, assessment of functional capacity) to optimize treatment and prevent addiction.

The warning on a package insert from the FDA containing seriously dated information will not do it.  Dire warnings about an epidemic won't do it.

George Dawson, MD, DFAPA

Treatment of chronic pain with opioids - back to the future

I thought I would wade in on this issue largely because I am not hearing a lot of rational discussion about the problem.  You might ask: "What does a psychiatrist know about this issue?" and the answer like most questions about psychiatry is "plenty".  I worked on a busy inpatient unit for 22 years and saw plenty of people with with severe chronic pain and episodic pain crises.  In that same facility, I also covered consults on medical and surgical patients many having problems with chronic pain and addiction.  As an addiction psychiatrist, I have talked with countless people who ran into problems with pain medications or relapsed to using another drug after being exposed to opiates for treatment of acute or chronic pain.  There seems to be very little reality based information out there to inform people about the risks and benefits of pain treatment with opiate medication.  The argument like most in our society is politically polarized to those who believe it is unconscionable to not treat pain even if it means a long course of opioids to those who believe that opioids are dangerous medications that should be conservatively prescribed.  So where does the truth lie?

I can tell you how it was in Minnesota in the 1990's.  There were very few pain specialists.  The wide spread prescription of opiate medications for chronic noncancer pain by generalists was uncommon.  In many cases if it seemed indicated, the generalist would refer their patient to a pain specialist who would provide them with a letter of agreement on the use of chronic opioids.  That all changed with a Joint Commission initiative on pain in 2000.  At least some authors see it that way and that was my experience.  Since then opioid prescriptions have been taking off with an associated increase in the production of these compounds.  This graphic from the CDC is instructive (click to enlarge).  The rates of increase of sales, deaths, and treatment admissions are all increasing at an astronomical rate relative to population growth.

The issue that is debated in the media and some government web sites is why is this happening and what is the best way to deal with it.  The FDA has recently incentivized drug manufacturers to come up with better tamper proof opioids.  The enforcement arm of the government is rigorously prosecuting some doctors.  The FDA has also initiated a course for doctors who prescribe opioids.  None of these measures addresses the core problems that were successfully addressed in Minnesota in the 1990s.  I will take a look at the specific issues involved:

1.  The genetics of opioid preference:   People at risk for abuse and addiction to opioids have intensely positive subjective experiences from taking opioids.  People not at risk have intensely negative experiences or the opioids make them physically ill.  We currently know nothing about the genetics of this response, but it makes sense to let patients know that if they do have an intensely positive response in terms of feeling euphoric or energetic that is not a good sign in terms of addiction potential.  It might even be reasonable to come up with a plan about what to do if that happens.  Seeing people back in a month who have no knowledge of this risk is probably not the best plan.  It is critical that there is a good therapeutic alliance between the patient and physician and that they are both focused on the full spectrum of problems.  

2.  The genetics of opioid response:  Individuals studies and reviews of studies generally show that a subset of patients respond to opioids.  There may be additional factors that should factor into patient selection such as the specific type of neuropathic pain.  The current concern and reaction to the opioid epidemic is based on the concept that opioid prescribing is a potentially high risk intervention.  If that is the case we need a better options for patient selection than a subjective report of pain.

3.  The public perception that opioids are the silver bullet of pain relief must be dispelled: This is the driving force behind escalating doses of opioids and the addition of benzodiazepines (an equally bad idea).  Excellent double blind placebo controlled studies of self titrated opioids in chronic neuropathic pain have showed moderate pain relief that is on par with non-opioid medication.

4.  Tolerance to analgesia and opioid induced hyperalgesia:  Education about these phenomena is needed because both lead to escalating doses of opioids.  The dose escalation may be appropriate, but in many cases the dose is increased with the goal of eradicating pain and that is an unrealistic goal.  In people who have analgesic induced hyperalgesia, they are often shocked that their pain improves with discontinuation of the opioids.

5.  Assessment of functional capacity is critical:  Functional capacity is the ability to function in daily life.  It must be carefully assessed in anyone who is on chronic opioid therapy.  At moderate doses and in combination with other pain medications opioids can impair coordination, cause excessive sedation, and lead to significant impairment in daily functioning.  This is a sign that the dose of the opioid may be too high and reducing the dose is indicated.

6.  A hierarchical approach to pain treatment is still necessary and is the most rational approach to reducing the current epidemic of excessive opioid prescriptions:  If the degree of pain relief across a population is the same, why not use the drug with the lowest abuse and overdose potential?  That was the default model in the 1990s in Minnesota.  The National Health Service in the United Kingdom has operationalized that as their current pathway for treating neuropathic pain in the algorithm below (click to enlarge).  Note that the medications with no abuse potential are at the entry levels in this diagram and that pain specialists are the gatekeepers for opioids.

  
Like most political debates the current debate about how to stop the epidemic of opioid overdoses ignores that fact that the problem may have originated with a political initiative in the first place.  Using the NICE algorithm to get us back to the Minnesota practice model of the 1990s is a logical solution.

George Dawson, MD, DFAPA


Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain. N Engl J Med. 2003 Mar 27;348(13):1223-32. PubMed PMID: 12660386.

National Institute for Health and Clinical Excellence. Neuropathic pain: the pharmacological management of neuropathic pain in adults in non-specialist settings. NHS. March 2010.

Supplementary 1:

The Care Pathway Graphic is copyrighted © National Institute for Health and Care Excellence (2010) and is posted based on their allowance for reproduction for educational and not-for-profit purposes.  See their updated and revised guideline at: http://www.nice.org.uk/nicemedia/live/14301/65782/65782.pdf

PROP Petitions the FDA on Opiates

Physicians for Responsible Opioid Prescribing (PROP) has petitioned the FDA to modify the warnings about opioids.  They cite the well known dimensions of the current epidemic including a four fold increase in opioid prescribing and a four fold increase in opioid related overdose deaths.  They also cite  numerous references about the real risks of prescribing opioids for chronic non cancer pain with very little guidance.

PROP highlights a big problem in medical research and associated public policy and that is the biasing influence of the pharmaceutical industry and a few people at the top.  The Institute of Medicine was instrumental in highlighting the issue of chronic pain and framing it as a discrete disease.  Although not mentioned specifically by PROP, the Joint Commission (then known as JCAHO) promoted pain recognition and treatment in the year 2000.  As this excerpt shows that initiative did not go well.

"In 2001, the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) introduced the concept that pain was the “fifth vital sign,” in an effort to increase the awareness of pain in the hospitalized patient, and by design, improve the treatment of that pain. Unfortunately, the current emphasis on pain assessment as the fifth vital sign has resulted in the potential overmedication of a group of patients (139)" (see ref 1).

Without going into detail at this time, I think that are recurrent patterns of federal and state governments, the managed care industry, and the pharmaceutical industry and their affiliated organisations driving practice patterns and treatment guidelines based on very little evidence.  That culminates in broad initiatives like the PPACA that are widely hyped as advances in medical treatment, but they are basically an experiment in medicine founded on business and financial rather than scientific principles.  There may be no better example than the practice of prescribing opioids for chronic non cancer pain.   

Another contrast for this essay is the comparison with what has been years of psychiatric criticism based on the same principles.  The basic argument from the media, antipsychiatrists, generic psychiatric critics, and grandstanding politicians has been that the pharmaceutical industry has been able to financially influence psychiatrists to prescribe drugs that are at the best worthless or at the worst downright dangerous (their characterizations).  That despite the fact that black box warnings on psychiatric medication may be held to a much higher standard than other medication even if they target the same level of morbidity and mortality.  After all, there is no known psychiatric medication that is mass prescribed and has resulted in overdose deaths at the rate that people are currently dying from prescribed opioids.

Just a few weeks ago, the FDA posted a number of initiatives on their web site focused on the prescription of extended release opioids.  My read through the most detailed document shows that it does not touch on the principles outlined by PROP.  The idea that this is strictly a matter of educating physicians is an oversimplification.  This is a matter of creating initiatives that governments and sanctioning bodies insist that physicians follow and then coming up with other rules when the original ideas fail.

George Dawson, MD, DFAPA

1.  Trescot AM, Helm S, Hansen H, Benyamin R, Glaser SE, Adlaka R, Patel S, Manchikanti L. Opioids in the management of chronic non-cancer pain: an update of American Society of the Interventional Pain Physicians' (ASIPP) Guidelines. Pain Physician. 2008 Mar;11(2 Suppl):S5-S62. Review. PubMed PMID: 18443640.