We appreciate both Dr. Boezaart’s interest and his concern. The facts do indeed speak for themselves. The adverse event figures as quoted above (from the abstract) were for all groups, which included the ivPCA morphine arm. This highlights an important point that we hope we made clear in our discussion, but welcome the opportunity to emphasize. Morphine produces similar adverse effects regardless of the route of administration. The incidence of side effects in all groups should be taken in the context of the study protocol, where no prophylaxis with drugs such as ondansetron was allowed. Further, DepoDur was not dosed according to age, but rather by random assignment.

Because no significant differences were observed between groups in the adverse events cited above, they were reported in aggregate. More specifically, adverse events for each subgroup (ivPCA morphine, DepoDur 20mg and DepoDur 30mg), as provided in the supplementary material (appendix Table E2)[1], were as follows: Nausea: ivPCA (76%); DepoDur 20mg (77%); DepoDur 30mg (82%); p=0.7 Vomiting: ivPCA (35%); DepoDur 20mg (41%); DepoDur 30mg (54%); p=0.13 Hypotension: ivPCA (29%); DepoDur 20mg (39%); DepoDur 30mg (39%); p=0.45 Hypoxia: ivPCA (9%); DepoDur 20 mg (4%); DepoDur 30mg (9%); p=0.56

Supplemental oxygen is recommended to prevent the well-described reductions in oxygen saturation associated with ivPCA morphine use [2]. However, all three groups experienced decreased oxygen saturation with similar frequency (ivPCA, 36%; DepoDur 20mg, 27%; DepoDur 30mg, 32%; p=0.63) [1]. Consequently, supplemental oxygen should be considered for all patients, but especially elderly patients, receiving opioids.

Our conclusion remains: “With appropriate patient selection and monitoring, perioperative single-dose epidural DepoDur was a safe and effective analgesic alternative to postoperative intravenous patient- controlled analgesia following knee arthroplasty,…”. Inherent in this statement is the assumption that the “gold standard”, ivPCA morphine, can be administered in a safe and effective manner. It cannot be overemphasized that the risk of respiratory depression with opioids is increased in the elderly. DepoDur is not recommended in patients over 65 years of age in doses exceeding 15mg.

References:

1. Hartrick CT, Martin G, Kantor G, Koncelik J, Manvelian G. Evaluation of a single-dose, extended-release epidural morphine formulation for pain after knee arthroplasty. J Bone Joint Surg Am 2006;88:273-281 (http://www.ejbjs.org/cgi/content/full/88/2/273/DC1).

2. Stone JG, Cozine KA, Wald A. Noctural oxygenation during patient- controlled analgesia. Anesth Analg 1999;89:104-10.

To the Editor:

It is with interest and concern that I read the article by Hartrick, et al, concerning Extended Release Epidural Morphine(1).

The authors should be commended on this well-executed and well- written study. Although the facts speak for themselves (160 of 162 patients experienced adverse events, highlighted by 78% nausea, 43% vomiting, 36% hypotension and 32% hypoxia, while 96% of these mostly elderly patients required supplemental oxygen), the authors conclude that “...epidural DepoDur was a safe and effective analgesic alternative...”. This is clearly an incorrect conclusion. A more appropriate conclusion should read: “...epidural DepoDur was poorly tolerated and was an unsafe alternative due to severe and frequent respiratory depression...”, and “...the drug was more effective than intravenous PCA for the first 24 hours only...”

I find it surprising that the authors suggest that smaller doses of the drug should be further evaluated, since three of the authors, including a company representative, were co-authors of a similar study on the use of DepoDur for total hip arthroplasty by Viscusi, et al,(2). This study reported very similar results for 15mg DepoDur, and the conclusions of that study were similarly somewhat “softened”.

References:

1. Hartrick CT, Martin G, Kantor G, Koncelik J, Manvelian G. Evaluation of single-dose extended-release epidural morphine formulation for pain after knee arthroplasty. J Bone Joint Surg Am 2006; 88: 273 – 281.

2. Viscusi ER, Martin G, Hartrick CT, Singla N, Marvelian G. Forty-eight hours of postoperative pain relief after total hip arthroplasty with a novel, extended-release epidural morphine formulation. Anesthesiology 2005; 102:1014 – 1022.