PAINWeek Blog

One of the problems in the Pharmaceutical world right now which affects everyone is that there aren’t that many new drugs in the pipeline. Many of the newer drugs coming on the market are slight variations on an older model. Just recently, for the first time in 50 years, a new medication was introduced for the management of Lupus. It’s a biologic agent and only works moderately well, but still, a momentous event for the treatment of patients with SLE.

I was interested to read of the development of a new compound named conolidine for pain management, announced just a few days ago. This compound may have the same pain alleviating properties as morphine, without the side effects. Morphine has the potential for many adverse reactions, some severe, such as respiratory depression, hypotension, and seizures, and some less severe but still serious, such as nausea, vomiting, constipation, and somnolence. Obviously a medicine that works as well as morphine but has few, if any, of the adverse reactions associated with it would be great.

Conolidine is a traditional Chinese Herbal medicine that has been used for centuries as an anti-inflammtory compound for wounds and can be chewed for the treatment of pain. It is derived from the bark of a tropical flowering plant (remember aspirin? Also the product of a plant, willow bark to be specific). Now, for the first time, researchers at the Scripps Research Institute in Florida have found a way to synthesize this product in the lab.

The studies done so far have all been mouse studies. But you have to start somewhere, and now that this compound can be synthesized, in a few years we may have a new type of medication for the treatment of pain. Interestingly, it appears the exact mechanism of action remains unknown, but with further research, it will surely be understood.

The other day a young woman came into the office and she looked exhausted. She told me her friend recommended that she come and see me. She had seen 4 different doctors over the past 3 months and none of them could tell her what was wrong. Here is what she complained of: fatigue, night sweats, intermittent sore throat, and body aches. She denied any weight loss. She had lots of blood tests performed, which she brought in with her.

She told me she thinks she has Chronic Fatigue Syndrome. She came to this conclusion by searching the internet. Her brother, who is a 4th year medical student, said no way. Each of the doctors previously seen had not mentioned this. We reviewed the major and minor criteria for Chronic Fatigue Syndrome, and it was a plausible diagnosis. She believes she did have an upper respiratory infection before all of her symptoms began as well. She states that her current condition is becoming debilitating and affecting her on a daily basis. The way she puts it, “I’m not the person I was 4 months ago.” On exam she had a mild temperature of 99 degrees Fahrenheit, but otherwise there were no specific findings.

It’s interesting that of the 4 previous physicians, both primary care and one specialist (infectious disease, and her brother in medical school, none of them came to this diagnosis and the patient came to this conclusion herself. My role in her care was to support her in her diagnosis and review the treatment options. (We found a cognitive behavioral therapist in the area and reviewed the need for a strong exercise regimen, even though it would be difficult at first.)

Doctors like understanding a disease. How does one explain chronic fatigue syndrome from a pathophysiological standpoint? Not easily. There have been some findings, like weakened immune systems, low cortisol levels, but what this actually means in terms of the disease etiology is uncertain.

What I take from this patient encounter is: Remember to believe your patient. Listen to the details of their story. Chronic fatigue syndrome is a complicated disease and, in the eyes of some, remains controversial.

Joint pain. It will happen to you eventually, and often it is due to the wear and tear we put on our joints on a daily basis. With the rise in obesity, not just in America, but throughout the world, we are putting more work on our knees than our bodies were designed for. When it comes to medications for the treatment of OA, the first line choices are acetaminophen or NSAIDs. Of course there are other treatment modalities that should be employed, such as physical therapy and weight loss (when overweight), but the use of medications is necessary for many people to get by from day to day.

For many people, though, the usual medications either do not work or are contraindicated. A typical example is my patient AS, who came into the office a few weeks ago. She is a 65 yo female with a history of hypertension on medication, and a BMI of 38. She has severe osteoarthritis of the knee, has difficulty ambulating, and cannot walk more than one block without having pain she describes as 8/10. She reports that Tylenol just does not work for her, and NSAIDs are not an ideal option due to her high blood pressure. According to the American College of Rheumatology, Tramadol would be the next choice. Tramadol is an interesting pain medication; it has opioid like properties in that it binds to mu opioid receptors, and it also weakly inhibits norepinephrine /serotonin reuptake producing analgesia. It is thought to be a stronger analgesic than acetaminophen or most NSAIDs but it also has more side effects.

There is a Cochrane review from 2009 however that reviewed tramadol for the treatment of osteoarthritis. It found little improvement if any, when compared to placebo, and was found to be less effective than cox 2 inhibition. Adverse Events were always more common in the tramadol group whether in comparison to placebo or another medication such as acetaminophen or diclofenac. The most common side effects found with tramadol are nausea, vomiting, dizziness and fatigue.

Pain is pain and we need treatment options. For some people tramadol works. For others it does not and the pain cannot be controlled. So the next question is, when is there a role for opioids for the treatment of osteoarthritis? There is also a Cochrane review from 2009 that examines the use oral and transdermal opioids for the treatment of OA. Overall they found that 35% of patients had a decrease by 50% in their pain score compared to 31% for those taking Placebo. Not a large difference. The opioid class of medications also has significantly more side effects as well as the potential for abuse and diversion. Like tramadol though, it is an option for certain patients, and the prescriber needs to review the risks and benefits of these medications and make a decision together with their patient on how to treat the pain.

Patients often ask about injections. Do they work? Are they painful? How long do they last? There have been a few studies to look at this, comparing glucocorticoid to saline (the placebo). Yes it does work, but it is short term...weeks to months, and overall it does not change the end result. After two years, the degree of joint narrowing and the degree of pain is no different between injecting saline and injecting a glucocorticoid. This does provide a good option for a select population of people, but like all things invasive, it is not without risk and developing infection post injection is always a concern.

We can also try to replace the synovial fluid in the knee by injecting hyaluronic acid into the knee, but few studies have shown anything more than a modest improvement in overall pain control.

Severe osteoarthritis of the knee is painful and debilitating, and for many people a total knee replacement is the only option.

For my patient AS, we discussed the pros and cons of tramadol and opioids. Interestingly, she had a cousin who she believed was addicted to Percocet and she wanted nothing to do with any narcotic medications. We decided on a glucocorticoid injection which she received from an orthopedist, and she is currently undergoing physical therapy...I’m waiting for her next office visit to see how she is progressing.

The adolescent mind does not finish developing until one reaches their mid 20’s. Different parts of the brain develop faster than others and unfortunately the pre-frontal cortex, the area responsible for a lot of our reasoning abilities and impulse control, is one of the last areas to fully develop. This leaves adolescents with a real challenge; making important decisions when it comes to risk taking behavior. According to an article published in the Journal of the American Medical Association (JAMA) in 2008, over 232,000 adolescents admitted inappropriately taking an opioid medication. The authors noted that in 2007, 3% of 8th graders, 7% of 10^th graders and 10% of 12^th graders used hydrocodone alone.

Now, a new article published in this month’s JAMA reveals more startling statistics regarding the use and abuse of opioids in the adolescent population. There is the misguided belief that since these medications were originally prescribed by a physician and are not an illegal substance, that they must be safe. Adolescents do not realize that accidental overdose from an opioid medication is now one of the leading causes of unintentional death in America, second only to motor vehicle accidents.

How are these children obtaining these medications?

Opioid prescriptions are being written more now than ever before. In the adult population, the use of opioids is a staple for the treatment of cancer pain, but they are also becoming more and more common in the treatment of non-cancer pain as well. Short acting opioids, especially those written as a combination pill with acetaminophen are often written as a PRN dose, meaning only take it if you need it, and the physician will prescribe more than enough so the patient does not run out of the medication. What happens to the leftover pills? They are usually stored in the bathroom closet, for a future emergency. Most patients are not instructed how to properly dispose of their extra opioid medications, and are not aware of the prevalence of opioid diversion.

There has also been an increase in opioid prescriptions being written specifically for adolescents. It is very common for healthy young adults to get their wisdom teeth removed, and the average oral surgeon does about 53 of these procedures a month. The preferred post operative analgesic is an NSAID, but it has been reported that up to 85% of patients also receive a prescription for a short acting opioid medication as well, usually with 20 pills in the container, to be taken on an as needed basis only. Most patients do not need this much (if any at all) and this opens up the door to drug diversion.

How do we help prevent the abuse of opioids in the adolescent population?

First, all prescribers need to take an individual assessment of a patient’s history of drug and alcohol addiction and substance abuse when prescribing an opioid.

Second, prescribers need to follow evidence based guidelines when available to treat non-cancer related pain.

Third, patients need to be instructed how to properly dispose of leftover medication, and the importance of not storing it for future use.

Adolescents who misuse opioid medications do not understand the physiologic changes that take place by repeated exposure that can lead to dependence and addiction, nor do they understand the very real potential for overdose and death. It is imperative that heath care providers prescribe these medications appropriately.

In one study by Reid et al in the Journal of General Internal Medicine, investigators sought to define the opioid medication prescribing habits for non-cancer pain in 2 separate primary care settings. When using short acting opioids, 50 out of 50 patients at one center received a combination medication – either acetaminophen with oxycodone or acetaminophen with codeine. At another center 38 of 48 received combination therapy while 10 patients received other—most likely combination therapy of hydrocodone with acetaminophen—but not specifically documented.

Should opioid acetaminophen combination medications be the first line therapy for moderate to severe pain? If not then why are so many prescriptions being written?

Pain medicine as a field is growing tremendously, and with it, clinicians’ exposure to pain management. In the past, most primary care programs felt that their training in pain management was not sufficient. These days many medical students and residents rotate through a pain service at some point during their training. With the changes being made by the FDA and the increase in pain education, it can be assumed that there will be a significant improvement in appropriate dispensing of opioid-containing medications.

The combination pills of acetaminophen with an opioid have been around since the 1970’s. They are short acting and effective and it is easy to see their usefulness in managing moderate to severe pain. It is only recently that the adverse effects of acetaminophen toxicity with these medications are coming to light.

Here are some very interesting facts regarding acetaminophen recently published in the Pharmacists Letter:

From 1998 to 2003, acetaminophen was the leading cause of acute liver failure in the United States, almost half of these cases due to accidental overdose. In 2005, the Toxic Exposure Surveillance System (a service that captures data from poison control centers) showed that calls about poisoning cases that resulted in major injury numbered 1,187 for over the counter single-ingredient products and 1,470 for prescription-opioid combination products.

From this information it is easy to see why, in January of this year, the FDA decided to limit the amount of acetaminophen in combination products with opioids to 325mg per tablet.

Yet Percocet and Vicodin are two of the most commonly prescribed medications in the nation. They are often a first choice for many healthcare professionals. Why is this the case? What has made the use of combination acetaminophen / opioid medications so popular.

The purpose of combining an opioid such as oxycodone with acetaminophen is to increase the efficacy by simultaneously using drugs with distinct mechanisms of action with the goal of reducing the amount of opioid necessary for optimal pain control. ln a Cochrane Intervention Review (2009), Gaskell and colleagues examined the use of oxycodone and oxycodone with acetaminophen for acute post-operative pain in adults. After a thorough review of the literature, they concluded that there is evidence that oxycodone plus acetaminophen was more effective than opioid alone or placebo. They also found that the higher the dose of the combination medication, the better the overall response. Although this was for post-surgical pain, it is reasonable to say that this holds true for the treatment of non-cancer pain in general.

The problem is that over 600 medications, both OTC and prescription, contain acetaminophen and as outlined above, many patients do not know that they are ingesting acetaminophen with their medication. The changes the FDA is instituting will play a large role in making these medications safer. But it is also essential that the healthcare clinician make an extra effort to educate their patients when prescribing these medications.

• Advise patients not to exceed the acetaminophen maximum total daily dose (4 grams/day)
• Warn them that severe liver injury, including cases of acute liver failure resulting in liver transplant and death, has been reported with the use of acetaminophen
• Educate patients about the importance of reading all prescription and OTC labels to ensure they are not taking multiple acetaminophen-containing products
• Advise patients not to drink alcohol while taking acetaminophen-containing medications

Should combination medications be eliminated from the market altogether? The answer is not to get rid of the combination medications, but to prescribe them more wisely.

I’d like to start by reviewing a recent encounter between two patients. The encounter is real, just a slight variation to maintain anonymity.

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Patient 1: I fell and hurt my wrist 4 months ago and I originally had an xray that made it seem like everything was ok, but now after 4 months and an orthopedic evaluation I just found out that I may have a slight fracture after all and I may even require surgery. Meanwhile my wrist is killing me. I started with over the counter medications and they just don’t help. My doctor wrote a prescription for Naproxen but it hurt my stomach more than it was helpful.

Patient 2: Did you try anything like Percocet for the pain?

Patient 1: I asked my doctor about that but he refused to write a prescription. He thought that it was too risky and was worried about me becoming addicted.

Patient 2: That’s just wrong. You need to find another doctor.

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Important things to know about patient 1: He is not a smoker. He has no history of addiction, nor does he have any family history of addiction or alcohol abuse of any sort.

How common is this scenario? The answer is more common than you would think. In my own practice, some of the physicians I work with rarely if ever write a prescription for an opioid containing medication. Why is this? There are multiple reasons.

1. Drug Seekers. Some patients are drug seekers. But this is not the norm. Every patient one treats with an opioid medication is a judgment call. If it’s a first time visit and they are asking for high doses of a specific opioid medication, then it might be an issue. Of course one can prescribe a limited quantity until they provide previous medical records supporting their medical history, or provide contacts for previous physicians. One can provide drug contracts in which the patient documents that they will only receive opioid medications from one physician
2. Fear of Malpractice / Loss of Licensure. As with everything in medicine, documentation is key. The DEA is watching, and knows the quantity of narcotics a doctor is writing for. But these are medications approved by the FDA. One must specifically dictate what medication is given, why, how much, review the potential side effects, and list the pertinent history of the patient including any addictive issues
3. Fear of Side Effects. The opioid class of medications has many serious reactions including: dependency, withdrawal with abrupt cessation, low blood pressure, respiratory depression, and seizures as well as more common reactions such as dizziness, sedation, nausea, vomiting, and constipation. As long as these side effects are reviewed appropriately and the patient is aware, the doctor and patient can make a decision together whether or not to try an opioid medication
4. Lack of Education. Pain management is a field in its infancy. Many primary care physicians may not have had proper exposure to the opioid class of medications during their training, and thus are not comfortable prescribing them in general

The encounter noted between the two patients is not uncommon. Pain is real and patients deserve a chance at better control. Often achieving complete pain relief is not possible, but obtaining a significant improvement in overall quality of life is. Prescribing opioids is not a crime, but must be done with respect and understanding of the patient’s situation each and every time.

The field of palliative care medicine is growing quite rapidly. What is palliative care medicine? It is a specialized area of health care that focuses on relieving and preventing the suffering of patients. The palliative care team helps the medical team, the patient, and the patient’s family and loved ones make decisions regarding goals of care.

I am a great supporter of palliative care medicine and believe it is a field that needs to grow. A palliative care team should be set up in every hospital. Now a new article from Morrison et al published in the journal Health Affairs supports this effort by a most critical aspect of health care: COST. Palliative care teams save money. They looked at Medicaid patients at four New York Hospitals over a 4-year period and found that there was a $6900 savings per patient who received a palliative care consultation. They then estimated that these savings could eventually range from $84 million to $252 million annually.

Palliative care does not mean we do not treat. It means respecting the wishes of the patient and the patient’s family in a time of critical illness and knowing what extraordinary measures should be undertaken to keep someone alive. Cost saving is obviously not the primary goal of a palliative care team, but in today’s changing healthcare climate, it cannot be overlooked either.

The use of non-steroidal anti-inflammatory medications is pervasive in the United States and throughout the world. Many of these medications, such as ibuprofen, have been around for a while. But just how safe are they? One of the common problems has been GI toxicity, and it is often recommended to take something to protect the stomach when taking an NSAID long term. But what about cardiovascular toxicity? Is there an increased risk for heart disease, for stroke and even death?

In January of this year, the British Medical Journal published a meta-analysis reviewing this very topic. They examined 31 trials, and incorporated 116,429 patients and 117,218 patient years-worth of data. They evaluated seven different NSAIDs in comparison with placebo medications. The primary outcome was fatal or non-fatal myocardial infarction. The authors also looked at stroke, death from cardiovascular disease, and death from any cause, and they found some interesting results.

And the winner is…Naproxen. When it comes to having a heart attack or death from cardiovascular disease, Naproxen did not show any signs of increased risk. When it comes to stroke, though, every NSAID reviewed has an increased risk for having a stroke.

What is really interesting is that ibuprofen, one of the most popular medications used worldwide, was associated with an increased risk of myocardial infarction, stroke, death from cardiovascular disease and death overall. Does this mean we should stop using this medication all together? One always needs to weigh the risks and benefits of any medication. Millions of people use ibuprofen for control of their musculoskeletal pain, and it works a lot better than other medications they have tried. For those with a significant cardiac history, the patient needs to be aware of the increased risk and make an educated decision on whether or not to proceed with this medication or switch to another.

No meta-analysis is perfect and there is a lack of good data out there. More trials are in the works but for now we make do with the information we have. NSAIDs are effective pain medications, but choose your target populations wisely.