Oxycodone

Oxycodone Postoperative Analgesia

Pharmacological Musings

Mark Anderson

Oxycodone is now a very commonly used orally administered opioid for acute postoperative pain. The efficacy of its oral administration appears to compare to that of PCAIV and neuraxial morphine after caesarean section and it has become a favoured drug of postcesarean analgesia in Australia. Rectal oxycodone for postcesarean analgesia is particularly popular in Australian hospitals.

Despite this widespread use, oxycodone remains relatively poorly studied for postsurgical and postcesarean acute pain. The choices of dose, dosage interval and formulation vary widely. I have been unable to find any work on rectal oxycodone after surgery apart from Seaton's paper on its effect on breastmilk . KP Leow of Brisbane has published much good work on oxycodone pharmacokinetics (including rectal 30mg) in palliative care patients which I shall refer to later.

Paech et al recently published the results from the SMOOTH trial which compared oral oxycodone analgesia to intrathecal morphine for post cesarean analgesia. They concluded oxycodone analgesia is a satisfactory means of analgesia, but some subjects recorded high pain scores and satisfaction was less with the oral oxycodone regimen.

Paech et used 20 mg Oxycontin® then followed with 10 mg of IRO 6 hourly, with 10 - 15 mg IRO 2 hrly prn.

They conceded in the paper that:

ﬁxed dose regimen of oxycodone cho-
sen empirically was not optimal and that different doses
or dose intervals or combinations of immediate and sus-
tained release oxycodone might prove more effective or
reduce side effects.

I have therefore explored the pharmacokinetics of oxycodone using the available pharmacological literature , pharmaceutical product information and the online pharmacokinetic calculators of David Bourne (www.boomer.org). I hope to formulate a regimen that readily achieves and maintains a plasma level of oxycodone.

In my calculations and estimations I have made some approximations:

the "desirable" plasma level of oxycodone in the first 24 hours after abdominal surgery is between 30 and 40 ng/ml (= .03 - .04 mg/L). The "desirable" level decreases over the subsequent days after surgery.

the bioavailability (F) of oral oxycodone is 0.7

the elimination half life of oxycodone is 4 hours, (the elimination constant K_el = 0.175 h^-1)

the absorption half life of immediate-release oxycodone is 0.7 h in volunteers, but I have estimated it is twice that in patients who have had neuraxial fentanyl and surgery (the absorption constant K_ab = 0.5 h^-1).

the absorption half life of controlled release oxycodone in volunteers is 7 hours but I have estimated it is twice this after surgery and neuraxial fentanyl. (the absorption constant K_ab = 0.05 h^-1). (The time to peak plasma concentration after CR oxycodone is 3 hours, but this value does not figure in my calculations.)

the volume of distribution V_d of oxycodone in an 80 kg subject is 250 L.

This graph (illustrating 10 mg IRO at 6 hours followed by a 15 mg IRO at 8 hours) shows that the SMOOTH regimen may have resulted in excessive troughs and peaks due to too widely spaced regular oxycodone and too heavy a dose of rescue

Paech used an initial dose of 20mg of Oxycontin. The time to peak effect in volunteers is 3 hours and the absorption halflife is about 7 hours. The time to peak effect after Oxycontin is hastened by a third of the tablet being rapidly absorbed.

^{This graph estimates the time course of plasma concentration of oxycodone after 20 mg controlled release oxycodone.}
CR oxycodone 20 mg seems unlikely to produce 40ng/ml within 2 hours, and indeed Oxycontin product information itself ¹ indicates that the Cmax is only 21 ng/ml.

It is notable that this product information warns against its use for acute postoperative pain.

After skipping throught the pharmacological mathematics², we can estimate the 3 hourly dose of oral oxycodone to achieve al evel of 40 ng/ml

= [ .04 * 250* 0.175*3] / 0.7 = 7.5 mg

Again, I'll skip throuugh the maths to state that a loading dose can be calculated with

where R = e^{-kel * [[tau]]}= e^-0.175*³= 0.59
^{Thus Loading Dose = 7.5/[1 - 0.59] = 18.29

So according to pharmacokinetic modelling , a loading dose of immediate release oxycodone 20 mg tablet should achieve around 40 ng/ml.

This calcualtion is supported by Lalovic et al³ : 20 mg oral doses of oxycodone to 4 volunteers led to peak plasma levels of 43 (±12) ng/ml .

It thus seems reasonable to offer 20 mg or IR oxycodone after caesarean section as it will achieve a level of 40 ng/l in about 2 hours: a time when the spinal bupivacaine is wearing off.

An Excel based pharmacokinetic calculator devised by D. Bourne can estimate and demonstrate the plasma levels of oral oxycodone.}

This graph estimates the time course of plasma concentration of oxycodone after 20 mg immediate release oxycodone.

The graph of plasma levels after 20 IRO show 40 ngml is reached in 2 hours, and fall below 30 ng/ml at 5 hours.

By considering the pharmacokinetics of both IRO and CRO I think we can can construct a more accurate "ball park" of oxycodone analgesia for caesarean section.

In the case of caesarean section with 12 mg bupivacaine and fentanyl anaesthesia we can expect 20 mg IRO will produce 40 ng/ml when the spinal wears off. At around 4 hours would seem an appropriate time to give a next oral dose because our calculations estimate that at 5 hours the plasma concentration will fall below 30 ng/ml and it takes 1 hour for IRO to have maximum effect.

The Excel calculator demonstrates that a 10 mg dose of IRO should promptly increase plasma concentration to over 40 ng/ml:

A 5 mg dose does little to the plasma concentration apart from maintaining it at the level at the time of ingestion for a brief time:

A second dose of 10 mg oral oxycodone at 8 hours will sustain levels further, but not excessively:

At around the 12 hour mark, the plasma level trends below 30 ng/ml. It is at this point that CRO 20 mg may be an appropriate choice to enable a comfortable night's rest at levels around 30 ng/ml:

Plasma concentration of oxycodone after 20 mg controlled release at 12 h

A comments from patients on the first postoperative day (i.e. after 24 hours) suggest that 10 mg of IRO may be too sedating or nauseating for many. This is a time when patietnst are keen to mobilise, shower, and independently care for their new baby. The paper of Kharash et al indicates that volunteers experience considerable reduced alertness and sedation when plasma levels exceed 10 ng/ml, wich typically lasts 6 hours after 15 mg IRO.

Ten mg CRO may be a more appropriate dose on the first postoperative morning: this dose will maintain levels around 10 ng /ml, but without high peak levels.

On this day of mobilisation tramadol for supplementary analgesia may be a better choice with its less sedating effects. Possible a 5 mg dose of CRO may be appropriate for the second and third postop days.

Rectal Oxycodone

Rectal oxycodone 30 mg has been widely used for many years in metropolitan Melbourne. This is despite it being a remarkably little studied formulation. Leow⁴et al studied it in cancer patients and found its bioavailability to vary greatly between individual patients from as low as 0.16 to as high as 1.0.

notes

¹http://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?id=3253

²http://www.boomer.org/c/p1/Ch15/Ch1503.html

³CLINICAL PHARMACOLOGY & THERAPEUTICS
MAY 2006

⁴REGIONAL ANESTHESIA AND PAIN MANAGEMENT LEOW ET AL. ANESTH ANALG
IV-RECTAL OXYCODONE IN CANCER PATIENTS 1995;80:296-302