In the mad rush by narcotic manufacturers to cash in on the rapidly growing narcotic medication bonanza currently underway in the U.S. and Europe, Endo Pharmaceutical, whose stock has skyrocketed in value by 300% in the last 3 years, has paid physicians connected with several major university medical schools to do what appears to be unethical research for its new long-acting epidural morphine, which lasts roughly 48 hours.

Every study I have been able to find, Endo Pharmaceuticals has been careful not to include any non-narcotic comparator.  This is the same story with its extended release oxymorphone which is about to be approved for release by the FDA.  Of the 15 oxymorphone studies funded by Endo, four compared the oxymorphone to placebos and 11 to other narcotics.  While it is rare for a comparative study to find a narcotic better than a standard NSAID non-narcotic comparator, roughly one third of studies find the non-narcotic comparators to be better than the narcotic with another third finding both drugs equal, but the narcotic causing more side-effects.

Endo and the FDA are guilty of highly unethical behavior, as are the many physicians and institutions colluding in this.  While it has become standard practice for teaching institutions to be heavily dependent on pharmaceutical company research grants and to try their hardest to please pharmaceutical companies in hopes of receiving more grants, this narcotics business is very dirty business.  It is all highly unethical and driven by greed.  The research is there, but no one bothers to look at it.  In 15 studies, morphine was inferior to non-narcotics, in six it was equal, and it was only better than acetaminophen, and nortriptyline by a small margin.  The only drug that morphine was clearly better than was the seizure medicine gabapentin, a poor pain reliever.  The research is extensive.  It is abundant clear that narcotics are not good pain relievers.  At best, they are equal to non-narcotic pain relievers, but they are causing huge amounts of drug dependence in patients and fueling a increasingly destructive black market.

Not only is this unethical, but it would appear to be malpractice.  So far to date, courts have protected doctors and manufacturers.  However, lawyers have not tried to introduce the extensive evidence that narcotics are poor pain relievers and should never have been given in the first place. 

Another Unethical Fentanyl Study From Thomas Jefferson University and Endo Pharmaceuticals: In a 48 hour DB PC study funded by Endo Pharmaceuticals to obtain FDA approval for its DepoDur extended-release epidural morphine (EREM) DepoDur, 200 patients undergoing total hip arthroplasty were given single doses of 15, 20, or 25 mg EREM or placebo. After surgery, patients had access to intravenous patient-controlled analgesia fentanyl for pain relief. All EREM doses reduced fentanyl use vs placebo (510 vs. 2,091 microg; P < 0.0001) and delayed the median time to first dose of fentanyl (21.3 vs. 3.6 h; P < 0.0001). All EREM groups had significantly improved pain control at rest through 48 h postdose (area under the curve [0-48 h]) compared with placebo (P < 0.0005). More EREM-treated patients rated their pain control as good or very good compared with placebo (at 24 h: 90 vs. 65%, P < 0.0001; at 48 h: 83 vs. 67%, P < 0.05). Viscusi ER, Martin G, Hartrick CT, Singla N, Manvelian G: EREM Study Group. Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. . Anesthes 2005 May;102(5):1014-22. Ed: Dr. Viscusi wrote back a very nice email.  He attempts to hold down the amount of narcotics by also using NSAIDs.  However, this is still a bogus study, designed to make Endo's narcotics look good. There is still no evidence that narcotics should be used at all.  Other research has already found that an NSAID (diclofenac) was superior to an opiate (meperidine[Demerol]). It is very likely that DepoDur is also inferior to various NSAIDs like diclofenac.  To needlessly expose humans to two days worth of narcotics is wrong.  An NSAID with no narcotic should have been included to determine whether DepoDur has enough of an advantage over a real pain reliever, not a sugar pill, to offset the disadvantage of priming a narcotic addiction. 

The following e-mail was sent 12/24/05: Dear Dr. Viscusi (above): (It was slightly modified for Dr. Carvalho (below))

I saw your DepoDur study in Anesthesia 2005 May;102(5):1014-22. I am having a hard time understanding why an NSAID was not used as an active comparator. Diclofenac has already been found to be superior to meperidine in patients undergoing hip replacement (Acta Orthop Scand 1985 Feb;56(1):28-31). Using only a placebo comparator appears unethical to me since needlessly exposing humans to 48 hours of continuous powerful narcotics is unethical and not using an active comparator in your research study leaves this issue unresolved for DepoDur. Practicing physicians are left in the ethical dilemma of whether to use DepoDur or a non-narcotic pain reliever with no information upon which to base their judgement, because the EREM group decided not to include an active comparator in all of its studies.

In fact, I suspect that it may have been intentional on the part of Endo to not include an active NSAID comparator. It could make their product look inferior. However, I would think that as an independent physician, their financial concerns cannot influence your ethical decisions on the most reasonable study design. Ibuprofen has also been used with success in hip arthroplasty (Acta Anaesthesiol Scand. 1995 Apr;39(3):323-6). 

I look forward to your response. I did my training in Philly and now practice in western PA.

Sincerely,

Tom Radecki, M.D.

Stanford Helps Narcotic Manufacturer by Comparing DepoDur Only to Another Narcotic for C-Sections:  In a DB study of 75 women having elective C-sections, a single-dose extended-release epidural morphine (DepoDur) of 5, 10, or 15 mg or 5 mg of regular morphine was given at cold clamping after a combined spinal/epidural with intrathecal bupivacaine 12-15 mg and fentanyl 10 mug. Single-dose EREM 10 and 15 mg groups significantly decreased total supplemental opioid medication use and improved functional ability scores for 48 h after surgery compared with those receiving 5 mg of standard morphine. Visual analog scale pain scores at rest and with activity at 24 to 48 h after dosing were significantly better in the 10- and 15-mg single-dose EREM groups. Single-dose, sustained-release epidural morphine in the management of postoperative pain after elective cesarean delivery: results of a multicenter randomized controlled study. Carvalho B, Riley E, Cohen SE, Gambling D, Palmer C, Huffnagle HJ, Polley L, Muir H, Segal S, Lihou C, Manvelian G: DepoDur Study Group. Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA 94305, USA. . Anesth Analg 2005 Apr;100(4):1150-8. Ed: Indoprofen, ketoprofen, and ketorolac have already been shown as effective as narcotics for women undergoing C-sections. Not to have included a similar non-narcotic in this study was, in my opinion, unethical practice. Stanford should be ashamed.  Stanford anesthesiologist has emailed me claiming the morphine is the "gold standard" for C-sections.  I have emailed him back asking for the scientific double-blind studies showing it better than non-narcotics.  Of course, there are none.  Their "gold standard" is made of dross.  Stanford Department of Anesthiology is not practicing evidence-based medicine.

Sharp Mary Birch Hospital in San Diego Helps Narcotic Manufacturer Conduct Unethical Study: In a DB Endo Pharmaceutical financed study of 541 patients undergoing lower abdominal surgery, a single-dose extended-release epidural morphine (Depodur) was given epidurally 30 min before surgery using 5 mg of single-dose extended-release epidural morphine (EREM) (dose control); and 10, 15, 20, and 25 mg of single-dose EREM vs. 5 mg of standard epidural morphine(active comparator). There was a dose-related reduction in the use of postoperative IV fentanyl through 48 h (P = 0.0002). Patients treated with 10, 20, and 25 mg of single-dose EREM used significantly less IV fentanyl (995 microg, P = 0.0446; 972 microg, P = 0.0221; and 683 microg, P < 0.0001, respectively) through 48 h after surgery compared with the 5-mg single-dose EREM group (1218 microg). At 48 h postdose, significantly more single-dose EREM patients (13%) than MS patients (2%) had required no IV fentanyl (P < 0.01). Patients in the single-dose EREM 15, 20, and 25 mg groups reported significantly lower pain-intensity scores and greater satisfaction with their pain relief. Side-effects were nausea, vomiting, pruritus, and hypotension, 3% of which were severe. A comparison of Depodur, a novel, single-dose extended-release epidural morphine, with standard epidural morphine for pain relief after lower abdominal surgery. Gambling D, et al. Sharp Mary Birch Hospital for Women, San Diego. . Ed: Even with EREM, pain control was inadequate and 87% used additional pain medication. In at least four studies of abdominal surgery, non-narcotics have been found as good as narcotics and usually with fewer side-effects.  Needlessly giving patients narcotics would appear unethical.  The industry-paid physicians in the DepoDur group were all unethical in leaving out non-narcotic comparators.  Now there is no way for practicing physicians to know if DepoDur is superior to non-narcotics in any way so as to justify its use. Also, the use of a narcotic rescue medication is questionable. Where is the research showing rescue narcotics are better than rescue non-narcotics?  Endo is an immensely wealthy company and certainly should be required to provide such studies.

Thomas E. Radecki, M.D., J.D.

modern-psychiatry.com