Method of fentanly administration for postoperative pain relief

A method of postoperative pain relief using transdermal delivery of fentanyl or its analgetically effective derivatives preceded by a dose of said material to increase the serum drug levels to steady state more quickly.

FIELD OF THE INVENTION 
This invention relates to the administration of analgesics. More 
particularly, this invention relates to the administration of fentanyl and 
its analgetically effective derivatives for analgetic purposes. Still more 
particularly, but without limitation thereto, this invention relates to 
the transdermal administration of such materials supplemented with a bolus 
dosage thereof. 
BACKGROUND OF THE INVENTION 
Fentanyl and its analgetically effective derivatives such as sufentanil, 
carfentanil, lofentanil and affentanil are classified in the art as being 
extremely potent narcotic analgesics and are used extensively as 
anesthetics. Fentanyl is described in U.S. Pat. No. 3,164,600 and its use 
as approved by the FDA in the United States is described in the 1984 
Physician's Desk Reference, pages 1027 through 1029 with reference to the 
drug SUBLIMAZE.RTM. manufactured by McNeil Lab for Janssen Pharmaceutica, 
Inc. 
In use, fentanyl is commonly administered as the citrate, either as a bolus 
injection or infusion or a continuous infusion for the purposes of 
producing anesthesia. More recently, transdermal delivery of fentanyl and 
its analgetically effective derivatives has been accomplished and one such 
transdermal delivery system is disclosed in U.S. Pat. No. 4,588,580, which 
is incorporated herein by reference. The advantages of transdermal 
delivery is the ability to continuously deliver the drug at analgetically 
effective rates over an extended period of time. This system has proven to 
be successful, as reported by P.M. Plezia, J. Linford, T.H. Kramer, R.P. 
Iacono, and S.R. Hameroff, in Transdermal Therapeutic System (Fentanyl) 
for Postoperative Pain: An Efficacy, Toxicity, and Pharmacokinetic Trial, 
ASA Abstracts, A210, Anesthesiology, vol. 65(3A), (September, 1986). 
In use,fentanyl transdermal systems exhibit a delay or "lag time" between 
the application of the transdermal delivery device and the onset of 
analgesia. Thus, transdermally administered fentanyl serum concentrations 
take longer to attain their plateau in comparison to intravenous 
administration primarily because of the requirement to saturate the drug 
binding sites in the skin. In effect, the skin beneath the transdermal 
system acts as a presystemic compartment, delaying the onset of systemic 
drug absorption. This lag time may present a problem in certain instances 
where fentanyl is being used to relieve postoperative pain. Similar 
problems may also occur with the analgetically effective derivatives of 
fentanyl. 
SUMMARY OF THE INVENTION 
An object of this invention is to provide an improved method of 
administration of fentanyl and its analgetically effective derivatives for 
the relief of postoperative pain. 
A further object of this invention is to reduce or eliminate the lag time 
to onset of analgesia experienced with transdermal delivery of fentanyl 
and its analgetically effective derivatives. 
These and other objects are accomplished by the present invention wherein 
the transdermal delivery of fentanyl and its analgetically effective 
derivatives is supplemented with a 100 to 300 .mu.g dosage of fentanyl and 
its analgetically effective derivatives.

DESCRIPTION OF THE PREFERRED EMBODIMENT 
As described in U.S. Pat. No. 4,588,580, incorporated herein by reference, 
it was found that fentanyl and its derivatives could be delivered 
transdermally to induce analgesia. To achieve this with fentanyl, 
administration should be range of from about 10 to 300 .mu.g/hr, with the 
preferable analgetically effective rate being within the range of about 25 
to 150 .mu.g/hr. The effective rates for the other derivatives will vary 
depending on potency as described in the above referenced patent. 
Transdermal administration is maintained at least until the patient 
recovers from anesthesia ,with a 1 to 3 day regimen being typical. 
Transdermal fentanyl delivery devices can be provided having varying 
effective durations, typically form 1 to 7 days. If analgesis is required 
for a time period greater than the duration of the device, continuous 
analgesia can be obtained by removing the depleted device and applying a 
fresh device preferably at a different location on the skin. 
When fentanyl is administered as described in U.S.Pat.No. 4,588,580, 
certain patients exhibited a lag time of about 12 hours before 
analgetically effective serum drug levels were achieved. This was too long 
to achieve analgesia when recovering from anesthesia after short duration 
surgical procedures. Part of this lag time can be taken care of according 
to our invention by placing the transdermal system on the patient prior to 
anesthesia and surgery. This, coupled with a 100 to 300 .mu.g dose of 
fentanyl given at the induction of anesthesia provides analgetically 
effective serum drug levels when pain relief is needed, even for short 
duration procedures. In this manner, transdermal fentanyl administration 
functions as maintenance therapy. The dosage may be higher than 300 .mu.g 
if necessary, but for most situations a 100-300 .mu.g range is suitable. 
This dose will be different for other derivatives based upon their 
relative potency as indicated in Table 1. 
TABLE 1 
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RELATIVE POTENCY 
DRUG (Fentanyl = 1) 
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(1) Fentanyl 1 
(2) Sulfentanyl 
15 
(3) Carfentanyl 
34 
(4) Lofentanyl 
15 
(5) Alfentanyl 
0.25 
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The preferred embodiment of this invention comprises an intravenous 100 to 
300 .mu.g dose of fentanyl or its analgetically effective derivatives such 
as sufentanil, carfentanil, lofentanil and alfentanil. for use in 
conjunction with a general anesthetic such as nitrous oxide. Alternately 
the 100 to 300 .mu.g dose may be epidural when anesthesia is by spinal 
injection. In the latter instance, the dose used can be a low as 50 .mu.g. 
A typical dosage composition is like that commercially available under the 
trademark SUBLIMAZE.RTM. manufactured by McNeil Lab for Janssen 
Pharmaceutica, Inc. 
A serum concentration of fentanyl within the range of 1 to 3 ng/ml provides 
effective analgesia. Because fentanyl is rapidly cleared from the body, 
when used in these ranges the serum levels from the initial dosage are 
dropping off as the serum levels from the transdermal administration are 
increasing. 
The following table shows suitable combinations of bolus dosages and 
transdermal delivery rates, it being recognized that there are variations 
from patient to patient and titration to individual patient requirements 
is recommended. 
TABLE II 
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Dose, .mu.g 
Transdermal Rate, .mu.g/hr 
______________________________________ 
100 50 
100-200 75 
200-300 100 
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It is preferable to vary the time of placement of the transdermal system, 
rather than increase the dosage of fentanyl at the induction of 
anesthesia. Effective serum fentanyl concentrations can be obtained by 
applying the transdermal system no later than the induction of anesthesia, 
ie. either simultaneously or before induction of anesthesia . This early 
placement will provide the plasma level needed while avoiding unacceptable 
respiratory depression. 
The full scope of this invention can be best understood in light of the 
following example. 
EXAMPLE I 
Ten adult patients undergoing elective shoulder surgery with regional 
anesthetic were given a 100 .mu.g IV fentanyl dose in conjunction with a 
fentanyl transdermal system capable of delivering 75 .mu.g/hr, placed on 
the anterior chest. The system was left in place for 24 hours. 
The following table provides the average hourly requirement for 
supplemental morphine in patients using the dose/transdermal fentanyl, 
compared with a similar group of shoulder surgery patients who only used 
intravenous morphine by patient-controlled infusion. Patients receiving 
the dose/transdermal fentanyl required significantly less morphine during 
the period of time that the transdermal system was in place, and over the 
first 48 hours of postoperative narcotic use 
TABLE III 
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Postoperative Morphine Requirements 
(mg morphine/patient/hr) 
Time Transdermal fentanyl 
IV Morphine Only 
______________________________________ 
0-12 hrs 0.78 + 0.6 1.69 + 1.0 
13-24 hrs 0.17 + 0.3 1.51 + 1.1 
25-36 hrs 0.92 + 0.8 1.32 + 1.0 
37-48 hrs 1.00 + 0.7 0.47 + 0.5 
Overall 0.70 + 0.4 1.35 + 0.9 
______________________________________ 
This data was reported by R.A. Caplan, L.B. Ready, G.L. Olsson and M.L. 
Nessley, "Transdermal Delivery of Fentanyl for Postoperative Pain 
Control", Anesthesiology, vol. 65(3A), (September 1986), said research 
being conducted under the sponsorship and according to protocols provided 
by Alza Corporation (Palo Alto, CA). 
This invention has been described in detail with particular reference to 
certain preferred embodiments thereof, but it will be understood that 
variations and modifications can be effected within the spirit and scope 
of the invention.