Opioids in the treatment of postoperative pain: old drugs with new options?

Abstract

New approved options with opioids in the postoperative setting may include new ways of administration, new combinations with other drugs and new opioid drugs. Newly approved devices for administration include sublingual sufentanil dispenser and transdermal iontophoretic fentanyl, with the purpose of almost mimicking the rapid and reliable onset of intravenous (IV) administration, without the problems of an ongoing IV cannula and cumbersome equipment. Still, potential problems of overdosing and misuse must be in focus when these devices come into use. Tapentadol is a new partial µ-receptor opioid agonist with a combined action on norepinephrine-induced analgesia, representing a promising drug in terms of less side effects at equianalgesic doses compared with pure agonists. The mixture of different opioids given together, such as oxycodone and morphine, for oral use may also have some analgesic synergy with an improved side-effect profile, although more studies are needed. Oral oxycodone is a reliable oral opioid option, but when combined with paracetamol in the same tablet or mixture, care should also be taken to avoid serious side effects from inadvertent paracetamol overdose.

Keywords::

• opioid
• pain
• pharmacology
• postoperative
• safety

1. Introduction

The opioids are still the most efficient, all-purpose analgesics we know. There is almost no ceiling in the efficacy of pure µ-opioid agonists; they may be dosed increasingly to cope with most types of pain, including postoperative pain. The traditional opioids are generally cheap; they may be administered by any route: spinally, epidurally, intravenously, subcutaneously, intramuscularly, transdermally, orally, sublingual, nasal and even locally when receptors are activated [1].

Still, the opioids we know so far are not ideal drugs in the postoperative setting; there are a lot of limitations and concerns about their use. Their analgesic effect is basically mediated through central (spinal cord and brain) opioid receptors. Opioid receptors are usually not well expressed in noninflamed peripheral tissue [2] and they have limited effect on the peripheral pathophysiology and origin of acute wound pain. Their efficacy on resting pain is better than on movement-induced pain, which is a problem during mobilization, physiotherapy and restitution. While postoperative pain basically is induced by relevant nociceptive pain nerve stimulation, there is also a neuropathic component in most cases. Opioids are not very effective in blocking neuropathic pain in low or moderate doses, but may still be an adjunct in severe, chronic neuropathic pain. Opioids do not have the potential to block the wind-up of pain when given before the start of surgical trauma. Rather, there is a problem of hyperalgesia being induced by continued opioid dosing or infusion, and being already evident after a 30-min infusion of low-dose remifentanil [3] and relevant for chronic pain [4]. Opioids also have an immunological depressive effect, which potentially may be harmful in the context of infection or cancer growth [5].

More known, and limiting the use of opioids, are the opioid side effects of constipation, nausea, sedation, itching, urinary retention, sleep disturbances, tolerance, abuse potential and respiratory depression. Especially, the very serious side effects of opioid abuse or opioid-induced respiratory depression has to be looked for closely in large postmarketing studies and also case reports; as these side-effects may not be fully evident in the limited clinical trials before registration and marketing.

Another problem with opioids is the huge variability in dose-effect relationship between different patients for fairly similar pain stimuli. This is thought partly to be a result of genetic variations in µ-receptor proteins and G-proteins between individuals, also partly explaining why opioid rotation is useful [6]: one opioid may be best for one patient, whereas another may be better for the next patient. For most opioids, the limitation and variations in oral and enteral availability is a further problem, adding to the unpredictable effect of a single dose and the need for careful titration of these drugs until proper effect level.

For these reasons, it is an established concept in postoperative pain management to limit the use of opioids, and actually abandon if possible. If not possible, the goal is to reduce the dose as much as possible by using a multimodal, nonopioid analgesic strategy [7,8]. This will include some or all of the following drugs in combination, often given prophylactically: paracetamol, NSAID or Cox-II inhibitor, local anesthesia infiltration, glucocorticoids, gabapentinoids.

The development of new opioids for the postoperative pain purpose has focused on both better modes of non-intravenous (IV) administration (i.e., oral, sublingual, transdermal, epidural, spinal, slow release) and new drugs. The goal of new administration modes may be to increase onset and improve ease of titration, as well as ensuring a more predictable bio-availability. The goal of new drug development has been both into new µ-receptor agonists, attempts to also include kappa-receptor effects and also partial agonists, either with or without nonopioid analgesic effects added. One purpose of addressing non-µ mechanisms is to avoid the danger of respiratory depression, which is the most acute and dangerous side effect of opioid overdose.

The purpose of this editorial is to focus on some new, available or soon available commercial options on new opioids, new opioid combinations and new modes of opioid administration for postoperative pain control.

2. New modes of administration

2.1 Transdermal iontophoretic fentanyl

Whereas patches with passive diffusion of transdermal fentanyl have been around for decades for treatment of chronic pain and cancer pain, there is an interesting development with the concept of a patch with an on-demand button delivering iontophoretic fentanyl 40 µg transdermally during 10 min. After the first promising review of this device 8 years ago [9], there has been a pause in development due to technical problems with corrotion in the device, but it is now back in the pipeline, planned for approval and launching during 2014. So far, almost 2500 patients have been tested in parallel studies with morphine IV patient-controlled analgesia (PCA) and there seems to be less hypoventilation, better patient mobility and equal analgesic effect with the fentanyl patch PCA [10,11].

2.1.1 Comment

This concept is a very promising alternative to IV PCA systems for both ongoing and breakthrough postoperative pain, as the onset of effect of iontophoretic fentanyl will be within 10 – 15 min allowing for tight titration to effect, with a fixed lock-out time of minimum 10 min between the doses. The patch makes the patient much more mobile than conventional PCA systems and there is no risk of IV contamination, hematoma, pain from needles, etc. Some limitations are that the preprogrammed dose of 40 µg is the only option, potential skin erythema in some patients and the cost of this disposable device not yet being settled. Also, there is a potential severe safety issue of the high total dose of fentanyl within each patch, both in terms of safe disposal and avoiding misuse and abuse.

2.2 Sublingual sufentanil

It has recently been an interesting development in using sublingual sufentanil as an alternative to intravenous opioid PCA. The idea is to avoid complications, such as infection, bleeding, dislocation and skin irritation from the PCA cannula, and also to provide simplicity in terms of a portable dispenser of sublingual tablets, which may be in a bag or shelf in between use, not needing any physical connection with the patient. Minkowitz et al. [12] evaluated the pharmacokinetics, efficacy and safety of sublingual sufentanil tablets for postoperative pain management in their recent Phase I and II study.

Lower pain intensity compared with placebo was observed for sublingual sufentanil after knee replacement or abdominal surgery. All doses of sublingual sufentanil were well tolerated, and the incidence of adverse events was similar between the sublingual sufentanil and placebo groups. In another case report, Passmore et al. successfully treated a patient with severe dementia, agitation and pain with sublingual sufentanil [13].

2.2.1 Comment

This concept is interesting as a simplification compared with IV PCA. The problems with this approach may be drug safety, even though the dispenser has a sophisticated electronic and mechanical design in order to try to avoid overdose or misuse by someone other than the patient. Also, there are questions regarding the pharmacological features of this administration form, such as reliability and fast bio-availability. There are still very limited clinical experiences published and we have to wait for more studies to conclude on the future role of this device. Whereas the sublingual administration will allow for a fairly rapid onset of effect on breakthrough pain lasting for about one hour, the duration of effect and side effects may be unpredictable if this very lipid soluble drug is used regularly for a few days or more.

3. New drugs

3.1 Tapentadol: a new opioid drug

Tapentadol is an interesting new molecule with a combined action as a partial µ-receptor antagonist and inhibitor of norepinephrine re-uptake in the synapsis in the medullary cord. The latter mimics the effect of pain-inhibiting descending pathways in humans; these are releasing both norepinephrine and serotonin in the dorsal horn of the medullary cord. Tapentadol has some resemblance to the mechanisms of tramadol with the exception that tapentadol does not inhibit serotonin re-uptake. This may be beneficial on the side-effect profile, as serotonin may cause nausea. Tapentadol was launched and is being successfully used for chronic pain and cancer pain [14], and also has a potential of being a useful adjunct in the area of postoperative pain. Studies have shown similar efficacy as oxycodone, but less nausea and constipation after dental surgery and orthopedic surgery [15-17]. One report also addresses a low potential of misuse with this partial µ-agonist [17]. In our group, we also have promising results with use after mamma surgery with reconstructive procedures added (Rian T, personal communication).

3.1.1 Comment

Tapentadol is a promising drug with an in-built nonopioid analgesic principle, reducing the total dose load of opioid. Also, the partial µ-agonist nature of the drug contributes to the beneficial side-effect profile. However, it remains to be seen what place this drug may have after different types of surgery, and also if there is a problem when pain is very strong and the partial agonist properties may either be too weak or potentially blocking for effect of potent, pure μ-agonists. So far, the drug is only available for oral use in humans, but IV formulations are being developed for veterinary medicine.

4. New opioid combinations

4.1 Oxycodon and morphine tablets/mixture

While both these drugs act basically on µ-receptors for analgesia, there are differences in time-profile and inter-individual receptor binding with these two opioids, suggesting a potential for synergy when they are combined [6].

4.1.1 Comment

So far, the clinical results in terms of less nausea and vomiting at equanalgesic doses compared with each drug alone are promising [18], but more studies are needed, with large-scale patient populations.

4.2 Oxycodone and paracetamol tablets

This combination will challenge the combination of paracetamol and codeine tablets, which have been very popular and extensively used for moderate-to-severe pain. While codeine is attractive as an oral opioid due to predictable absorption and fairly low first-pass effect, there are some shortcomings with this drug. Firstly, it is an inactive prodrug converted to active morphine by the CYP2D6 enzyme, a process that is slow, and in some patients, unpredictable. Secondly, in the Caucasian population, 5 – 10% of patients do not have this enzyme and have no effect of codeine, whereas some patients may have a very active enzyme, creating dangerous levels of morphine in the blood, and eventually, breast milk.

Thus, oxycodone emerges as a better oral opioid alternative combined with paracetamol due to rapid absorption, low first-pass effect and direct action on µ-receptors.

4.2.1 Comment

A special problem with all paracetamol and opioid combinations is the risk of paracetamol overdose when patients take paracetamol by themselves on top of a combination drug. Whereas 3 – 4 g paracetamol actually is the recommended total 24-h dose for a healthy adult during the first days after surgery, even a 50% increase of this dose may be severely hepatotoxic [19].

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.