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10 Articles in Volume 17, Issue #5
Cross-Linked Hyaluronic Acid Injection for Neuropathic Pain
Discussing Migraine: What to Try When Nothing Is Working
IV Propofol for Treatment of Chronic Intractable Cluster Headache: A Case Series
Letters to the Editor: Rapid Opioid Metabolizer, Intractable Pain, Adrenal Suppression, Traumatic Brain Injury
Migraine Treatment: What’s Old, What’s New
Schizophrenia Spectrum and Chronic Pain: Is Pain Insensitivity a Myth?
Spinal Fluid Flow and Pain Management
Step-by-Step Technique for Targeting Superficial Radial Nerve Pain
The Primary Care Provider’s Role in Diagnosing and Treating Rheumatoid Arthritis
What is the appropriate use of phone texting between physicians and patients?

Letters to the Editor: Rapid Opioid Metabolizer, Intractable Pain, Adrenal Suppression, Traumatic Brain Injury

June 2017

Rapid Opioid Metabolizer

In January 2015, I was working in the emergency room when a young lady presented with signs and symptoms consistent with ureterolithiasis. In addition to standard treatment (tamsulosin, ketorolac, pyridium) and intravenous (IV) fluids, I prescribed the usual amount of hydromorphone (Dilaudid). I generally start with a 0.5 mg IV push; this dosage of medication did nothing to reduce the patient’s pain, and over the next 90 minutes, I slowly increased the dosage of IV hydromorphone to 2 mg.


On questioning the patient, she mentioned having a prior experience with severe pain that required high doses of opioid medication to control the pain.

Although the CT scan offered no evidence of a kidney stone, a prior history of having passed stones and her present signs and symptoms (hematuria on urinalysis) suggested that she had a stone despite the lack of confirmation on CT, which does happen. Because we could not get the pain under control, she was admitted to our small rural hospital and put on telemetry and oximetry.

Over the next 24 hours, the patient received 2 mg of hydromorphone every 2 hours; yet, her pain level never dropped below 6 to 7 out of 10 (based on a numeric pain scale). When prompted, she stated that while she was getting some relief it wasn’t sufficient to relax or rest. In response, I increased the delivery of hydromorphone to 2 mg every 1-1/2 hours and that brought her pain level down to about a 5 out of 10, permitting the patient to rest.

However, the patient stated that she could not sleep due to the noise from the cardiac monitor and the oximeter, and she removed them herself. The experienced nurse who was on duty did not call me. If she had, I would have informed the patient that unless she permitted the medical monitoring, she would have to seek care elsewhere.

When I was finally called at 4:30 AM the patient was found unresponsive with shallow breathing. The nurse stated that the patient responded to a sternal rub briefly and had been checking on her every half hour. Retrospectively, the patient had a stone that was passed during hypersedation.

The reason for my inquiry is that I had to use 4 single use vials of naloxone (Narcan) to wake her up. She had difficulty with short-term memory for several weeks. An MRI ordered 7 days after the event did not show evidence of acute cerebral anoxia.

Now, a full year later, the patient stated that she is still having problems with her short-term memory. The patient is suing the hospital for $10 million. It is evident that she is a rapid opioid metabolizer.

In looking for support for our case, I came across an article on genetic testing from the May 2016 issue of Practical Pain Management (PPM).1 Are there any other articles that might lend support to our pain care?

I feel that I gave this patient the best care possible, and now I feel betrayed for doing what I could to meet her pain needs.

(Doctor, Name Withheld)

Dear Doctor,

Your situation in which a patient is attempting to sue you and your hospital raises more than one ramification for pain practitioners. First, any patient who refused telemetry and oximetry when acutely ill and against medical advice, in my opinion, would lose all liability rights.

Clinically, the genetic factors with regard to this patient are significant. This patient has a history of kidney stones, which is a genetic disease. Given that she was a rapid metabolizer on cytochrome P450 testing offers further evidence of genetic variations. A patient with a known genetic propensity to stone formation and/or presentation of other intermittent pain-related disease, such as sickle cell anemia or porphyria, and who presented in acute pain would bring an extra risk of aberrant drug metabolism.  

Hydromorphone would be an excellent choice in these pain patients, since it doesn’t utilize the cytochrome P450 system for metabolism. In addition, it is very short-acting, so the every 2-hour dosage you administered would be most appropriate, and in a typical patient, would not accumulate or cause a toxic reaction.

In this case, your patient may have a genetic variation in her mu opioid receptor binding capacity and/or hydromorphone degradation capacity. Unfortunately, genetic testing to determine the presence of genetic variations is only in the formative stages.

Since you detected the hydromorphone accumulation problem and corrected it with naloxone, your patient should be grateful. Her complaint of any injury can only be a guess on her part, and her claim is not provable, as she would have required mental testing before and after the supposed offending event to demonstrate any clinically relevant decline.

Forest Tennant, MD, DrPH

Clinical Advances In Pain Care

I was pleased to see your attention to Ehlers-Danlos syndrome (EDS) and ankylosing spondylitis (AS) with regard to Elvis Presley and Howard Hughes,2-4 but I am concerned that “making a diagnosis does not a cure make.”

As you mentioned, Elvis and Howard Hughes both had at least 1 significant head trauma.2 Additionally, creative individuals like these 2 famous men exhibit greater facility (via altered dopaminergic signaling) in which they moved in and out of REM-like states, which built new cognitive associations that most typical patients may not achieve. In addition, these super-achievers had an ability to subsume normal “stop” signals in their sense of mission (known as passion for the rest of us).

Understanding these distinctions, it would be constructive to mention that amyloid is a structural repair protein, meaning there had to be structural damage, and that autoimmunity (as observed in multiple sclerosis [MS] and similar conditions) would be considered a secondary or tertiary consequence of a prior injury.

This knowledge puts us in a position to look with less bias at the [unpublished] practice of Brendan Stack, DDS, who treats dystonia, and David Williams, DDS, who dissected cadavers of patients with MS, adrenoleukodystrophy, Parkinson’s, and Alzheimer’s diseases.5 In these conditions, hypermobile temporal bone structures, as well as abnormal skull flexion, have been reported in people with MS—a test I replicated.

We have a better foundation to move beyond diagnosis and palliation to slow or arrest the progression of these diseases. For over 25 years, some doctors of osteopathy, doctors of chiropractic, physical therapists, dentists, and myofunctional (breathing) therapists have met and collaborated in treating small numbers of similar cases employing the ALF (advanced lightwire functional) appliance.6

A more comprehensive understanding of the consequences of head trauma, and how the incomplete natural reparative processes and predisposing factors like genetics, and gestational hypovitamin D3 result in clinical manifestations of EDS and AS, would enable collaborative treatment approaches that more closely align with the underlying disease processes.

Unfortunately, as we are learning with AS to Alzheimer’s, the most effective therapy may involve a more comprehensive understanding of the body than fits within our Western specialty-based system, as well as lifestyle changes and ongoing supportive therapies that don’t lend themselves to traditional research protocols.

We also see the potential to intercept many associated diseases before they become clinical and life-threatening (like ALS). Practical Pain Management has done a superb job of bringing together the most critical components of pain diseases, and it is our hope that you will continue to showcase so many seemingly unrelated aspects of chronic pain.

Darick Nordstrom, DDS
Fallbrook, California

Dear Dr. Nordstrom,

Your observation about arriving at a better clinical foundation to slow or stop the progression of some neurologic diseases, including head trauma and similar pain conditions, is most welcome. I agree; it is time to face the fact that, heretofore, pain management has largely been one of symptomatic treatment. Even in my own practice, I have seen less disease progression because of our utilization of neurohormones and nutrition.  

Would you please share more detail on your work for readers of this journal? The use of ALF therapy holds promise as a nonpharmacologic approach to pain relief that should be shared with frontline pain practitioners as case studies or in a review of treatment. Also, your comment that “making a diagnosis does not a cure make” is accurate. To help move this challenge along, might I suggest that every pain practitioner ask about every pain patient, “What am I doing to slow the disease process and promote neuroregeneration?”

Forest Tennant, MD, DrPH

Intractable Pain

I just read the article on Intractable Pain, by Forest Tennant.7 This is the best, most accurate presentation of the topic that I have ever come across. I say this because it describes my own pain circumstances very closely. I have had chronic pain—both idiopathic and due to physical trauma, and hypogonadism, excess cortisol, and high blood pressure. And yet, I haven’t found a single physician in the state of Washington who understands the issue so clearly as it was presented in this article.

Sean Lengyel, MBA, DEd Candidate
Seattle, Washington

Dear Sean,

In medicine, we normally describe the severity of a disease or condition as mild, moderate, or severe, acute or chronic. All astute physicians, however, recognize that among any group of patients with a similar medical condition, there are some who experience a super-severity of pain. Sometimes these patients won’t get sufficient attention because they are outliers, which require expense, time, study, and an abundance of understanding. This is often the case with patients who face intractable pain.

About 30 years ago, long before chronic pain management became a major issue, I and a few other physicians recognized the existence of a “super-severity” group of chronic pain patients. These patients demonstrated autoimmune and hormonal disturbances that were reflected in their serum labs. High dosages of opioids were needed to control their pain, or they were rendered totally non-functional and incapacitated.

In 1990, this recognition of hyper-severe pain led to the passage of intractable pain treatment laws in Texas and California. There was no appreciable controversy in this classification, as diagnosing intractable pain was clinically obvious and the patients were extremely ill and hardly noncompliant or abusive with their prescribed pain medication.

In those days, opioid medication was inexpensive, with no concerned party looking to deny these patients access to whatever dosage was required or a need to punish doctors who were willing to prescribe the opioids to these patients in severe pain.

After the turn of the 20th century, an industrial and commercial drive to treat pain was approached as an opportunity to generate profits. Along came the 5th vital sign, the Decade of Pain,8 emergence of professional organizations, new opioid formulations, and a generalized push to provide opioids to patients in a one-size-fits-all manner.

In addition, there has been too little effort within the pain profession to formalize a pain category of super-severe. The super-severe or intractable pain patient is hardly appreciated and not formally accepted.

Fortunately, behind-the-scenes research in recent years has offered an explanation as to why some unfortunate individuals, such as you, develop a super-severity pain state. As we are beginning to understand, some painful conditions will activate microglial cells, leading to neuroinflammation and embedding the memory of pain in the central nervous system.

This process may lead to a cascade of pathologic events, including constant, 24-hour pain, fatigue, depression, insomnia, anorexia, and endocrine abnormalities—all symptoms typically experienced by the intractable pain patient.

Recently, most of the common underlying causes of super-severity in centralized pain have been identified such as adhesive arachnoiditis, reflex sympathetic dystrophy (chronic regional pain syndrome), genetic connective tissue disease, post-viral autoimmune disorder, and post-stroke/traumatic brain injury. Clinical protocols to treat centralized pain and neuroinflammation with agents and measures other than purely symptomatic drugs such as opioids are under development.

Despite great advances in the understanding and treatment of intractable pain conditions, the wider pain community has not embraced the concept of super-severe chronic pain. In lieu of a better descriptor, I still refer to the super severe pain patient as intractable, but I would gladly adopt another name were there general recognition and consensus that this special group of patient outliers exists and is in need of specialized pain care.

Forest Tennant, MD, DrPH

Adrenal Suppression

I read the article on adrenal suppression among chronic pain patients who fail standard treatment by Dr. Tennant.9 For the last month, I have had a very unusual experience that is best described by an article, Adrenal Suppression From Topical Corticosteroids Surprisingly High, which I found online.10

I have been using hydrocodone (17.7 mg to 30 mg daily) to treat a bad case of groin fungus, which worked, but on the 15th day, my body from the neck to my toes erupted in pimples, welts, and hives that wouldn’t resolve. My doctor said he has never seen such an attack in his 35 years. 

Could there be a connection between low adrenaline and this skin reaction? My doctor reduced the hydrocodone to 7.5 mg per day. While my physician is not a pain specialist, he offered to become better acquainted with the recommended treatment for adrenal suppression. Any insights that I could pass along would be most helpful. 

Robert Zornes
Wishram, Washington

Dear Robert,

It is well known that both severe, chronic pain and opioids may suppress serum adrenocorticotropic hormone (ACTH) and cortisol. In a patient, such as yourself, it is not possible to precisely determine which factor—pain or opioids, or both—may be the cause of adrenal suppression.

Without knowing your specific serum hormone levels, it is not possible to positively determine the causation of the skin breakout. However, it is likely that the cumulative combination of topical corticosteroid, pain, and opioid therapy further suppressed ACTH and cortisol, resulting in an allergic reaction or infection. The pimples may be indicative of a hormone imbalance that may lead to a relative increase in testosterone.

Your experience highlights an important issue in pain management and the use of opioids. When opioids must be taken daily, it is common for endocrine suppression to result. While testosterone deficiency is the best-known hormone disruption, daily opioids also may suppress a number of other hormones, including cortisol, dehydroepiandrosterone (DHEA), pregnenolone, estradiol, and progesterone.

If a corticosteroid must be taken for an ancillary medical condition, use should be limited to no longer than about 7 days or additional suppression of ACTH and serum cortisol may be quite severe.

In your case, you were using a steroid for 15 days, which is too long for a chronic pain patient on opioids. Should a chronic pain patient need a potent or long-acting opioid on a daily basis, the physician should periodically order a hormone profile so a deficiency of any hormone(s) will be identified and replenished. This is critical since hormone deficiencies may cause opioids to provide poor analgesia as well as fatigue, depression, and mental impairments.

Forest Tennant, MD, DrPH


Traumatic Brain Injury

I have been reading about traumatic brain injury (TBI) in Practical Pain Management.11 Of greatest interest was the article about Elvis and his head trauma,2,3 as I am experiencing similar symptoms as a result of martial arts and military traumas, a brain tumor, and epilepsy injuries.

My doctors in Utah have not been able to provide me with any relief so I wonder if you might be able to suggest how I might lessen my pain? In addition to TBI, I was recently diagnosed with lupus, and now gastroparesis, leaving my digestive tract completely paralyzed such that I require total parenteral nutrition for meals and I receive my medications intravenously.

Charli Gordon
Roosevelt, Utah

Dear Charli,

It seems that your medical history of multiple insults to the central nervous system is one that has, to date, stymied the physicians you have sought out for pain relief. Fortunately, we now have some solid research and clinical experience to begin helping most people who experience TBI.

First, you describe a syndrome or pattern of pain sequelae that may occur with brain injury regardless of cause, including stroke, trauma, infection, and toxin exposure (see Figure). The pathologic result may include pain, pituitary abnormalities, autoimmune manifestations, and autonomic nervous system dysfunction. Pain resulting from brain insult may manifest in the form of a headache, upper torso pain, or fibromyalgia-like (“all-over”) pain.

Injured central nervous tissue may activate microglial cells, leading to neuro-inflammation. Pituitary abnormalities may result, producing fatigue, immune and sexual impairment, and interference with pain-relieving medications. We understand now that neuroinflammation may generate waste that enters the general circulation, producing autoimmune manifestations such as a lupus state, which you report.

In addition, various autonomic nervous system dysfunctions may occur, such as vagus nerve impairment. This often results in gastrointestinal motility disturbances and malabsorption of some drugs and nutrients.

In my opinion, you might want to ask your doctor to order a blood test to assess serum inflammatory and autoimmune markers and hormone deficiencies. A basic treatment regimen should include medication for pain relief and simultaneous hormone replenishment for any deficiencies. Secondarily, you may benefit from some of the new approaches used to control neuroinflammation and promote neurogenesis (nerve growth).

Unfortunately, the medical protocols and regimens for neuroinflammation control and neurogenesis are in the formative (early) stages, so a specific medical regimen cannot be recommended at this time. The new approaches, however, will include glial cell modulators, anti-neuroinflammatory agents, neurohormones, and cranial electric stimulation. These are worth discussing with your pain management specialist.

Forest Tennant, MD, DrPH

Last updated on: June 17, 2020
Continue Reading:
Migraine Treatment: What’s Old, What’s New

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