Data have confirmed.... not so!

Only recently have clinical trials been undertaken to investigate the improved therapeutic benefit of combining opioid analgesics with ultra- low dose opioid receptor antagonists. To date, clinical trials have confirmed that combinations of opioids and ultra-low dose antagonists both enhance and prolong opioid-induced analgesia, and prevent analgesic tolerance and physical dependence [23,24].

Reference 23 referered to a phase II trial, and reference 23 a phase III trial. ^[1][2]

This is a verbatim quote from the introduction of a recent paper, published as said in Molecular Pain. ^[3] Even in the abstract of this paper we can identify the same statement, and we quote:

The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. 

The references 23 and 24, the cornerstones of the clinical evidence refered to as confirmation for combining opioids with low dose opioid-antagonists, are actually much less suportive as the quotes suggest. Only if one reads solely the abstract of these two clinical studies one could arrive at such a positive statement. Both studies were flawed in a number of ways, for instance in the phase III trial more than 50% of all patients entered in the study were drop-outs. We will discuss the flaws of these studies in some detail.

Biased phase II and biased and negative phase III trials

The first reference in the Molecular Pain article was refering to a 3-week, phase II clinical trial were Oxytrex was tested for its safety and analgesic efficacy in patients with moderate to severe pain from osteoarthritis. Patients with a pain score ≥5 received placebo, oxycodone 4 times a day (qid), Oxytrex qid, or Oxytrex twice a day (bid). By week 3, the Oxytrex bid group achieved a 39% reduction in pain intensity from baseline, and this reduction was significantly greater than that of placebo (21.5%, P < .001), oxycodone qid (24.6%, P = .006), and Oxytrex qid (26%, P = .003).

The study was flawed considerably, as of the 362 patients randomized to treatment, 119 patients (32.2%) did not complete the study, and most of these discontinuations (60.5%) occurred during the first week of treatment. Moreover, a comparison between oxycodon b.i.d. was not possible, as this arm was lacking from the study. So the superior effects of Oxytrex might be due solely because of frequence of dosing. Furthermore, the duration of this trial was extremely short, 3 weeks.

In a subsequent trial at 45 U.S. sites, 719-patients suffering from chronic low back pain entered in a double-blind, placebo- and active-controlled Phase III clinical trial in chronic low back pain, and patients were randomized to receive placebo, oxycodone qid, or oxytrex qid or bid. ^[4] Of all patients randomized to treatment, 391 patients (54%) did not complete the study, and most of these discontinuations (65%) occurred during the titration period.

Base line pain scores were around 7.5, and after 12 weeks the end pain scores were placebo: 5.2 ± 3.05, oxycodon qid: 4.0 ± 2.53, oxytrex qid 4.2 ± 2.56 and oxytrex bid 4.3 ± 2.55. Not a very impressive score after 12 weeks of treatment, neither a clear clinical difference between the various active groups. The major limitation of this trial was the large number of dropouts (>50%)!

Clinical data referred to in fact did NOT support the preclinical hypothesis  

Those two clinical trials reerred to in the Molecular Pain journal, conbining oxycodon with a very low dose of naltrexone, cannot be regarded as convincing to clinicians that this combination therapy has much relevance in everyday life.

Both trials were flawed due to a high percentage of drop outs, and due to the fact that there was incomplete dose-finding, as well as a absent clinical relevant difference in dosing arms.

Personally I think the dose of naltrexone selected in the fixed combination with oxycodon is far to low to enhance the analgesic effects of oxycodon. In our hands doses of 1-2.5 mg naloxone as a booster for for instance Tramadol seem to be more useful. It is exactly this dose-range which is supported by preliminary clinical data. ^[5][6][7]

Take home message

Never relay solely on abstracts and introductions, always read the full paper before quoting it, and stay critical.... 

Jan M. Keppel Hesselink, MD, PhD, september 2010 

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