The forces of nature appear intent on reversing mankind’s progress toward better health. An example is the ever-increasing resistance of bacteria to antibiotics. A timeline of the existence of humans and bacteria shows that bacteria have been around for a very long time— much longer than mammals, and much, much longer than humans. In fact by the dawn mankind, bacteria had been thriving, relatively uninhibited, for over 2 billion years.
Modern humans have been around for 40,000-200,000 years or so, depending on the definition of ‘modern.’ Bacteria have had the upper hand during all of mans’ existence, save for the past 100 years after penicillin and other antibiotics were discovered. Only the most self-centered of species would look at a timeline and conclude that humans have won the battle with bacterial diseases. There are always reasons for optimism, but a fair assessment of our current struggle with antibiotic resistance suggests that someday, people will look back on the current sliver of time, when humans can treat most bacterial infections, as a golden era of medicine that wasn’t appreciated as such at the time.
Viruses adapt to mankind’s health efforts too, with new variants arising from the sludge at the bottom of the food chain to infect birds, swine, or other creatures before moving on to human hosts. The CDC and other scientists work to predict the vulnerabilities of the next super-virus, hoping to reduce the severity of the next pandemic. As with bacteria, we are enjoying an era without smallpox, polio, or other dreaded viral diseases that used to kill otherwise-healthy people. We take the victor’s position for granted to the point that our children don’t know why chlorine was first added to swimming pools. Gone with the last generation are the fears associated with iron lungs, orange window-signs, and leg braces.
Even the Human Immunodeficiency Virus, an agent of certain death in the 1980’s was transformed into a chronic, treatable illness. I was new to medicine when ‘universal precautions’ were first instituted (can our children even imagine having their teeth examined by someone not wearing latex gloves?!) Researchers don’t celebrate, though, since medication-resistant strains of HIV were expected …
We can now leave naloxone out of the discussion, and focus on the side effects of Suboxone that are caused by buprenorphine.
Side effects are symptoms caused by a given medication that are not part of the therapeutic benefit of that medication. Whether a symptom is a side effect depends on the reason for taking the medication. For example, decreased intestinal motility is the desired effect of opioids used to treat diarrhea, but a bothersome side effect when taking opioids for pain. The term ‘side effect’ is not on the package insert for medication, the symptoms and actions instead referred to as ‘adverse reactions.’ Package inserts also have a section entitled ‘warnings and precautions’ where the most dangerous adverse reactions are listed.
Some medications have a ‘black box warning’ for adverse reactions that are particularly common or particularly dangerous, consisting of a frightening statement at the start of the package insert (enclosed, naturally, by a black box). Black box warnings in psychiatry include the warning for increased suicidal ideation in children and adolescents treated with antidepressants, and the increased risk of death in people with dementia treated with atypical antipsychotics.
Increased risk of cancer or mutations, and effects on fertility or fetal development, are listed in yet another section entitled ‘nonclinical toxicology.’ They are listed as ‘nonclinical’ because the events do not involve the intended physiologic system or pathway targeted by the medication. For example, slowing of intestinal activity by opium is either treatment of diarrhea or unwanted constipation, but in either case the outcome is caused by actions of opioids at opioid receptors. If the opium molecule happened to bind to DNA and cause cancer, the cancer would be nonclinical toxicology, not a side effect. Carbamazepine decreases the excitability of neurons to prevent seizures, and the sedation caused by the slowing of neurons is considered an adverse reaction. Carbamazepine impairs fetal development through different actions, considered nonclinical toxicology.
All of these divisions can be picked apart so that division of symptoms to one category or another will appear arbitrary. The system …
Today I read about the stereotactic brain surgery used to treat opioid dependence in China over the past ten years. The procedure is relatively straightforward; the patient’s skull is clamped in place while small holes are drilled, guided by computerized, 3-dimensional maps of the brain. Probes are inserted deeply through brain tissue to the nucleus accumbens, where electric current destroys varying amounts of brain tissue. Patients are awake and talking during the procedure, so that surgeons know if the probes are too close to brain regions that control speech or other functions.
A large number of ablations for the treatment of addiction were performed in China about ten years ago. The rapid growth in popularity of the technique, before full knowledge of the risks and long-term effects, led to a ban on the procedures by the Chinese Ministry of Health in 2004. Still, ablations were performed as part of research studies, with over 1000 people treated by ablation since 2004.
The scientific community outside of China overwhelmingly condemns the technique, and medical journals are pressured to withhold publication of ablation studies. Human rights advocates claim that such experiments are performed on people who are not fully aware of the risks, or who are pressured to participate in the studies to avoid harsh punishments for drug offenses. The veracity of the results from ablation studies has also been challenged. Ablation treatment of opioid dependence is in the news lately because of a recent paper describing the five-year follow-up of opioid addicts treated by the procedure.
Neuroscientists distinguish between DBS (deep brain stimulation by electric current) vs. procedures where brain tissue is destroyed. I’m surprised by the intensity of the distinction, given the similarity of the procedures. In both cases long probes are passed through brain tissue, risking hemorrhage, stroke, or seizures. For DBS, wires are left behind and connected to power-packs that release different patterns of electrical current. In the ablation studies, small areas of tissue at the end of the probes are destroyed, and the probes removed. If there is a …
People who read this blog are aware of the shortage of physicians who can prescribe buprenorphine to treat people addicted to pain pills, even as an epidemic of addiction to heroin and pain pills devastates the heartland of the country. In order to prescribe buprenorphine, physicians take a short course and obtain special certification. To obtain certification, physicians must promise to treat no more than 30 patients at one time, a number that can be increased to 100 patients after one year.
If you only have a few minutes, please take the time to go to the White House web site and add you name to a petition to allow individual doctors to treat more than 100 patients using buprenorphine. The whole process is fast and easy, and only requires your name and email address through this link: http://wh.gov/QR6K
If you have more time, need convincing, or just like hearing a 52-y-o rage against the machine, continue reading my thoughts about limiting treatment for this one health condition.
The reason for the patient cap, according to cap proponents, is to prevent pill-mill practices where patients could obtain narcotic medications without adequate care for their underlying addiction. That concern is reasonable, I suppose, but I often discover that proponents of the cap have other motives to keep the limits in place. For example, one person at a ‘linked in’ group argued that individual physicians don’t provide the all-encompassing care that he provides… to the 800+ patients he ‘counsels’ at the methadone clinic where he works! According to that counselor, all people addicted to opioids need years of counseling—largely from other people with addictions, who after a couple years of school have all the answers.
He would be surprised to see just how well people can do on buprenorphine, a medication that selectively removes craving for opioids. After years of treating and knowing patients on buprenorphine I realized that ‘character defects’ are largely maintained by active craving. Yes– people with antisocial tendencies before and during active addiction have the same antisocial tendencies on buprenorphine. But people who …
In my last post, I wrote about the work-up of a patient who experiences symptoms similar to opioid withdrawal that start about an hour after each dose of Suboxone. We decided that the symptoms were signs of withdrawal—i.e. reduced activity of mu-opioid pathways—and that the symptoms were triggered by taking a daily dose of Suboxone (buprenorphine/naloxone).
Note that I wrote that the symptoms seemed to be caused by reduced mu activity, i.e. not necessarily by reduced mu-receptor binding. Endogenous opioid pathways are very complex. Decreased activity in opioid pathways may arise from decreased binding of agonist at the receptor, or from changes in a number of other chemical or neuronal pathways.
This diagram shows the processes that are triggered by mu-receptor binding in humans before and after opioid tolerance. The diagram only shows the complexity of processes within the neuron with opioid receptors; realize that each neuron 1. Has receptors for many other neurotransmitters as well, and 2. Receives input from thousands of other neurons. As we sort through possible causes of our patient’s symptoms, keep in mind the complexity of neural pathways.
While we are on the subject of complexity, the web site linked above is an incredible resource for those interested in biochemistry. The site includes diagrams of a number of metabolic pathways that describe how different molecules, including neurotransmitters, are manufactured by the human body. I encourage people to browse the site. You will gain insight into why the actions of substances are difficult to fully predict.
The withdrawal symptoms experienced by our patient might arise from dysfunction in any one of the many chemical pathways that affect opioid tone. But since a dose of Suboxone contains naloxone, a mu-receptor inverse agonist, it is possible, maybe even likely, that the naloxone is related to symptoms.
Naloxone is less lipid-soluble than buprenorphine and so only a small portion—about 3%– of a dose is absorbed through mucous membranes. The rest of the naloxone is swallowed, consciously or inadvertently, and eventually absorbed from the small intestine, to pass to the liver via the portal vein. …
I struggle with the length of my posts. I shoot for 1000 words—an amount of reading that most people can knock off in a typical trip to the bathroom— but I find it difficult to limit posts to that size. So as I have done in the past, I will break this post into a couple of sections. In the first, I’ll lay the groundwork for investigating symptoms of withdrawal in a patient taking buprenorphine. The second post will go into greater detail.
A patient recently contacted me to complain that he was experiencing withdrawal symptoms for several hours after each dose of Suboxone. I will describe my thought process, in case the description helps someone else experiencing similar symptoms.
My first decision point is whether or not the person is truly experiencing symptoms of withdrawal. Some people will misinterpret symptoms from excess opioid stimulation as withdrawal symptoms, for example. Nausea is a not-uncommon complaint among people taking buprenorphine, and patients often assume that nausea is the result of insufficient opioid activity, and so take higher doses of buprenorphine. But nausea is actually more common in opioid overdose than during opioid withdrawal, along with constipation, whereas withdrawal primarily causes diarrhea.
Pupil diameter is a good indicator of withdrawal vs. overdose; small or ‘pinpoint’ pupils suggest an excess of opioid activity, whereas withdrawal is associated with very large pupil diameter.
Other symptoms are also misinterpreted as withdrawal. Many opioid addicts develop a strong fear of withdrawal over years of using, and so ‘withdrawal’ is often the first thing to come to mind, during unpleasant symptoms. I also believe that the experience of withdrawal becomes learned in a way that allows the symptoms to re-occur after certain triggers. I remember an experience years ago, when I awoke from a dream experiencing significant withdrawal symptoms, even though I had not taken an opioid agent for years. I feel back asleep, and was grateful to find that the symptoms were gone, when I woke the second time.
People are angered by the notion that their symptoms have ‘psychological’ origins. But as …
The FDA recently released a Drug Safety Announcement regarding the use of codeine in young children after tonsillectomy/adenoidectomy surgery for obstructive sleep apnea. I was somewhat surprised to see a safety announcement on a medication that has been in use for decades, but the release underscores our improved knowledge of drug metabolism, and the broadening demographics of the United States.
Codeine has little activity at opioid receptors. The analgesic effects of codeine are actually caused by morphine, after the conversion of codeine to morphine at the liver. The conversion is catalyzed by an enzyme called CYP2D6, part of the cytochrome system of enzymes that are involved in the breakdown of a number of compounds.
I have written about the addictiveness of narcotic pain medications. People addicted to opioids often go to significant lengths to obtain prescriptions for narcotic pain relievers from healthcare practitioners. Emergency room physicians and nurses become aware of the efforts of ‘narcotic-seekers’, which range from faking pain symptoms or dental injuries to self-catheterization and instilling blood into the bladder to fake kidney stones. Distinguishing those with real pain from those who are addicted and not experiencing pain is a serious situation, but doctors roll their eyes at some of the more-typical presentations. One such situation is the patient who reports an ‘allergy’ to all of the weaker narcotics, and claims that ‘the only drug that works is (insert Dilaudid, morphine, oxycodone, or another potent opioid here).
Codeine is one drug that is commonly rejected as ‘ineffective’ as part of a request for something stronger. When I was a medical student, we assumed that requests for something other than codeine were disingenuous. But at some point, maybe 15 years ago, I remember reading an article that described the conversion of codeine to morphine by the liver. The article reported that the enzyme that performs the conversion exists in varying forms across the population, with some ethnic groups having more active forms of the enzyme than others. Some people have very low levels of CYP2D6, and therefore get very little analgesia from codeine. In …
A couple weeks ago the manufacturer of Suboxone, Reckitt-Benckiser, filed a Citizens Petition with the FDA, announcing a voluntary recall of one of the company’s signature products, Suboxone Tablets. Suboxone was sold in tablet form for almost ten years, and the patent ran out on Suboxone Tablets last year. A couple years ago the same company began making Suboxone Film; a rapidly-dissolving form of the medication that comes with each dose individually packaged.
Suboxone is used to treat opioid dependence, and the medication has been a vital, albeit expensive, tool for saving the lives of patients addicted to narcotic pain medications or heroin.
Last week I expressed anger at the company for their actions. Uninsured patients treated for opioid dependence pay a high cost for the medication that helps keep them safe, and have been looking forward to a generic form of the medication for years. It appeared to me that Reckitt Benckiser was trying to tarnish the tablets, perhaps to reduce insurance or Medicaid coverage of the tablets when they inevitably (?) hit the market.
I have carefully read through the entire Citizens Petition, and I now have a better understanding of what, exactly, was accomplished by that action by the manufacturer of Suboxone. It turn out that I underestimated the people at Reckitt-Benckiser.
The Citizens Petition explains that Reckitt-Benckiser (RB) hired an independent group, RADARS (Researched Abuse, Diversion, and Addiction-Related Surveillance), to investigate the exposure of small children to Suboxone tabs and Suboxone Film. The results of the RADARS findings are spelled out in detail in the Petition.
RADARS showed an increase in exposure to Suboxone Tabs over the past ten years. They also show an increased rate of exposure, i.e. number of exposures, divided by the number of tabs prescribed. Reckitt-Benckiser wrote that they instituted REMS over the past few years to counter that increase. What are REMS, you ask?
From the FDA site: The Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require a Risk Evaluation and Mitigation Strategy (REMS) from manufacturers to ensure that the benefits of a drug …
I’ve described the ongoing debate over the use of opioids to treat chronic pain. To catch new readers up to speed, the country is in the midst of an epidemic of deaths due to overdose on pain medications or heroin. The epidemic is evident to anyone who spends even a few minutes searching the internet using the keywords ‘overdose deaths.’ Another increasing phenomenon is the prosecution of physicians whose patients have died from overdose. Physicians have been found guilty of manslaughter, even when people used the prescribed medication inappropriately, far outside of prescribed guidelines. It is no surprise that in response, many doctors have stopped treating pain with opioids altogether.
I’ve described one group of physicians, Physicians for Responsible Opioid Prescribing or PROP, who have taken a position seen as extreme by some other physician groups, particularly groups involved in advocating for pain relief. The latest efforts by PROP have resulted in a direct conflict with pain advocacy groups. Readers of this blog who are interested in the issue can have a direct impact on the outcome of the situation.
Medications approved by the FDA have been shown through scientific study to be effective and safe enough to justify their use. At present, opioid pain medications are indicated for moderate or severe pain. There are no other restrictions on the use of pain medications from the FDA, but use of all medications, including opioids, must be within the ‘standard of care,’ a general pattern of practice in a given area that is sometimes difficult to pinpoint.
PROP has asked the FDA to change the indications to state that opioid pain medications are to be used only for severe pain. They also asked that opioids be recommended for use for a maximum of 90 days, and never in doses greater than the equivalent of 100 mg of morphine. They base their request on studies that have shown that some patients develop a condition of increased pain, when maintained on opioids for a prolonged period of time. They are also concerned about the large numbers of deaths from opioids, …
I subscribe to Google news alerts for the phrase ‘overdose deaths.’ Google Alerts are a great way to follow any topic; subscribers receive headlines from newspapers and web sites for certain keywords from around the world. One thing that has become clear from my subscription is that there is no shortage of stories about deaths from opioids! Every day I see one article after the next, as news reporters notice the loss of more and more of their communities’ young people.
Along with the reports of overdoses are stories about doctors who are increasingly being prosecuted for the deaths of their patients. In an earlier post I described the case of Dr. Schneider and his wife, a nurse, who were tied to a number of overdose deaths in Kansas. That case stood out by the sheer number of deaths; the State charged the couple with the deaths of 56 patients. Cases involving fewer patients have become relatively common. The latest case that I’ve read about is a doctor in Iowa, who is accused of causing or contributing to the deaths of 8 people.
I try to present both sides of the argument when I write about this topic. I have been faced with the difficult decision over whether or not to prescribe narcotics many times, and I understand a doctor’s dilemma. The doctor sees a person who is in pain, and knows that there is a pill that will reduce that pain. But the doctor also knows, or SHOULD know, that initiating a prescription for narcotic pain medication always has unintended consequences, no matter how good the intentions of both doctor and patient.
In the Iowa case, the dilemma over narcotic-prescribing is very clear. The prosecution states that the doctor prescribed pain medication to drug addicts. On the surface, that sounds bad, right? One gets the mental picture of dirty, lazy people, dissolving tablets in a spoon, over a candle, and then injecting the mixture. But reality is much more complicated. Patients with histories of opioid dependence do not always have track marks. And even …