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Letters to the Editor: Pregnenolone, Acute Porphyria, Opioid Calculator, Arachnoiditis

January/February 2015
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Pregnenolone Dosing

Is there any clinical significance between dosing pregnenolone once a day vs twice daily (bid)? I have a patient who is a 36-year-old white male. His pregnenolone level measured 11 (range 12-208); dehydroepiandrosterone (DHEA) measured 323 (range 61-1636). I started him on a dose of 50 mg pregnenolone bid. The patient complained of excessive hair loss within a few days of starting pregnenolone replacement therapy. I reduced the dosage to 25 mg/d taken in the morning. He reported that his hair was no longer coming out in clumps, but he complained of new-onset insomnia since starting pregnenolone. Can you comment on either of these complaints?

Robert L. Anglin, CPhT

Dr. Anglin,

Your question about pregnenolone is a critical one. I have learned that dosing pregnenolone isn’t as simple as it first appears. After considerable trial and error, I’ve settled on a starting dose of 50 mg bid—but as you noted with your patient, this may not be optimal for all patients. Some patients who ingest too much pregnenolone can become very ill with dysphoria, confusion, headache, and dizziness. On the other hand, some patients with very low serum pregnenolone levels seem to adjust to trace amounts—so even a low starting dose can make them ill.

Your patient on pregnenolone is rather typical. His level was 11, which is marginal. Some patients are extremely sensitive to pregnenolone and I’ve learned to start them at about 25 to 50 mg a day. Also, better pain control usually elevates pregnenolone so supplementation isn’t needed longterm.

Thanks for a most informative case report. Please let me know your experiences.

Forest Tennant, MD, DrPH

Acute Intermittent Porphyria

I am seeking your expertise about the management of episodic pain and drug withdrawal.

I have a young woman with acute intermittent porphyria diagnosed 12 years ago. Since then she has been receiving opioids for the management of acute attacks of porphyria, which is precipitated by her menses and other stressors.

The problem arises when the attacks are over and she needs to stop the opioid. The withdrawal symptoms precipitate another attack forcing her to keep taking medications unnecessarily. She does not want to be labelled a drug addict, therefore we worked together over the years to manipulate around the pain and the withdrawal by different means, none of them worked effectively. We tried Ultram, Xanax, herbs, morphine extended release, and others.

I am asking for help in managing the periods between the attacks with minimal opioids, as much as possible.

Azza Kenawy, MD

Dr. Kenawy,

You present a dilemma that has simply not been addressed—that is, the patient who has intermittent severe pain that requires opioids. Besides porphyria, you can put chronic pancreatitis, sickle cell disease, and migraine or cluster headaches in this category. Here are some of my thoughts and experiences. 

First, porphyria is a rare disease. I’ve had 3 cases referred to me in recent years. All 3 patients died before age 60.  All 3 chose to take daily opioids to prevent severe attacks. I’ve had some luck with chronic pancreatitis, migraine, and sickle cell patients by prescribing them transmucosal fentanyl (Actiq, Fentora, Subsys) or injectable morphine, meperidine, or hydromorphone. Patients have been instructed to use these potent opioids at the first sign of an attack or flare.  I’ve sometimes mixed methylprednisolone with the injectable. 

Also, early, aggressive treatment prevents opioid withdrawal problems, which I believe occurs after about a week of opioid administration.

I’m currently experimenting with cortisol sub-replacement as a means to prevent acute attacks. Many of the migraine and other patients who have severe intermittent attacks have low serum or saliva cortisol levels. I’m encouraged, but it’s too early for me to make any claims. I’m hopeful, however, that maintenance with hydrocortisone or cortisol (5 to 15 mg a day) will prevent painful attacks that require opioids.

In closing, let me compliment you on dealing with one of the most difficult problems in pain management.

Forest Tennant, MD, DrPH

Opioid Calculator

I have a question about the PPM opioid calculator. I notice that the result differ greatly when I calculate using fentanyl intravenous (IV) and fentanyl transdermal (TD) either to or from other opioids. Why is that?  TD patch is 97% absorbed so calculation should be the same.


100 mcg/hr IV fentanyl coverts to 10 mg/hr of IV morphine

100 mcg/hr TD fentanyl coverts to 2.5 mg/hr of IV morphine.


Mary Morris, MD

Dr. Morris,

Thank you very much for identifying this issue and for writing. The IV to transdermal fentanyl conversion is generally thought to be 92%. According to the original Duragesic TD Reservoir patch package insert, “Clinical trials indicate that the skin does not appear to metabolise fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation.” Although this data is for the reservoir patch, they are presumably bioequivalent to the matrix technology.

The PPM Opioid Calculator is intended for patients receiving chronic opioid therapy when converting from one opioid to another. An opioid naïve patient receiving IV fentanyl for an acute surgical intervention does not fit into that category.

You are correct that the conversions to/from fentanyl transdermal patches are out of sync when compared with IV fentanyl. This is because two separate equations have been used to keep the transdermal fentanyl conversions very conservative when going to/from a transdermal patch. In part this was done because of the tremendous absorption variability with transdermal products, as published within the package insert.

The 1:100 ratio of morphine to fentanyl is the only available conversion that we can reference, as accepted by the American Pain Society. In general, we do not recommend using the calculator for acute care opioid conversions.

Jeffrey Fudin, BS, PharmD

Albany, New York

Arachnoiditis Management

I am currently conducting a “Designated Doctor” Workers’ Comp Exam on an injured worker that has arachnoiditis. The patient was injured in 2005, which led to lumbar laminectomy with fusion and cage hardware in 2007 and removal of hardware in 2009. Current motion films show solid fusion from L4 to sacrum.

Last updated on: May 12, 2015
First published on: January 31, 2015