Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

Trial Examines 5-HT3 Antagonist for Opioid Withdrawal

Anesthesiology News has an article describes a study looking at the use of ondansetron (Zofran), a 5-HT3 receptor antagonist, to treat opioid withdrawal. There are some interesting related points.

According to primary investigator Sean Mackey, MD, PhD, chief of pain management, and associate professor at Stanford University School of Medicine, in Stanford, Calif., studies in mice have shown that 5-HT3 receptors are triggered by opioid withdrawal (Hum Psychopharmacol Clin 2008;28:189-194). To examine whether ondansetron also can help relieve opioid withdrawal symptoms, Dr. Mackey and his team enrolled nine chronic pain inpatients at Stanford’s Comprehensive Pain Interdisciplinary Pain Program. Subjects had a diverse set of diagnoses and used a variety of opioids, including methadone, oxycodone and hydrocodone. Morphine-equivalent daily doses at the time of admission ranged from 0 to 1.178 g, and between 0 and 40 mg on the day of opioid withdrawal. The study included three women and six men (average age, 44 years).[1]

The 5-HT3 receptors include:

GABA (Gamma-AminoButyric Acid) receptors. Drugs that stimulate GABA include: alcohol, barbiturates, benzodiazepines, etomidate, and propofol.

Nicotinic acetylcholine receptors, which are stimulated by acetylcholine, choline, nicotine, succinylcholine (suxamethonium in Commonwealth countries) and varenicline (Chantix).

Serotonin – SSRIs (Selective Serotonin Reuptake Inhibitors) and other anti-depression drugs.

There are a lot of different potential effects that might result from treatment with ondansetron. Too much hedging? No. We are still learning a lot about this drug.

Pennsylvania has a protocol that includes ondansetron as an optional drug – 4 mg IM, oral dissolving tablet, or slowly IV (over 2-5 minutes)[2] to patients 14 years old or older with nausea/vomiting.

Anything with so many different effects should be expected to produce some unusual effects.

Here is the part that you might want to sit down for, if you weren’t paying attention as you read the quote. This is also the part I find most interesting.

Subjects had a diverse set of diagnoses and used a variety of opioids, including methadone, oxycodone and hydrocodone. Morphine-equivalent daily doses at the time of admission ranged from 0 to 1.178 g

The morphine equivalent means the dose of morphine that would be expected to produce the same effect as the dose of the drug that is not morphine that the patient is taking. For example, 1 mg hydromorphone (Dilaudid) is about a 5 mg morphine equivalent, because 1 mg hydromorphone is expected to have the same effect as 5 mg morphine.[3]

I am familiar with a slightly different conversion that would lead me to be using hydromorphone more often under those protocols.

Why is someone with a daily dose of zero mg going through withdrawal. I have not seen the full study. The article only mentions the presentation at a conference. So, I do not have any details on that. I would expect them to use the most recent morphine equivalent, if the patient is experiencing withdrawal.

Anyway, here is the interesting part.

1.178 grams

1.178 grams is the equivalent of 1,178 mg morphine per day.

That is the equivalent of just under 50 mg morphine per hour (49.1 mg) – every hour.

This is what was being used to manage baseline pain and maybe to get high as well. We don’t know. We do know that the person is seeking help at an addiction treatment program.

What if this patient is not seeking treatment for addiction and the patient has a valid prescription for the doses of opioid being taken?

Remember that there is no maximum dose for morphine, or for any other opioid, as long as there are no adverse effects, such as depressed respirations, altered mental status, hypotension, or bradycardia.

What do we do when this patient has something like a femur fracture that produces severe pain?

This patient is opioid tolerant, so the standard doses of opioid are unlikely to produce a satisfactory effect.

The patient will probably receive more relief by releasing some flatulence than he will from 2 mg morphine. The flatulence may even provide more benefit than 10 mg morphine.

Standard doses are not going to work, so do we just ignore this patient’s pain?

Do we tell this patient that our medical director does not trust us to give larger doses of morphine/fentanyl/hydromorphone than standard, because the medical director either has not really considered this possibility or doesn’t think that patients, who are legally prescribed high doses of opioids, deserve to have their severe pain treated effectively. Or maybe the medical director is just so irrationally afraid of opioid medications that he is not interested in understanding tolerance.

It isn’t necessarily the medical director who is the obstacle to treatment. I know of plenty of medics who would not even start treatment of this patient’s pain. Maybe out of fear of causing respiratory depression. Maybe out of fear of causing addiction, in which case they really need to work on their response time, because it is a bit late to be considering that.

What do you think are the chances of causing dangerous respiratory depression for this patient:

With 10 mg morphine?

Low Medium High

With 20 mg morphine?

Low Medium High

With 30 mg morphine?

Low Medium High

With 40 mg morphine?

Low Medium High

With 50 mg morphine?

Low Medium High

With 60 mg morphine?

Low Medium High

With 70 mg morphine?

Low Medium High

With 80 mg morphine?

Low Medium High

With 90 mg morphine?

Low Medium High

With 100 mg morphine?

Low Medium High

Why?

Footnotes:

[1] Trial Examines 5-HT3 Antagonist for Opioid Withdrawal
David Wild
Anesthesiology News
July 2010
Registration may be required, but registration is free.
Article

[2] Nausea/Vomiting
Pennsylvania Statewide Advanced Life Support Protocols
Pennsylvania Department of Health Bureau of Emergency Medical Services
Effective November 1, 2008
Page 96/121 in pdf counter
Page with link to the full text PDF of the protocols.

[3] Morphine Equivalents
My Variables Only Have 6 Letters
By Christopher
Article

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