Oral immediate and prolonged release oxycodone for safe and effective patient controlled analgesia after surgery Can opioid for acute postoperative pain be improved by adding a peripheral opioid antagonist?

1 Pragmatic clinical studies and explanatory clinical studies

A pragmatic study seeks to find the best way to treat patients in a specific clinical situation, whereas an explanatory study seeks to find a causal relationship that has general validity outside the particular clinical situation being studied [2]. A pragmatic study like the present study [1], in which patients and those treating the patients and evaluating the outcomes were not blinded, will have a number of confounding factors, and the results may not be valid for other populations in other circumstances [2]. However, a pragmatic study can document that a new regimen of pain management is at least as effective and safe as the standard of care therapy used before. The pragmatic study of Niklasson and co-workers documents that their new regimen of oral oxycodone (added to paracetamol and ibupro-fen) needs less personnel resources and is at least as safe as their standard of care with nurse-administered IV morphine at start and oral codeine containing tablets later on [1]. Their study confirms results of other studies on acute pain management after other types of surgery when the patients are able to take oral medication soon after end of surgery [3,45].

2 Slow-onset pain-relief from depot morphine tablets for acute pain can be unsafe

Patients with severe acute pain who take a morphine depot, slow-release tablet for severe acute pain will not experience any immediate pain relief. Therefore, they are tempted to swallow one more, and one more, and when finally pain relief is experienced, too much morphine is absorbed and respiratory depression ensues. This is due to the slow onset of pain relief of the “slow- release” morphine tablets with a time to max concentration that is up to more than 3 h [6]. When the first morphine sustained release depot tablets (Dolcontin® Contalgin®, MST-Continus®) came on the marked and were prescribed for acute postoperative pain in the early 1980s [7], near fatal and fatal complications from respiratory depression were reported, and that practice stopped.

3 Rapid onset and prolonged pain relief is ideal for acute postoperative pain

To our knowledge the only controlled/prolonged release depot opioid tablet with a pharmacokinetic profile that avoids this titration-trap, is OxyContin^®. OxyContin^® releases a large part of the content of a tablet (about 40%) soon after intake (peak pain relief in about one hour), leaving the remaining oxycodone to be released from the tablet during the next 8-10 h [8]. In addition, oxycodone has a more rapid onset of analgesic effect than morphine, in part due to its more rapid transport across the blood-brain- barrier [9]. This is why oral OxyContin^® has become such a success also for treating acute postoperative pain: Patients will experience a significant onset of pain relief already after half-an hour as the CNS-concentration of oxycodone rapidly increases and stays above a minimally effective concentration for the next few hours.

Unfortunately, this rapid onset of OxyContin^® is possibly one contributing factor for the rampant epidemic of OxyContin^® abuse in the USA [8]. This original OxyContin^® was also easily crushed and snuffed by addicted persons. It is not marketed any more in the USA. A tamperproof and hopefully less addictive version is available instead in the USA.

It makes sense to administer a dose of OxyContin^® that is sufficient for most patients with severe pain when deep- breathing/coughing after abdominal surgery (20 mg) on top of paracetamol and ibuprofen, letting the patient take the immediate release and shorter acting oxycodone tablet, when needed [1,8].

4 Opioid-induced gastro-intestinal dysfunction and constipation

All opioids with MOP-receptor agonist effects that cause pain relief by CNS-mechanisms also have effects on the MOP-receptors in the wall of the entire gastrointestinal tract [10]. This is true whether opioids are administered orally, by IV or IM injection, or transdermally via a patch. After abdominal operations there is a slowing of propulsive motility and decreased secretions into the gastro-intestinal (GI)-lumen. This postoperative ileus is aggravated by opioids [10]. It is dose-dependent and varies somewhat with the type of opioid administered. Codeine is particularly potent as a GI- inhibitor. This is because it is metabolized to morphine, and there is a specific effect of oral codeine on the GI-tract. It is therefore particularly unfortunate to prescribe codeine-containing tablets for postoperative pain relief. Thus, Niklasson and co-workers found that oral oxycodone shortened the time to first defecation after CS compared with IV morphine and oral codeine [1].

5 Oral prolonged release naloxone and PAMORAs reduce the opioid-induced GI-dysfunctions

The standard of care at the Karolinska Hospital, Huddinge included oral paraffin emulsion as a prophylactic against postoperative constipation. This mineral oil is intended to lubricate the intestinal lumen, but its effects are questionable.

6 Exploit non-opioid analgesic combinations before adding opioids for postoperative pain

It is important to remember that the required dose of opioids can be markedly reduced, and so is the risk for opioid-aggravated postoperative ileus, by administering non-opioid drugs with different mechanisms of analgesic effects. They will have at least additive effects on acute pain, minimizing the need for opioids, thereby reducing the many dose-related adverse effects of opioids. This has been documented for paracetamol and ibuprofen, and for paracetamol and diclofenac [16]. Niklasson and co-workers did administer paracetamol and ibuprofen to all of their post caesarean women, thus reducing the need for opioids [1].

7 Important implication of the Niklasson study: stop using codeine for pain after CS

Codeine is probably the most unfavourable opioid for a post- CS mother in acute pain. Even a small dose of codeine (30 mg × 4 daily = only 4 tablets of Citodon^® in Sweden, Paralgin Forte^® or Pinex forte^® in Norway) is enough to cause significant slowing of gastro-colon transit time [17]. Up to 10% of Caucasian patients [18] metabolize codeine poorly and slowly to morphine, ant they will have almost no analgesic effect of normal doses of codeine. However, 1-7% of Caucasians and around 25% of people from North-Eastern Africa are ultrarapid codeine metabolizers [18]. In an ultrarapid codeine metabolizing mother taking codeine for post CS-pain, more morphine is produced and transferred to breast milk in high enough amounts to cause respiratory depression, and even respiratory arrest in a breast-feeding baby has been reported. The risk of exposing mothers and babies accidentally for these risks is avoided by using better and safer alternatives than codeine for post-Caesarean section pain [1].